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Holt LM, Gyles TM, Parise EM, Minier-Toribio AM, Rivera M, Markovic T, Yeh SY, Nestler EJ. Astrocytic CREB in Nucleus Accumbens Promotes Susceptibility to Chronic Stress. Biol Psychiatry 2025; 97:862-873. [PMID: 39369762 PMCID: PMC11971392 DOI: 10.1016/j.biopsych.2024.09.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 09/18/2024] [Accepted: 09/25/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Increasing evidence implicates astrocytes in stress and depression in both rodent models and human major depressive disorder. Despite this, little is known about the transcriptional responses to stress of astrocytes within the nucleus accumbens (NAc), a key brain reward region, and their influence on behavioral outcomes. METHODS We used whole-cell sorting, RNA sequencing, and bioinformatic analyses to investigate the NAc astrocyte transcriptome in male mice in response to chronic social defeat stress (CSDS). Immunohistochemistry was used to determine stress-induced changes in astrocytic CREB (cAMP response element binding protein) within the NAc. Finally, astrocytic regulation of depression-like behavior was investigated using viral-mediated manipulation of CREB in combination with CSDS. RESULTS We found a robust transcriptional response in NAc astrocytes to CSDS in stressed mice, with changes seen in both stress-susceptible and stress-resilient animals. Bioinformatic analysis revealed CREB, a transcription factor widely studied in neurons, as one of the top-predicted upstream regulators of the NAc astrocyte transcriptome, with opposite activation states implicated in resilient versus susceptible mice. This bioinformatic deduction was confirmed at the protein level with immunohistochemistry. Moreover, NAc astrocyte morphological complexity correlated with CREB activation and was reduced selectively in astrocytes of resilient mice. Viral overexpression of CREB selectively in NAc astrocytes promoted susceptibility to chronic stress. CONCLUSIONS Together, our data demonstrate that the astrocyte transcriptome responds robustly to CSDS and that transcriptional regulation in astrocytes contributes to depressive-like behaviors. A better understanding of transcriptional regulation in astrocytes may reveal unknown molecular mechanisms underlying neuropsychiatric disorders.
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Affiliation(s)
- Leanne M Holt
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Trevonn M Gyles
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Eric M Parise
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Angelica M Minier-Toribio
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Matthew Rivera
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Tamara Markovic
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Szu-Ying Yeh
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Eric J Nestler
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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Bollinger JL, Johnsamuel S, Vollmer LL, Kuhn AM, Wohleb ES. Stress-induced dysfunction of neurovascular astrocytes in the prefrontal cortex contributes to sex-dependent deficits in cognition and behavior. Mol Psychiatry 2025:10.1038/s41380-025-02993-3. [PMID: 40185903 DOI: 10.1038/s41380-025-02993-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 03/14/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
Astrocytes form an integral component of the neurovascular unit, ensheathing brain blood vessels with endfeet high in aquaporin-4 (AQP4) expression. These AQP4-rich endfeet facilitate interaction between the vascular endothelium, astrocytes, and neurons, and help stabilize vascular morphology. Studies using preclinical models of psychological stress and post-mortem tissue from patients with major depressive disorder (MDD) have reported reductions in AQP4, loss of astrocytic structures, and vascular impairment in the prefrontal cortex (PFC). Though compelling, the role of AQP4 in mediating stress-induced alterations in neurovascular function and behavior remains unclear. Here, we address this, alongside potential sex differences in chronic unpredictable stress (CUS) effects on astrocyte phenotype, blood-brain barrier integrity, and behavior. CUS led to more pronounced shifts in stress-coping behavior and working memory deficits in male- as compared to female mice. Following behavioral testing, astrocytes from the frontal cortex were isolated for gene expression analyses. We found that CUS increased transcripts associated with blood vessel maintenance in males, but either had no effect on- or decreased- these transcripts in females. Furthermore, CUS caused a reduction in vascular-localized AQP4 and elevated extravasation of a small fluorescent reporter (Dextran) in the PFC in males but not females. Studies showed that knockdown of AQP4 in the PFC is sufficient to disrupt astrocyte phenotype and increase behavioral susceptibility to a sub-chronic stressor in males yet has little effect on stress susceptibility in females. Our findings provide evidence that sex-specific alterations in astrocyte phenotype and neurovascular integrity in the PFC contribute to cognitive-behavioral consequences following stress.
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Affiliation(s)
- Justin L Bollinger
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Shobha Johnsamuel
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lauren L Vollmer
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Alexander M Kuhn
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Eric S Wohleb
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Mongi-Bragato B, Sánchez MA, Avalos MP, Boezio MJ, Guzman AS, Rigoni D, Perassi EM, Mas CR, Bisbal M, Bollati FA, Cancela LM. Activation of Nuclear Factor-kappa B in the nucleus accumbens core is necessary for chronic stress-induced glutamate and neuro-immune alterations that facilitate cocaine self-administration. Brain Behav Immun 2025; 128:1-15. [PMID: 40139275 DOI: 10.1016/j.bbi.2025.03.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 03/18/2025] [Accepted: 03/23/2025] [Indexed: 03/29/2025] Open
Abstract
Stressful events are associated with impaired glutamate signaling and neuroimmune adaptations that may increase the vulnerability of individuals to cocaine addiction. We previously demonstrated that chronic stress induced reactive microglia and increased TNF-α expression in the nucleus accumbens core (NAcore), both alterations strongly linked with impaired glutamate homeostasis and the facilitation of cocaine self-administration. The nuclear factor kappa-B (NF-κB) is a critical regulator of many immune- and addiction-related genes, such as the gene coding for glutamate transporter (GLT-1), and it is considered a master regulator of inflammation, reported to be a key driver of microglia activation in psychiatric diseases. However, no studies have examined the role of NF-κB signaling within the NAcore in the neuroimmune and glutamate mechanism, underpinning stress-induced vulnerability to cocaine self-administration. Here we investigate whether viral dominant negative inhibition of I kappa B kinase (IKKdn), a signaling molecule responsible for NF-κB activation, would prevent stress-induced facilitation to cocaine self-administration and associated changes in accumbal GLT-1 and TNF-α expression. We also explore N-myc proto-oncogene protein (N-myc) levels as a link between NF-κB and stress-induced GLT-1 downregulation. For seven days (days 1-7), adult male rats were restrained for 2 h/day. Animals were administered an intra-NAcore with IKKdn or empty lentiviruses on day 14 after the first restraint stress session. Marked activation of NF-κB was detected in the NAcore of stressed subjects, along with increased NF-κB expression in astrocytes. Consistently, viral NF-κB inhibition prevented stress-induced facilitation of cocaine self-administration. Moreover, NF-κB blockade results in the restoration of stress-induced reduction in GLT-1 levels and was effective in suppressing stress-induced TNF-α within the NAcore. These findings suggest that accumbal NF-κB signaling exerts a central control over stress-altered downstream neuroimmune and glutamate function underlying vulnerability to cocaine use disorders.
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Affiliation(s)
- Bethania Mongi-Bragato
- Instituto de Farmacología Experimental de Córdoba, IFEC-CONICET, Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba X5000HUA Córdoba, Argentina.
| | - Marianela Adela Sánchez
- Instituto de Farmacología Experimental de Córdoba, IFEC-CONICET, Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba X5000HUA Córdoba, Argentina
| | - María Paula Avalos
- Instituto de Farmacología Experimental de Córdoba, IFEC-CONICET, Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba X5000HUA Córdoba, Argentina
| | - María Julieta Boezio
- Instituto de Farmacología Experimental de Córdoba, IFEC-CONICET, Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba X5000HUA Córdoba, Argentina
| | - Andrea Susana Guzman
- Instituto de Farmacología Experimental de Córdoba, IFEC-CONICET, Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba X5000HUA Córdoba, Argentina
| | - Diana Rigoni
- Instituto de Farmacología Experimental de Córdoba, IFEC-CONICET, Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba X5000HUA Córdoba, Argentina
| | - Eduardo Marcelo Perassi
- Instituto de Investigaciones en Físico-Química de Córdoba, INFIQC-CONICET, Departamento de Química Teórica y Computacional, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba X5000HUA Córdoba, Argentina
| | - Carlos Ruben Mas
- Centro de Investigaciones en Química Biológica de Córdoba, CIQUIBIC-CONICET, Departamento de Química Bilógica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba X5000HUA Córdoba, Argentina
| | - Mariano Bisbal
- Instituto de Investigación Médica Mercedes y Martin Ferreyra, INIMEC-CONICET, Friuli 2434, Colinas de Vélez Sarsfield (5016) Córdoba, Argentina, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Flavia Andrea Bollati
- Instituto de Farmacología Experimental de Córdoba, IFEC-CONICET, Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba X5000HUA Córdoba, Argentina.
| | - Liliana Marina Cancela
- Instituto de Farmacología Experimental de Córdoba, IFEC-CONICET, Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba X5000HUA Córdoba, Argentina.
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4
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Algaidi SA. Chronic stress-induced neuroplasticity in the prefrontal cortex: Structural, functional, and molecular mechanisms from development to aging. Brain Res 2025; 1851:149461. [PMID: 39864644 DOI: 10.1016/j.brainres.2025.149461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/28/2025]
Abstract
Chronic stress profoundly affects the structure and function of the prefrontal cortex (PFC), a brain region critical for executive functions and emotional regulation. This review synthesizes current knowledge on stress-induced PFC plasticity, encompassing structural, functional, and molecular changes. We examine how chronic stress leads to dendritic atrophy, spine loss, and alterations in neuronal connectivity within the PFC, particularly affecting the medial PFC. These structural changes are accompanied by disruptions in neurotransmitter systems, most notably glutamatergic and GABAergic signaling, and alterations in synaptic plasticity mechanisms. At the molecular level, we discuss the intricate interplay between stress hormones, neurotrophic factors, and epigenetic modifications that underlie these changes. The review highlights the significant behavioral and cognitive consequences of stress-induced PFC plasticity, including impairments in working memory, decision-making, and emotional regulation, which may contribute to the development of stress-related psychiatric disorders. We also explore individual differences in stress susceptibility, focusing on sex-specific effects and age-dependent variations in stress responses. The role of estrogens in conferring stress resilience in females and the unique vulnerabilities of the developing and aging PFC are discussed. Finally, we consider potential pharmacological and non-pharmacological interventions that may mitigate or reverse stress-induced changes in the PFC. The review concludes by identifying key areas for future research, including the need for more studies on the reversibility of stress effects and the potential of emerging technologies in unraveling the complexities of PFC plasticity. This comprehensive overview underscores the critical importance of understanding stress-induced PFC plasticity for developing more effective strategies to prevent and treat stress-related mental health disorders.
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Affiliation(s)
- Sami Awda Algaidi
- Department of Basic Medical Sciences Faculty of Medicine Taibah University Saudi Arabia.
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5
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Lu CL, Ren J, Cao X. An Astroglial Basis of Major Depressive Disorder: Molecular, Cellular, and Circuit Features. Biol Psychiatry 2025; 97:217-226. [PMID: 39084500 DOI: 10.1016/j.biopsych.2024.07.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 06/17/2024] [Accepted: 07/15/2024] [Indexed: 08/02/2024]
Abstract
Major depressive disorder is a common psychiatric disorder and a leading cause of disability worldwide. Astrocytes play a role in the maintenance of the function of the central nervous system, both physiologically and pathologically. Accumulated evidence indicates that the astrocyte is an important contributor to the pathophysiology of major depressive disorder including blood-brain barrier integrity, gap junctions, gliotransmission, glutamate homeostasis, and energy metabolism. Here, we comprehensively summarize an astroglial basis for major depressive disorder based on molecular, cellular, and circuit properties, suggesting that astrocytes appear to be highly sensitive to stress and are likely to be uniquely positioned to integrate peripheral and central stress responses.
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Affiliation(s)
- Cheng-Lin Lu
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China; Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Jing Ren
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China
| | - Xiong Cao
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China; Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
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6
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Neyama H, Wu Y, Nakaya Y, Kato S, Shimizu T, Tahara T, Shigeta M, Inoue M, Miyamichi K, Matsushita N, Mashimo T, Miyasaka Y, Dai Y, Noguchi K, Watanabe Y, Kobayashi M, Kobayashi K, Cui Y. Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia. SCIENCE ADVANCES 2025; 11:eadp8494. [PMID: 39813331 PMCID: PMC11734720 DOI: 10.1126/sciadv.adp8494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 12/13/2024] [Indexed: 01/18/2025]
Abstract
Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR+) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR+ neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABAA receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR+ neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice.
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Affiliation(s)
- Hiroyuki Neyama
- Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
- Multiomics Platform, Center for Cancer Immunotherapy and Immunobiology, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yuping Wu
- Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
| | - Yuka Nakaya
- Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Shigeki Kato
- Department of Molecular Genetics, Fukushima Medical University Institute of Biomedical Sciences, 1 Hikariga-oka, Fukushima 960-1295, Japan
| | - Tomoko Shimizu
- Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
| | - Tsuyoshi Tahara
- Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
| | - Mika Shigeta
- Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
| | - Michiko Inoue
- Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
| | - Kazunari Miyamichi
- Laboratory for Comparative Connections, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
| | - Natsuki Matsushita
- Division of Laboratory Animal Research, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan
| | - Tomoji Mashimo
- Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Yoshiki Miyasaka
- Laboratory of Reproductive Engineering, Institute of Experimental Animal Sciences, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yi Dai
- Department of Anatomy and Neuroscience, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan
| | - Koichi Noguchi
- Department of Anatomy and Neuroscience, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan
| | - Yasuyoshi Watanabe
- Laboratory for Brain-Gut Homeostasis, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan
| | - Masayuki Kobayashi
- Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Kazuto Kobayashi
- Department of Molecular Genetics, Fukushima Medical University Institute of Biomedical Sciences, 1 Hikariga-oka, Fukushima 960-1295, Japan
| | - Yilong Cui
- Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
- Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
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7
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Bonomi RE, Pietrzak R, Cosgrove KP. Neuroglia in anxiety disorders. HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:335-346. [PMID: 40148054 DOI: 10.1016/b978-0-443-19102-2.00008-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Anxiety disorders are some of the most prevalent in the world and are extraordinarily debilitating to many individuals, costing millions in disability. One of the most disabling is posttraumatic stress disorder (Snijders et al., 2020). Understanding the pathophysiology of these illnesses further and the cell types involved will allow better targeting of treatments. Glial cells, encompassing microglia, astrocytes, and oligodendrocytes, play critical roles in the pathophysiology of PTSD and other anxiety illnesses. Each of these cell types interacts with aspects of neuro-epigenetics, neuroimmune, and neuronal signaling and may contribute to the pathophysiology of anxiety illnesses. This chapter covers the literature on the role of glial cells in the neurobiology and pathology of anxiety disorders, more specifically PTSD. PTSD is one of the most debilitating anxiety disorders and one of the most complicated from a neurobiologic perspective. This chapter also features a discussion surrounding the current state of treatment and some of the hypothesized mechanisms for novel treatments including tetrahydrocannabidiol and 3,4-methylenedioxymethamphetamine. Finally, thoughts on the future directions for precision treatment and pharmacologic development with a focus on neuroglia are undertaken.
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Affiliation(s)
- Robin E Bonomi
- Department of Psychiatry, Yale University, New Haven, CT, United States
| | - Robert Pietrzak
- Department of Psychiatry, Yale University, New Haven, CT, United States
| | - Kelly P Cosgrove
- Department of Psychiatry, Yale University, New Haven, CT, United States.
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Nagai H. Deciphering prefrontal circuits underlying stress and depression: exploring the potential of volume electron microscopy. Microscopy (Oxf) 2024; 73:391-404. [PMID: 39045685 DOI: 10.1093/jmicro/dfae036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 06/07/2024] [Accepted: 07/23/2024] [Indexed: 07/25/2024] Open
Abstract
Adapting to environmental changes and formulating behavioral strategies are central to the nervous system, with the prefrontal cortex being crucial. Chronic stress impacts this region, leading to disorders including major depression. This review discusses the roles for prefrontal cortex and the effects of stress, highlighting similarities and differences between human/primates and rodent brains. Notably, the rodent medial prefrontal cortex is analogous to the human subgenual anterior cingulate cortex in terms of emotional regulation, sharing similarities in cytoarchitecture and circuitry, while also performing cognitive functions similar to the human dorsolateral prefrontal cortex. It has been shown that chronic stress induces atrophic changes in the rodent mPFC, which mirrors the atrophy observed in the subgenual anterior cingulate cortex and dorsolateral prefrontal cortex of depression patients. However, the precise alterations in neural circuitry due to chronic stress are yet to be fully unraveled. The use of advanced imaging techniques, particularly volume electron microscopy, is emphasized as critical for the detailed examination of synaptic changes, providing a deeper understanding of stress and depression at the molecular, cellular and circuit levels. This approach offers invaluable insights into the alterations in neuronal circuits within the medial prefrontal cortex caused by chronic stress, significantly enriching our understanding of stress and depression pathologies.
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Affiliation(s)
- Hirotaka Nagai
- Division of Pharmacology, Graduate School of Medicine, Kobe University, Research Building B 4F, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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9
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Yu P, Cheng M, Wang N, Wu C, Qiang K. Pubertal maternal presence reduces anxiety and increases adult neurogenesis in Kunming mice offspring. Pharmacol Biochem Behav 2024; 243:173839. [PMID: 39079561 DOI: 10.1016/j.pbb.2024.173839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/20/2024] [Accepted: 07/24/2024] [Indexed: 08/10/2024]
Abstract
Puberty is a critical period of emotional development and neuroplasticity. However, most studies have focused on early development, with limited research on puberty, particularly the parental presence. In this study, four groups were established, and pubertal maternal presence (PMP) was assessed until postnatal days 21 (PD21), 28 (PD28), 35 (PD35), and 42 (PD42), respectively. The social interaction and anxiety behaviors, as well as the expression of oxytocin (OT) in the paraventricular nucleus (PVN) and supraoptic nucleus (SON), and the number of new generated neurons and the expression of estrogen receptor alpha (ERα) in the dentate gyrus (DG) were assessed. The results suggest that there is a lot of physical contact between the mother and offspring from 21 to 42 days of age, which reduces anxiety in both female and male offspring in adulthood; for example, the PMP increased the amount of time mice spent in the center area in the open field experiment and in the bright area in the light-dark box experiment. PMP increased OT expression in the PVN and SON and the number of newly generated neurons in the DG. However, there was a sexual difference in ERα, with ERα increasing in females but decreasing in males. In conclusion, PMP reduces the anxiety of offspring in adulthood, increases OT in the PVN and SON, and adult neurogenesis; ERα in the DG may be involved in this process.
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Affiliation(s)
- Peng Yu
- Institute of Behavioral and Physical Sciences, College of Life Sciences, Northwest Normal University, Lanzhou 730070, Gansu, China.
| | - Miao Cheng
- Institute of Behavioral and Physical Sciences, College of Life Sciences, Northwest Normal University, Lanzhou 730070, Gansu, China
| | - Na Wang
- College of Life and Geographic Sciences, Kashi University, Kashi 844099, Xinjiang, China
| | - Chendong Wu
- Institute of Behavioral and Physical Sciences, College of Life Sciences, Northwest Normal University, Lanzhou 730070, Gansu, China
| | - Keju Qiang
- Institute of Behavioral and Physical Sciences, College of Life Sciences, Northwest Normal University, Lanzhou 730070, Gansu, China
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10
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Kim HH, Jang W, Kim CW, Choi JY. Longitudinal investigation of optic chiasm in patients with traumatic brain injury. BMC Ophthalmol 2024; 24:422. [PMID: 39334049 PMCID: PMC11437778 DOI: 10.1186/s12886-024-03697-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 09/24/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Traumatic brain injury (TBI) often precipitates a cascade of neurophysiological alterations, impacting structures such as the optic nerve and ocular motor system. However, the literature lacks expansive investigations into the longitudinal changes in the optic chiasm and its relationship with the clinical recovery of visual processing. This study aimed to scrutinize longitudinal changes in optic chiasm volume (OCV) and establish the relationship of OCV with process speed index at 12 months post-injury. Process speed index is derived from Wechsler Adult Intelligence Scale IV. METHODS Thorough cross-sectional and longitudinal analyses were executed, involving 42 patients with moderate to severe TBI and 35 healthy controls. OCV was acquired at 3, 6, and 12 months post-injury using T1-weighted images. OCV of healthy controls and that of patients with TBI at 3, 6, and 12 months post-injury were compared using a Mann-Whitney U test. A multiple linear regression model was constructed to assess the association between OCV and PSI and to predict PSI at 12 months post-injury using OCV at 3 months post-injury. RESULTS OCV of patients with TBI was significantly larger compared to healthy controls, persisting from 3 to 12 months post-injury (p < 0.05). This increased OCV negatively correlated with PSI at 12 months post-injury, indicating that larger OCV sizes were associated with decreased PSI (p = 0.031). Furthermore, the multiple linear regression model was significant in predicting PSI at 12 months post-injury utilizing OCV at 3 months post-injury (p = 0.024). CONCLUSION For the first time, this study elucidates the increased OCV and the significant association between OCV in sub-chronic stage and PSI at 12 months post-injury, potentially providing clinicians with a tool for anticipatory cognitive rehabilitation strategies following TBI.
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Affiliation(s)
- Hyun-Ho Kim
- Department of Biomedical Engineering, Yonsei University, Wonju, Gangwon-do, Republic of Korea
- School of Medicine, Kangwon National University, Chuncheon, Republic of Korea
- Mongji Hospital, Goyang, Republic of Korea
| | - Wonpil Jang
- Department of Biomedical Engineering, Yonsei University, Wonju, Gangwon-do, Republic of Korea
| | - Cheol-Woon Kim
- Department of Biomedical Engineering, Yonsei University, Wonju, Gangwon-do, Republic of Korea
| | - Joon Yul Choi
- Department of Biomedical Engineering, Yonsei University, Wonju, Gangwon-do, Republic of Korea.
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11
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Farinha-Ferreira M, Magalhães DM, Neuparth-Sottomayor M, Rafael H, Miranda-Lourenço C, Sebastião AM. Unmoving and uninflamed: Characterizing neuroinflammatory dysfunction in the Wistar-Kyoto rat model of depression. J Neurochem 2024; 168:2443-2460. [PMID: 38430009 DOI: 10.1111/jnc.16083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 03/03/2024]
Abstract
Reductionistic research on depressive disorders has been hampered by the limitations of animal models. Recently, it has been hypothesized that neuroinflammation is a key player in depressive disorders. The Wistar-Kyoto (WKY) rat is an often-used animal model of depression, but no information so far exists on its neuroinflammatory profile. As such, we compared male young adult WKY rats to Wistar (WS) controls, with regard to both behavioral performance and brain levels of key neuroinflammatory markers. We first assessed anxiety- and depression-like behaviors in a battery consisting of the Elevated Plus Maze (EPM), the Novelty Suppressed Feeding (NSFT), Open Field (OFT), Social Interaction (SIT), Forced Swim (FST), Sucrose Preference (SPT), and Splash tests (ST). We found that WKY rats displayed increased NSFT feeding latency, decreased OFT center zone permanence, decreased EPM open arm permanence, decreased SIT interaction time, and increased immobility in the FST. However, WKY rats also evidenced marked hypolocomotion, which is likely to confound performance in such tests. Interestingly, WKY rats performed similarly, or even above, to WS levels in the SPT and ST, in which altered locomotion is not a significant confound. In a separate cohort, we assessed prefrontal cortex (PFC), hippocampus and amygdala levels of markers of astrocytic (GFAP, S100A10) and microglial (Iba1, CD86, Ym1) activation status, as well as of three key proinflammatory cytokines (IL-1β, IL-6, TNF-α). There were no significant differences between strains in any of these markers, in any of the regions assessed. Overall, results highlight that behavioral data obtained with WKY rats as a model of depression must be carefully interpreted, considering the marked locomotor activity deficits displayed. Furthermore, our data suggest that, despite WKY rats replicating many depression-associated neurobiological alterations, as shown by others, this is not the case for neuroinflammation-related alterations, thus representing a novel limitation of this model.
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Affiliation(s)
- Miguel Farinha-Ferreira
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Daniela M Magalhães
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Mariana Neuparth-Sottomayor
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Hugo Rafael
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Catarina Miranda-Lourenço
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Ana M Sebastião
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
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12
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Vivi E, Di Benedetto B. Brain stars take the lead during critical periods of early postnatal brain development: relevance of astrocytes in health and mental disorders. Mol Psychiatry 2024; 29:2821-2833. [PMID: 38553540 PMCID: PMC11420093 DOI: 10.1038/s41380-024-02534-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 03/12/2024] [Accepted: 03/14/2024] [Indexed: 09/25/2024]
Abstract
In the brain, astrocytes regulate shape and functions of the synaptic and vascular compartments through a variety of released factors and membrane-bound proteins. An imbalanced astrocyte activity can therefore have drastic negative impacts on brain development, leading to the onset of severe pathologies. Clinical and pre-clinical studies show alterations in astrocyte cell number, morphology, molecular makeup and astrocyte-dependent processes in different affected brain regions in neurodevelopmental (ND) and neuropsychiatric (NP) disorders. Astrocytes proliferate, differentiate and mature during the critical period of early postnatal brain development, a time window of elevated glia-dependent regulation of a proper balance between synapse formation/elimination, which is pivotal in refining synaptic connectivity. Therefore, any intrinsic and/or extrinsic factors altering these processes during the critical period may result in an aberrant synaptic remodeling and onset of mental disorders. The peculiar bridging position of astrocytes between synaptic and vascular compartments further allows them to "compute" the brain state and consequently secrete factors in the bloodstream, which may serve as diagnostic biomarkers of distinct healthy or disease conditions. Here, we collect recent advancements regarding astrogenesis and astrocyte-mediated regulation of neuronal network remodeling during early postnatal critical periods of brain development, focusing on synapse elimination. We then propose alternative hypotheses for an involvement of aberrancies in these processes in the onset of ND and NP disorders. In light of the well-known differential prevalence of certain brain disorders between males and females, we also discuss putative sex-dependent influences on these neurodevelopmental events. From a translational perspective, understanding age- and sex-dependent astrocyte-specific molecular and functional changes may help to identify biomarkers of distinct cellular (dys)functions in health and disease, favouring the development of diagnostic tools or the selection of tailored treatment options for male/female patients.
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Affiliation(s)
- Eugenia Vivi
- Laboratory of Neuro-Glia Pharmacology, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053, Regensburg, Germany
| | - Barbara Di Benedetto
- Laboratory of Neuro-Glia Pharmacology, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053, Regensburg, Germany.
- Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany.
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13
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Jellinger AL, Suthard RL, Yuan B, Surets M, Ruesch EA, Caban AJ, Liu S, Shpokayte M, Ramirez S. Chronic activation of a negative engram induces behavioral and cellular abnormalities. eLife 2024; 13:RP96281. [PMID: 38990919 PMCID: PMC11239178 DOI: 10.7554/elife.96281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/13/2024] Open
Abstract
Negative memories engage a brain and body-wide stress response in humans that can alter cognition and behavior. Prolonged stress responses induce maladaptive cellular, circuit, and systems-level changes that can lead to pathological brain states and corresponding disorders in which mood and memory are affected. However, it is unclear if repeated activation of cells processing negative memories induces similar phenotypes in mice. In this study, we used an activity-dependent tagging method to access neuronal ensembles and assess their molecular characteristics. Sequencing memory engrams in mice revealed that positive (male-to-female exposure) and negative (foot shock) cells upregulated genes linked to anti- and pro-inflammatory responses, respectively. To investigate the impact of persistent activation of negative engrams, we chemogenetically activated them in the ventral hippocampus over 3 months and conducted anxiety and memory-related tests. Negative engram activation increased anxiety behaviors in both 6- and 14-month-old mice, reduced spatial working memory in older mice, impaired fear extinction in younger mice, and heightened fear generalization in both age groups. Immunohistochemistry revealed changes in microglial and astrocytic structure and number in the hippocampus. In summary, repeated activation of negative memories induces lasting cellular and behavioral abnormalities in mice, offering insights into the negative effects of chronic negative thinking-like behaviors on human health.
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Affiliation(s)
- Alexandra L Jellinger
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
| | - Rebecca L Suthard
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
- Graduate Program for Neuroscience, Boston University, Boston, United States
| | - Bingbing Yuan
- Whitehead Institute for Biomedical Research, MIT, Cambridge, United States
| | - Michelle Surets
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
| | - Evan A Ruesch
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
| | - Albit J Caban
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
- Graduate Program for Neuroscience, Boston University, Boston, United States
| | - Shawn Liu
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
| | - Monika Shpokayte
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
- Graduate Program for Neuroscience, Boston University, Boston, United States
| | - Steve Ramirez
- Department of Psychological and Brain Sciences, The Center for Systems Neuroscience, Boston University, Boston, United States
- Neurophotonics Center, and Photonics Center, Boston University, Boston, United States
- Department of Biomedical Engineering, Boston University, Boston, United States
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14
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Bansal Y, Codeluppi SA, Banasr M. Astroglial Dysfunctions in Mood Disorders and Rodent Stress Models: Consequences on Behavior and Potential as Treatment Target. Int J Mol Sci 2024; 25:6357. [PMID: 38928062 PMCID: PMC11204179 DOI: 10.3390/ijms25126357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 05/30/2024] [Accepted: 06/02/2024] [Indexed: 06/28/2024] Open
Abstract
Astrocyte dysfunctions have been consistently observed in patients affected with depression and other psychiatric illnesses. Although over the years our understanding of these changes, their origin, and their consequences on behavior and neuronal function has deepened, many aspects of the role of astroglial dysfunction in major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) remain unknown. In this review, we summarize the known astroglial dysfunctions associated with MDD and PTSD, highlight the impact of chronic stress on specific astroglial functions, and how astroglial dysfunctions are implicated in the expression of depressive- and anxiety-like behaviors, focusing on behavioral consequences of astroglial manipulation on emotion-related and fear-learning behaviors. We also offer a glance at potential astroglial functions that can be targeted for potential antidepressant treatment.
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Affiliation(s)
- Yashika Bansal
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada
| | - Sierra A. Codeluppi
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5G 2C8, Canada
| | - Mounira Banasr
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5G 2C8, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON M2J 4A6, Canada
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15
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Li Y, Luo Y, Zhu P, Liang X, Li J, Dou X, Liu L, Qin L, Zhou M, Deng Y, Jiang L, Wang S, Yang W, Tang J, Tang Y. Running exercise improves astrocyte loss, morphological complexity and astrocyte-contacted synapses in the hippocampus of CUS-induced depression model mice. Pharmacol Biochem Behav 2024; 239:173750. [PMID: 38494007 DOI: 10.1016/j.pbb.2024.173750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 03/10/2024] [Accepted: 03/11/2024] [Indexed: 03/19/2024]
Abstract
Although the antidepressant effects of running exercise have been widely reported, further research is still needed to determine the structural bases for these effects. Astrocyte processes physically contact many synapses and directly regulate the numbers of synapses, but it remains unclear whether running exercise can modulate astrocyte morphological complexity and astrocyte-contacted synapses in the hippocampus of the mice with depressive-like behavior. Male C57BL/6 J mice underwent four weeks of running exercise after four weeks of chronic unpredictable stress (CUS). The sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were used to assess anhedonia in mice. Western blotting was used to measure the expression of astrocyte- and synapse-related proteins. Immunofluorescence and 3D reconstruction were used to quantify the density and morphology of astrocytes, and astrocyte-contacted synapses in each hippocampal subregion. Four weeks of running exercise alleviated depressive-like symptoms in mice. The expression of astrocyte- and synapse-related proteins in the hippocampus; astrocyte process lengths, process numbers, and dendritic arborization; and the number of astrocyte-contacted PSD95 positive synapses in the CA2-3 and DG regions were significantly decreased in the mice with depressive-like behavior, and running exercise successfully reserved these changes. Running exercise improved the decreases in astrocyte morphological complexity and astrocyte-contacted PSD95 positive synapses in the CA2-3 and DG regions of the mice with depressive-like behavior, suggesting that the physical interactions between astrocytes and synapses can be increased by running exercise, which might be an important structural basis for the antidepressant effects of running exercise.
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Affiliation(s)
- Yue Li
- Department of Histology and Embryology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Yanmin Luo
- Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Peilin Zhu
- Department of Histology and Embryology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Xin Liang
- Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Department of Pathology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Jing Li
- Department of Histology and Embryology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Xiaoyun Dou
- Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Li Liu
- Department of Histology and Embryology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Lu Qin
- Department of Histology and Embryology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Mei Zhou
- Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Yuhui Deng
- Department of Histology and Embryology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Lin Jiang
- Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Lab Teaching & Management Center, Chongqing Medical University, Chongqing 400016, PR China
| | - Shun Wang
- Department of Histology and Embryology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Wenyu Yang
- Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Jing Tang
- Department of Histology and Embryology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China.
| | - Yong Tang
- Department of Histology and Embryology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, PR China.
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16
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Liu Y, Chen L, Lin L, Xu C, Xiong Y, Qiu H, Li X, Li S, Cao H. Unveiling the hidden pathways: Exploring astrocytes as a key target for depression therapy. J Psychiatr Res 2024; 174:101-113. [PMID: 38626560 DOI: 10.1016/j.jpsychires.2024.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 04/18/2024]
Abstract
Depressive disorders are widely debilitating psychiatric disease. Despite the considerable progress in the field of depression therapy, extensive research spanning many decades has failed to uncover pathogenic pathways that might aid in the creation of long-acting and rapid-acting antidepressants. Consequently, it is imperative to reconsider existing approaches and explore other targets to improve this area of study. In contemporary times, several scholarly investigations have unveiled that persons who have received a diagnosis of depression, as well as animal models employed to study depression, demonstrate a decrease in both the quantity as well as density of astrocytes, accompanied by alterations in gene expression and morphological attributes. Astrocytes rely on a diverse array of channels and receptors to facilitate their neurotransmitter transmission inside tripartite synapses. This study aimed to investigate the potential processes behind the development of depression, specifically focusing on astrocyte-associated neuroinflammation and the involvement of several molecular components such as connexin 43, potassium channel Kir4.1, aquaporin 4, glutamatergic aspartic acid transporter protein, SLC1A2 or GLT-1, glucocorticoid receptors, 5-hydroxytryptamine receptor 2B, and autophagy, that localized on the surface of astrocytes. The study also explores novel approaches in the treatment of depression, with a focus on astrocytes, offering innovative perspectives on potential antidepressant medications.
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Affiliation(s)
- Ying Liu
- Department of Psychiatry, The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Department of Psychiatry, Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Changsha, Hunan, 410007, China.
| | - Lu Chen
- Department of Gastroenterology, The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Department of Gastroenterology, Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Changsha, Hunan, 410007, China.
| | - Lin Lin
- Scientific Research Management Department, Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Changsha, Hunan, 410007, China.
| | - Caijuan Xu
- Department of Psychiatry, The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Department of Psychiatry, Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Changsha, Hunan, 410007, China.
| | - Yifan Xiong
- Department of Psychiatry, The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Department of Psychiatry, Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Changsha, Hunan, 410007, China.
| | - Huiwen Qiu
- Department of Psychiatry, The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Department of Psychiatry, Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Changsha, Hunan, 410007, China.
| | - Xinyu Li
- Department of Psychiatry, The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Department of Psychiatry, Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Changsha, Hunan, 410007, China.
| | - Sixin Li
- Department of Psychiatry, The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Department of Psychiatry, Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Changsha, Hunan, 410007, China.
| | - Hui Cao
- Department of Psychiatry, The School of Clinical Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Department of Psychiatry, Brain Hospital of Hunan Province (The Second People's Hospital of Hunan Province), Changsha, Hunan, 410007, China.
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17
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Wu Y, Lu Y, Kong L, Xie Y, Liu W, Yang A, Xin K, Yan X, Wu L, Liu Y, Zhu Q, Cao Y, Zhou Y, Jiang X, Tang Y, Wu F. Gender differences in plasma S100B levels of patients with major depressive disorder. BMC Psychiatry 2024; 24:387. [PMID: 38783266 PMCID: PMC11112965 DOI: 10.1186/s12888-024-05852-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 05/15/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Low concentrations of S100B have neurotrophic effects and can promote nerve growth and repair, which plays an essential role in the pathophysiological and histopathological alterations of major depressive disorder (MDD) during disease development. Studies have shown that plasma S100B levels are altered in patients with MDD. In this study, we investigated whether the plasma S100B levels in MDD differ between genders. METHODS We studied 235 healthy controls (HCs) (90 males and 145 females) and 185 MDD patients (65 males and 120 females). Plasma S100B levels were detected via multifactor assay. The Mahalanobis distance method was used to detect the outliers of plasma S100B levels in the HC and MDD groups. The Kolmogorov-Smirnov test was used to test the normality of six groups of S100B samples. The Mann-Whitney test and Scheirer-Ray-Hare test were used for the comparison of S100B between diagnoses and genders, and the presence of a relationship between plasma S100B levels and demographic details or clinical traits was assessed using Spearman correlation analysis. RESULTS All individuals in the HC group had plasma S100B levels that were significantly greater than those in the MDD group. In the MDD group, males presented significantly higher plasma S100B levels than females. In the male group, the plasma S100B levels in the HC group were significantly higher than those in the MDD group, while in the female group, no significant difference was found between the HC and MDD groups. In the male MDD subgroup, there was a positive correlation between plasma S100B levels and years of education. In the female MDD subgroup, there were negative correlations between plasma S100B levels and age and suicidal ideation. CONCLUSIONS In summary, plasma S100B levels vary with gender and are decreased in MDD patients, which may be related to pathological alterations in glial cells.
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Affiliation(s)
- Yifan Wu
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Yihui Lu
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Lingtao Kong
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Yu Xie
- Faculty of Public Health, China Medical University, 110001, Liaoning, P.R. China
| | - Wen Liu
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Anqi Yang
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Kaiqi Xin
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Xintong Yan
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Longhai Wu
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Yilin Liu
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Qianying Zhu
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Yang Cao
- Shenyang Mental Health Center, 110001, Liaoning, P.R. China
| | - Yifang Zhou
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
| | - Xiaowei Jiang
- Brain Function Research Section, Department of Radiology, The First Hospital of China Medical University, 110001, Liaoning, P.R. China
| | - Yanqing Tang
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China
- Department of Geriatric Medicine, The First Hospital of China Medical University, 110001, Liaoning, P.R. China
| | - Feng Wu
- Department of Psychiatry, The First Hospital of China Medical University, 155 Nanjing North Street, 110001, Liaoning, P.R. China.
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18
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Bollinger JL, Johnsamuel S, Vollmer LL, Kuhn AM, Wohleb ES. Stress-induced dysfunction of neurovascular astrocytes contributes to sex-specific behavioral deficits. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.14.594147. [PMID: 38798398 PMCID: PMC11118421 DOI: 10.1101/2024.05.14.594147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Astrocytes form an integral component of the neurovascular unit, ensheathing brain blood vessels with projections high in aquaporin-4 (AQP4) expression. These AQP4-rich projections facilitate interaction between the vascular endothelium, astrocytes, and neurons, and help stabilize vascular morphology. Studies using preclinical models of psychological stress and post-mortem tissue from patients with major depressive disorder (MDD) have reported reductions in AQP4, loss of astrocytic structures, and vascular impairment in the prefrontal cortex (PFC). Though compelling, the role of AQP4 in mediating stress-induced alterations in blood vessel function and behavior remains unclear. Here, we address this, alongside potential sex differences in chronic unpredictable stress (CUS) effects on astrocyte phenotype, blood-brain barrier integrity, and behavior. CUS led to pronounced shifts in stress-coping behavior and working memory deficits in male -but not female- mice. Following behavioral testing, astrocytes from the frontal cortex were isolated for gene expression analyses. We found that CUS increased various transcripts associated with blood vessel maintenance in astrocytes from males, but either had no effect on- or decreased- these genes in females. Furthermore, CUS caused a reduction in vascular-localized AQP4 and elevated extravasation of a small molecule fluorescent reporter (Dextran) in the PFC in males but not females. Studies showed that knockdown of AQP4 in the PFC in males is sufficient to disrupt astrocyte phenotype and increase behavioral susceptibility to a sub-chronic stressor. Collectively, these findings provide initial evidence that sex-specific alterations in astrocyte phenotype and neurovascular integrity in the PFC contribute to behavioral and cognitive consequences following chronic stress.
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Affiliation(s)
- Justin L Bollinger
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Shobha Johnsamuel
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Lauren L Vollmer
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Alexander M Kuhn
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Eric S Wohleb
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
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19
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Somelar-Duracz K, Jürgenson M, Viil J, Zharkovsky A, Jaako K. 'Unpredictable chronic mild stress does not exacerbate memory impairment or altered neuronal and glial plasticity in the hippocampus of middle-aged vitamin D deficient mice'. Eur J Neurosci 2024; 59:1696-1722. [PMID: 38269959 DOI: 10.1111/ejn.16256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 12/10/2023] [Accepted: 01/02/2024] [Indexed: 01/26/2024]
Abstract
Vitamin D deficiency is a worldwide health concern, especially in the elderly population. Much remains unknown about the relationship between vitamin D deficiency (VDD), stress-induced cognitive dysfunctions and depressive-like behaviour. In this study, 4-month-old male C57Bl/6J mice were fed with control or vitamin D free diet for 6 months, followed by unpredictable chronic stress (UCMS) for 8 weeks. VDD induced cognitive impairment and reduced grooming behaviour, but did not induce depressive-like behaviour. While UCMS in vitamin D sufficient mice induced expected depressive-like phenotype and impairments in the contextual fear memory, chronic stress did not manifest as an additional risk factor for memory impairments and depressive-like behaviour in VDD mice. In fact, UCMS restored self-care behaviour in VDD mice. At the histopathological level, VDD mice exhibited cell loss in the granule cell layer, reduced survival of newly generated cells, accompanied with an increased number of apoptotic cells and alterations in glial morphology in the hippocampus; however, these effects were not exacerbated by UCMS. Interestingly, UCMS reversed VDD induced loss of microglial cells. Moreover, tyrosine hydroxylase levels decreased in the striatum of VDD mice, but not in stressed VDD mice. These findings indicate that long-term VDD in adulthood impairs cognition but does not augment behavioural response to UCMS in middle-aged mice. While VDD caused cell loss and altered glial response in the DG of the hippocampus, these effects were not exacerbated by UCMS and could contribute to mechanisms regulating altered stress response.
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Affiliation(s)
- Kelli Somelar-Duracz
- Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, Tartu, Estonia
| | - Monika Jürgenson
- Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, Tartu, Estonia
| | - Janeli Viil
- Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, Tartu, Estonia
| | - Alexander Zharkovsky
- Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, Tartu, Estonia
| | - Külli Jaako
- Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, Tartu, Estonia
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20
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Zißler J, Rothhammer V, Linnerbauer M. Gut-Brain Interactions and Their Impact on Astrocytes in the Context of Multiple Sclerosis and Beyond. Cells 2024; 13:497. [PMID: 38534341 PMCID: PMC10968834 DOI: 10.3390/cells13060497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/04/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) that leads to physical and cognitive impairment in young adults. The increasing prevalence of MS underscores the critical need for innovative therapeutic approaches. Recent advances in neuroimmunology have highlighted the significant role of the gut microbiome in MS pathology, unveiling distinct alterations in patients' gut microbiota. Dysbiosis not only impacts gut-intrinsic processes but also influences the production of bacterial metabolites and hormones, which can regulate processes in remote tissues, such as the CNS. Central to this paradigm is the gut-brain axis, a bidirectional communication network linking the gastrointestinal tract to the brain and spinal cord. Via specific routes, bacterial metabolites and hormones can influence CNS-resident cells and processes both directly and indirectly. Exploiting this axis, novel therapeutic interventions, including pro- and prebiotic treatments, have emerged as promising avenues with the aim of mitigating the severity of MS. This review delves into the complex interplay between the gut microbiome and the brain in the context of MS, summarizing current knowledge on the key signals of cross-organ crosstalk, routes of communication, and potential therapeutic relevance of the gut microbiome. Moreover, this review places particular emphasis on elucidating the influence of these interactions on astrocyte functions within the CNS, offering insights into their role in MS pathophysiology and potential therapeutic interventions.
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Affiliation(s)
| | - Veit Rothhammer
- Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany
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21
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Deckers C, Karbalaei R, Miles NA, Harder EV, Witt E, Harris EP, Reissner K, Wimmer ME, Bangasser DA. Early resource scarcity causes cortical astrocyte enlargement and sex-specific changes in the orbitofrontal cortex transcriptome in adult rats. Neurobiol Stress 2024; 29:100607. [PMID: 38304302 PMCID: PMC10831308 DOI: 10.1016/j.ynstr.2024.100607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 01/06/2024] [Accepted: 01/08/2024] [Indexed: 02/03/2024] Open
Abstract
Astrocyte morphology affects function, including the regulation of glutamatergic signaling. This morphology changes dynamically in response to the environment. However, how early life manipulations alter adult cortical astrocyte morphology is underexplored. Our lab uses brief postnatal resource scarcity, the limited bedding and nesting (LBN) manipulation, in rats. We previously found that LBN augments maternal behaviors and promotes later resilience to adult addiction-related behaviors, reducing impulsivity, risky decision-making, and morphine self-administration. These behaviors rely on glutamatergic transmission in the medial orbitofrontal (mOFC) and medial prefrontal (mPFC) cortex. Here we tested whether LBN changed astrocyte morphology in the mOFC and mPFC of adult rats using a novel viral approach that, unlike traditional markers, fully labels astrocytes. Prior exposure to LBN causes an increase in the surface area and volume of astrocytes in the mOFC and mPFC of adult males and females relative to control-raised rats. We next used bulk RNA sequencing of OFC tissue to assess transcriptional changes that could increase astrocyte size in LBN rats. LBN caused mainly sex-specific changes in differentially expressed genes. Pathway analysis revealed that OFC glutamatergic signaling is altered by LBN in males and females, but the gene changes in that pathway differed across sex. This may represent a convergent sex difference where glutamatergic signaling, which affects astrocyte morphology, is altered by LBN via sex-specific mechanisms. Collectively, these studies highlight that astrocytes may be an important cell type that mediates the effect of early resource scarcity on adult brain function.
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Affiliation(s)
- Claire Deckers
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, USA
| | - Reza Karbalaei
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, USA
| | - Nylah A. Miles
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, USA
| | - Eden V. Harder
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Emily Witt
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Erin P. Harris
- Neuroscience Institute, Georgia State University, Atlanta, USA
- Center for Behavioral Neuroscience, Georgia State University, Atlanta, USA
| | - Kathryn Reissner
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Mathieu E. Wimmer
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, USA
| | - Debra A. Bangasser
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia, USA
- Neuroscience Institute, Georgia State University, Atlanta, USA
- Center for Behavioral Neuroscience, Georgia State University, Atlanta, USA
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22
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Holt LM, Gyles TM, Parise EM, Minier-Toribio A, Markovic T, Rivera M, Yeh SY, Nestler EJ. Astrocytic CREB in nucleus accumbens promotes susceptibility to chronic stress. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.15.575728. [PMID: 38293227 PMCID: PMC10827054 DOI: 10.1101/2024.01.15.575728] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
Background Increasing evidence implicates astrocytes in stress and depression in both rodent models and human Major Depressive Disorder (MDD). Despite this, little is known about the transcriptional responses to stress of astrocytes within the nucleus accumbens (NAc), a key brain reward region, and their influence on behavioral outcomes. Methods We used whole cell sorting, RNA-sequencing, and bioinformatic analyses to investigate the NAc astrocyte transcriptome in male mice in response to chronic social defeat stress (CSDS). Immunohistochemistry was used to determine stress-induced changes in astrocytic CREB within the NAc. Finally, astrocytic regulation of depression-like behavior was investigated using viral-mediated manipulation of CREB in combination with CSDS. Results We found a robust transcriptional response in NAc astrocytes to CSDS in stressed mice, with changes seen in both stress-susceptible and stress-resilient animals. Bioinformatic analysis revealed CREB, a transcription factor widely studied in neurons, as one of the top-predicted upstream regulators of the NAc astrocyte transcriptome, with opposite activation states seen in resilient versus susceptible mice. This bioinformatic result was confirmed at the protein level with immunohistochemistry. Viral overexpression of CREB selectively in NAc astrocytes promoted susceptibility to chronic stress. Conclusions Together, our data demonstrate that the astrocyte transcriptome responds robustly to CSDS and, for the first time, that transcriptional regulation in astrocytes contributes to depressive-like behaviors. A better understanding of transcriptional regulation in astrocytes may reveal unknown molecular mechanisms underlying neuropsychiatric disorders.
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Affiliation(s)
- Leanne M. Holt
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Trevonn M Gyles
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Eric M. Parise
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Angelica Minier-Toribio
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Tamara Markovic
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Matthew Rivera
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Szu-Ying Yeh
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Eric J. Nestler
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
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23
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Wulaer B, Holtz MA, Nagai J. Homeostasis to Allostasis: Prefrontal Astrocyte Roles in Cognitive Flexibility and Stress Biology. ADVANCES IN NEUROBIOLOGY 2024; 39:137-163. [PMID: 39190074 DOI: 10.1007/978-3-031-64839-7_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
In the intricate landscape of neurophysiology, astrocytes have been traditionally cast as homeostatic cells; however, their mechanistic involvement in allostasis-particularly how they modulate the adaptive response to stress and its accumulative impact that disrupts cognitive functions and precipitates psychiatric disorders-is now starting to be unraveled. Here, we address the gap by positing astrocytes as crucial allostatic players whose molecular adaptations underlie cognitive flexibility in stress-related neuropsychiatric conditions. We review how astrocytes, responding to stress mediators such as glucocorticoid and epinephrine/norepinephrine, undergo morphological and functional transformations that parallel the maladaptive changes. Our synthesis of recent findings reveals that these glial changes, especially in the metabolically demanding prefrontal cortex, may underlie some of the neuropsychiatric mechanisms characterized by the disruption of energy metabolism and astrocytic networks, compromised glutamate clearance, and diminished synaptic support. We argue that astrocytes extend beyond their homeostatic role, actively participating in the brain's allostatic response, especially by modulating energy substrates critical for cognitive functions.
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Affiliation(s)
- Bolati Wulaer
- Laboratory for Glia-Neuron Circuit Dynamics, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Mika A Holtz
- Laboratory for Glia-Neuron Circuit Dynamics, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Jun Nagai
- Laboratory for Glia-Neuron Circuit Dynamics, RIKEN Center for Brain Science, Wako, Saitama, Japan.
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24
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Gore IR, Gould E. Developmental and adult stress: effects of steroids and neurosteroids. Stress 2024; 27:2317856. [PMID: 38563163 PMCID: PMC11046567 DOI: 10.1080/10253890.2024.2317856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 02/03/2024] [Indexed: 04/04/2024] Open
Abstract
In humans, exposure to early life adversity has profound implications for susceptibility to developing neuropsychiatric disorders later in life. Studies in rodents have shown that stress experienced during early postnatal life can have lasting effects on brain development. Glucocorticoids and sex steroids are produced in endocrine glands and the brain from cholesterol; these molecules bind to nuclear and membrane-associated steroid receptors. Unlike other steroids that can also be made in the brain, neurosteroids bind specifically to neurotransmitter receptors, not steroid receptors. The relationships among steroids, neurosteroids, and stress are multifaceted and not yet fully understood. However, studies demonstrating altered levels of progestogens, androgens, estrogens, glucocorticoids, and their neuroactive metabolites in both developmental and adult stress paradigms strongly suggest that these molecules may be important players in stress effects on brain circuits and behavior. In this review, we discuss the influence of developmental and adult stress on various components of the brain, including neurons, glia, and perineuronal nets, with a focus on sex steroids and neurosteroids. Gaining an enhanced understanding of how early adversity impacts the intricate systems of brain steroid and neurosteroid regulation could prove instrumental in identifying novel therapeutic targets for stress-related conditions.
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Affiliation(s)
- Isha R Gore
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
| | - Elizabeth Gould
- Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
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25
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Okeowo OM, Oke OO, David GO, Ijomone OM. Caffeine Administration Mitigates Chronic Stress-Induced Behavioral Deficits, Neurochemical Alterations, and Glial Disruptions in Rats. Brain Sci 2023; 13:1663. [PMID: 38137111 PMCID: PMC10741929 DOI: 10.3390/brainsci13121663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/11/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
Prolonged exposure to stress has detrimental effects on health, and the consumption of caffeine, mostly contained in energy drinks, has become a widely adopted stress coping strategy. Currently, there is limited information regarding the effects of caffeine intake on chronic stress exposure. Thus, this study investigated the effects of caffeine administration on chronic stress-induced behavioral deficits, neurochemical alterations, and glial disruptions in experimental rats. Thirty male Wistar rats were randomly assigned to five groups (n = 6): non-stress control, stress control, and caffeine groups of doses 12.5, 25, and 50 mg/kg. The stress control and caffeine groups were subjected to an unpredictable chronic mild stress (UCMS) protocol daily for 14 days. The rats were evaluated for phenotypic and neurobehavioral assessments. Thereafter, the rat brains were processed for biochemical and immunohistochemical assays. Caffeine administration was found to ameliorate behavioral dysfunctions in rats exposed to UCMS. The UCMS-induced changes in brain levels of monoamines, cholinesterases, and some oxidative stress biomarkers were reversed by caffeine. Caffeine administration also produced mild protective effects against UCMS-induced changes in GFAP and Iba-1 expression in stress-specific brain regions. These results showed that low and moderate doses of caffeine reversed most of the stress-induced changes, suggesting its ameliorative potential against chronic stress-induced alterations.
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Affiliation(s)
- Oritoke M. Okeowo
- Department of Physiology, School of Basic Medical Sciences, Federal University of Technology, Akure 340252, Ondo State, Nigeria; (O.M.O.); (O.O.O.)
- Laboratory for Experimental and Translational Neurobiology, University of Medical Sciences, Ondo 351101, Ondo State, Nigeria
| | - Olanrewaju O. Oke
- Department of Physiology, School of Basic Medical Sciences, Federal University of Technology, Akure 340252, Ondo State, Nigeria; (O.M.O.); (O.O.O.)
| | - Gloria O. David
- Department of Anatomy, School of Basic Medical Sciences, Federal University of Technology, Akure 340252, Ondo State, Nigeria;
| | - Omamuyovwi M. Ijomone
- Laboratory for Experimental and Translational Neurobiology, University of Medical Sciences, Ondo 351101, Ondo State, Nigeria
- Department of Anatomy, School of Basic Medical Sciences, Federal University of Technology, Akure 340252, Ondo State, Nigeria;
- Department of Anatomy, Faculty of Basic Medical Sciences, University of Medical Sciences, Ondo 351101, Ondo State, Nigeria
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26
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Wang J, Deng X, Jiang J, Yao Z, Ju Y, Luo Y. Evaluation of electroacupuncture as a non-pharmacological therapy for astrocytic structural aberrations and behavioral deficits in a post-ischemic depression model in mice. Front Behav Neurosci 2023; 17:1239024. [PMID: 37700911 PMCID: PMC10493307 DOI: 10.3389/fnbeh.2023.1239024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/07/2023] [Indexed: 09/14/2023] Open
Abstract
Background Ascending clinical evidence supports that electroacupuncture (EA) is effective in treating post-ischemic depression (PID), but little is known about how it works at the cellular level. Astrocytes are exquisitely sensitive to their extracellular environment, and under stressful conditions, they may experience aberrant structural remodeling that can potentially cause neuroplastic disturbances and contribute to subsequent changes in mood or behavior. Objectives This study aimed to investigate the effect of EA on behavioral deficits associated with PID in mice and verify the hypothesis that astrocytic morphology may be involved in this impact. Methods We established a PID animal model induced by transient bilateral common carotid artery occlusion (BCCAO, 20 min) and chronic restraint stress (CRS, 21 days). EA treatment (GV20 + ST36) was performed for 3 weeks, from Monday to Friday each week. Depressive- and anxiety-like behaviors and sociability were evaluated using SPT, FST, EPM, and SIT. Immunohistochemistry combined with Sholl and cell morphological analysis was utilized to assess the process morphology of GFAP+ astrocytes in mood-related regions. The potential relationship between morphological changes in astrocytes and behavioral output was detected by correlation analysis. Results Behavioral assays demonstrated that EA treatment induced an overall reduction in behavioral deficits, as measured by the behavioral Z-score. Sholl and morphological analyses revealed that EA prevented the decline in cell complexity of astrocytes in the prefrontal cortex (PFC) and the CA1 region of the hippocampus, where astrocytes displayed evident deramification and atrophy of the branches. Eventually, the correlation analysis showed there was a relationship between behavioral emotionality and morphological changes. Conclusion Our findings imply that EA prevents both behavioral deficits and structural abnormalities in astrocytes in the PID model. The strong correlation between behavioral Z-scores and the observed morphological changes confirms the notion that the weakening of astrocytic processes may play a crucial role in depressive symptoms, and astrocytes could be a potential target of EA in the treatment of PID.
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Affiliation(s)
- Jingwen Wang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Deng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jin Jiang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhengyu Yao
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yaxin Ju
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yong Luo
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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27
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Deckers C, Karbalaei R, Miles NA, Harder EV, Witt E, Harris EP, Reissner K, Wimmer ME, Bangasser DA. Early resource scarcity causes cortical astrocyte enlargement and sex-specific changes in the orbitofrontal cortex transcriptome in adult rats. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.01.547315. [PMID: 37425737 PMCID: PMC10327175 DOI: 10.1101/2023.07.01.547315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Astrocyte morphology affects function, including the regulation of glutamatergic signaling. This morphology changes dynamically in response to the environment. However, how early life manipulations alter adult cortical astrocyte morphology is underexplored. Our lab uses brief postnatal resource scarcity, the limited bedding and nesting (LBN) manipulation, in rats. We previously found that LBN promotes later resilience to adult addiction-related behaviors, reducing impulsivity, risky decision-making, and morphine self-administration. These behaviors rely on glutamatergic transmission in the medial orbitofrontal (mOFC) and medial prefrontal (mPFC) cortex. Here we tested whether LBN changed astrocyte morphology in the mOFC and mPFC of adult rats using a novel viral approach that, unlike traditional markers, fully labels astrocytes. Prior exposure to LBN causes an increase in the surface area and volume of astrocytes in the mOFC and mPFC of adult males and females relative to control-raised rats. We next used bulk RNA sequencing of OFC tissue to assess transcriptional changes that could increase astrocyte size in LBN rats. LBN caused mainly sex-specific changes in differentially expressed genes. However, Park7, which encodes for the protein DJ-1 that alters astrocyte morphology, was increased by LBN across sex. Pathway analysis revealed that OFC glutamatergic signaling is altered by LBN in males and females, but the gene changes in that pathway differed across sex. This may represent a convergent sex difference where glutamatergic signaling, which affects astrocyte morphology, is altered by LBN via sex-specific mechanisms. Collectively, these studies highlight that astrocytes may be an important cell type that mediates the effect of early resource scarcity on adult brain function.
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Affiliation(s)
- Claire Deckers
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia
| | - Reza Karbalaei
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia
| | - Nylah A Miles
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia
| | - Eden V Harder
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Emily Witt
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Erin P Harris
- Neuroscience Institute, Georgia State University, Atlanta
- Center for Behavioral Neuroscience, Georgia State University, Atlanta
| | - Kathryn Reissner
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Mathieu E Wimmer
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia
| | - Debra A Bangasser
- Department of Psychology and Neuroscience Program, Temple University, Philadelphia
- Neuroscience Institute, Georgia State University, Atlanta
- Center for Behavioral Neuroscience, Georgia State University, Atlanta
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28
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Galindo-Paredes G, Flores G, Morales-Medina JC. Olfactory bulbectomy induces nociceptive alterations associated with gliosis in male rats. IBRO Neurosci Rep 2023; 14:494-506. [PMID: 37388490 PMCID: PMC10300455 DOI: 10.1016/j.ibneur.2023.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 05/12/2023] [Accepted: 05/13/2023] [Indexed: 07/01/2023] Open
Abstract
Major depressive disorder (MDD) is a major health concern worldwide with a wide array of symptoms. Emerging evidence suggests a high comorbidity between MDD and chronic pain, however, the relationship between these two diseases is not completely understood. Growing evidence suggests that glial cells play a key role in both disorders. Hence, we examined the effect of olfactory bulbectomy (OBX), a well-known model of depression-related behavior, on nociceptive behaviors and the number and morphology of astrocytes and glial cells in brain regions involved in the control of nociceptive processes in male rats. The brain regions analyzed included the basolateral amygdala (BLA), central amygdala (CeA), prefrontal cortex (PFC), and CA1 subregion of the hippocampus. A battery of behavioral tests, mechanical allodynia, thermal cold allodynia and mechanical hyperalgesia, was evaluated before and four weeks after OBX. Quantitative morphological analysis, as well as assessment of the number of glial fibrillary acidic protein (GFAP) and ionizing calcium-binding adaptor molecule 1 (Iba1) positive astrocytes and microglia were carried out to characterize glial remodeling and density, respectively. OBX caused mechanical and cold allodynia in an asynchronous pattern. The cold allodynia was noticeable one week following surgery, while mechanical allodynia became apparent two weeks after surgery. In the BLA, CeA and CA1, OBX caused significant changes in glial cells, such as hypertrophy and hypotrophy in GFAP-positive astrocytes and Iba1-positive microglia, respectively. Iba1-positive microglia in the PFC underwent selective hypotrophy due to OBX and OBX enhanced both GFAP-positive astrocytes and Iba1-positive microglia in the BLA. In addition, OBX increased the number of GFAP-positive astrocytes in the CeA and CA1. The amount of Iba1-positive microglia in the PFC also increased as a result of OBX. Furthermore, we found that there was a strong link between the observed behaviors and glial activation in OBX rats. Overall, our work supports the neuroinflammatory hypothesis of MDD and the comorbidity between pain and depression by demonstrating nociceptive impairment and significant microglial and astrocytic activation in the brain.
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Affiliation(s)
- Gumaro Galindo-Paredes
- Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, AP 62, CP 90000 Tlaxcala, Mexico
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Cinvestav del IPN, Av. IPN 2508, San Pedro Zacatenco, 07360 Ciudad de México, Mexico
| | - Gonzalo Flores
- Lab. Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, 14 Sur 6301, San Manuel 72570, Puebla, Mexico
| | - Julio César Morales-Medina
- Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, AP 62, CP 90000 Tlaxcala, Mexico
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Lin SS, Zhou B, Chen BJ, Jiang RT, Li B, Illes P, Semyanov A, Tang Y, Verkhratsky A. Electroacupuncture prevents astrocyte atrophy to alleviate depression. Cell Death Dis 2023; 14:343. [PMID: 37248211 DOI: 10.1038/s41419-023-05839-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/16/2023] [Accepted: 04/26/2023] [Indexed: 05/31/2023]
Abstract
Astrocyte atrophy is the main histopathological hallmark of major depressive disorder (MDD) in humans and in animal models of depression. Here we show that electroacupuncture prevents astrocyte atrophy in the prefrontal cortex and alleviates depressive-like behaviour in mice subjected to chronic unpredictable mild stress (CUMS). Treatment of mice with CUMS induced depressive-like phenotypes as confirmed by sucrose preference test, tail suspension test, and forced swimming test. These behavioural changes were paralleled with morphological atrophy of astrocytes in the prefrontal cortex, revealed by analysis of 3D reconstructions of confocal Z-stack images of mCherry expressing astrocytes. This morphological atrophy was accompanied by a decrease in the expression of cytoskeletal linker Ezrin, associated with formation of astrocytic leaflets, which form astroglial synaptic cradle. Electroacupuncture at the acupoint ST36, as well as treatment with anti-depressant fluoxetine, prevented depressive-like behaviours, astrocytic atrophy, and down-regulation of astrocytic ezrin. In conclusion, our data further strengthen the notion of a primary role of astrocytic atrophy in depression and reveal astrocytes as cellular target for electroacupuncture in treatment of depressive disorders.
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Affiliation(s)
- Si-Si Lin
- International Joint Research Centre on Purinergic Signalling of Sichuan Province /Research Centre on TCM-Rehabilitation and Neural Circuit, School of Acupuncture and Tuina/Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Bin Zhou
- Laboratory of Anaesthesia and Critical Care Medicine, Department of Anaesthesiology, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Bin-Jie Chen
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
| | - Ruo-Tian Jiang
- Laboratory of Anaesthesia and Critical Care Medicine, Department of Anaesthesiology, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Baoman Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
| | - Peter Illes
- International Joint Research Centre on Purinergic Signalling of Sichuan Province /Research Centre on TCM-Rehabilitation and Neural Circuit, School of Acupuncture and Tuina/Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany
| | - Alexey Semyanov
- College of Medicine, Jiaxing University, Jiaxing, China
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Yong Tang
- International Joint Research Centre on Purinergic Signalling of Sichuan Province /Research Centre on TCM-Rehabilitation and Neural Circuit, School of Acupuncture and Tuina/Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
- Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, China.
| | - Alexei Verkhratsky
- International Joint Research Centre on Purinergic Signalling of Sichuan Province /Research Centre on TCM-Rehabilitation and Neural Circuit, School of Acupuncture and Tuina/Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China.
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
- Achucarro Centre for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
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30
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Aten S, Du Y, Taylor O, Dye C, Collins K, Thomas M, Kiyoshi C, Zhou M. Chronic Stress Impairs the Structure and Function of Astrocyte Networks in an Animal Model of Depression. Neurochem Res 2023; 48:1191-1210. [PMID: 35796915 PMCID: PMC9823156 DOI: 10.1007/s11064-022-03663-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 06/18/2022] [Indexed: 01/11/2023]
Abstract
Now astrocytes appear to be the key contributors to the pathophysiology of major depression. Evidence in rodents shows that chronic stress is associated with a decreased expression of astrocytic GFAP-immunoreactivity within the cortex in addition to changes in the complexity and length of astrocyte processes. Furthermore, postmortem brains of individuals with depression have revealed a decrease in astrocyte density. Notably, astrocytes are extensively coupled to one another through gap junctions to form a network, or syncytium, and we have previously demonstrated that syncytial isopotentiality is a mechanism by which astrocytes function as an efficient system with respect to brain homeostasis. Interestingly, the question of how astrocyte network function changes following chronic stress is yet to be elucidated. Here, we sought to examine the effects of chronic stress on network-level astrocyte (dys)function. Using a transgenic aldh1l1-eGFP astrocyte reporter mouse, a six-week unpredictable chronic mild stress (UCMS) paradigm as a rodent model of major depression, and immunohistochemical approaches, we show that the morphology of individual astrocytes is altered by chronic stress exposure. Additionally, in astrocyte syncytial isopotentiality measurement, we found that UCMS impairs the syncytial coupling strength of astrocytes within the hippocampus and prefrontal cortex-two brain regions that have been implicated in the regulation of mood. Together, these findings reveal that chronic stress leads to astrocyte atrophy and impaired gap junction coupling, raising the prospect that both individual and network-level astrocyte functionality are important in the etiology of major depression and other neuropsychiatric disorders.
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Affiliation(s)
- Sydney Aten
- Department of Neuroscience, Ohio State University Wexner Medical Center, Graves Hall, Rm 4066C, 333 W. 10th Ave, Columbus, OH, 43210, USA
- Department of Neurology, Division of Sleep Medicine, and Program in Neuroscience, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Yixing Du
- Department of Neuroscience, Ohio State University Wexner Medical Center, Graves Hall, Rm 4066C, 333 W. 10th Ave, Columbus, OH, 43210, USA
| | - Olivia Taylor
- Department of Neuroscience, Ohio State University Wexner Medical Center, Graves Hall, Rm 4066C, 333 W. 10th Ave, Columbus, OH, 43210, USA
| | - Courtney Dye
- Department of Neuroscience, Ohio State University Wexner Medical Center, Graves Hall, Rm 4066C, 333 W. 10th Ave, Columbus, OH, 43210, USA
| | - Kelsey Collins
- Department of Neuroscience, Ohio State University Wexner Medical Center, Graves Hall, Rm 4066C, 333 W. 10th Ave, Columbus, OH, 43210, USA
| | - Matthew Thomas
- Department of Neuroscience, Ohio State University Wexner Medical Center, Graves Hall, Rm 4066C, 333 W. 10th Ave, Columbus, OH, 43210, USA
| | - Conrad Kiyoshi
- Department of Neuroscience, Ohio State University Wexner Medical Center, Graves Hall, Rm 4066C, 333 W. 10th Ave, Columbus, OH, 43210, USA
- Northern Marianas College, Saipan, MP, USA
| | - Min Zhou
- Department of Neuroscience, Ohio State University Wexner Medical Center, Graves Hall, Rm 4066C, 333 W. 10th Ave, Columbus, OH, 43210, USA.
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31
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Costello A, Linning-Duffy K, Vandenbrook C, Lonstein JS, Yan L. Daytime Light Deficiency Leads to Sex- and Brain Region-Specific Neuroinflammatory Responses in a Diurnal Rodent. Cell Mol Neurobiol 2023; 43:1369-1384. [PMID: 35864429 PMCID: PMC10635710 DOI: 10.1007/s10571-022-01256-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 07/07/2022] [Indexed: 11/30/2022]
Abstract
Seasonal changes in peripheral inflammation are well documented in both humans and animal models, but seasonal changes in neuroinflammation, especially the impact of seasonal lighting environment on neuroinflammation remain unclear. To address this question, the present study examined the effects of environmental lighting conditions on neuroinflammation in a diurnal rodent model, Nile grass rats (Arvicanthis niloticus). Male and female grass rats were housed in either bright (brLD) or dim (dimLD) light during the day to simulate a summer or winter light condition, respectively. After 4 weeks, microglia markers Iba-1 and CD11b, as well as pro-inflammatory cytokines TNF-α and IL-6, were examined in the anterior cingulate cortex (ACC), basolateral amygdala (BLA), and dorsal hippocampus (dHipp). The results revealed that winter-like dim light during the day leads to indicators of increased neuroinflammation in a brain site- and sex-specific manner. Specifically, relatively few changes in the neuroinflammatory markers were observed in the ACC, while numerous changes were found in the BLA and dHipp. In the BLA, winter-like dimLD resulted in hyper-ramified microglia morphology and increased expression of the pro-inflammatory cytokine IL-6, but only in males. In the dHipp, dimLD led to a higher number and hyper-ramified morphology of microglia as well as increased expression of CD11b and TNF-α, but only in females. Neuroinflammatory state is thus influenced by environmental light, differently in males and females, and could play a role in sex differences in the prevalence and symptoms of psychiatric or neurological disorders that are influenced by season or other environmental light conditions. Diurnal Nile grass rats were housed under bright or dim light during the day for 4 weeks, simulating seasonal fluctuations in daytime lighting environment. Dim light housing resulted in hyper-ramified morphology of microglia (scale bar, 15 μm) and altered expression of pro-inflammatory cytokines (TNF-α) in a sex- and brain region-specific manner.
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Affiliation(s)
- Allison Costello
- Behavioral Neuroscience Program, Department of Psychology, Michigan State University, 766, Service Road, East Lansing, MI, 48824, USA
| | - Katrina Linning-Duffy
- Behavioral Neuroscience Program, Department of Psychology, Michigan State University, 766, Service Road, East Lansing, MI, 48824, USA
| | - Carleigh Vandenbrook
- Behavioral Neuroscience Program, Department of Psychology, Michigan State University, 766, Service Road, East Lansing, MI, 48824, USA
| | - Joseph S Lonstein
- Behavioral Neuroscience Program, Department of Psychology, Michigan State University, 766, Service Road, East Lansing, MI, 48824, USA
- Neuroscience Program, Michigan State University, East Lansing, MI, 48824, USA
| | - Lily Yan
- Behavioral Neuroscience Program, Department of Psychology, Michigan State University, 766, Service Road, East Lansing, MI, 48824, USA.
- Neuroscience Program, Michigan State University, East Lansing, MI, 48824, USA.
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32
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Fessel J. Supplementary Pharmacotherapy for the Behavioral Abnormalities Caused by Stressors in Humans, Focused on Post-Traumatic Stress Disorder (PTSD). J Clin Med 2023; 12:1680. [PMID: 36836215 PMCID: PMC9967886 DOI: 10.3390/jcm12041680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/17/2023] [Accepted: 02/18/2023] [Indexed: 02/22/2023] Open
Abstract
Used as a supplement to psychotherapy, pharmacotherapy that addresses all of the known metabolic and genetic contributions to the pathogenesis of psychiatric conditions caused by stressors would require an inordinate number of drugs. Far simpler is to address the abnormalities caused by those metabolic and genetic changes in the cell types of the brain that mediate the behavioral abnormality. Relevant data regarding the changed brain cell types are described in this article and are derived from subjects with the paradigmatic behavioral abnormality of PTSD and from subjects with traumatic brain injury or chronic traumatic encephalopathy. If this analysis is correct, then therapy is required that benefits all of the affected brain cell types; those are astrocytes, oligodendrocytes, synapses and neurons, endothelial cells, and microglia (the pro-inflammatory (M1) subtype requires switching to the anti-inflammatory (M2) subtype). Combinations are advocated using several drugs, erythropoietin, fluoxetine, lithium, and pioglitazone, that benefit all of the five cell types, and that should be used to form a two-drug combination, suggested as pioglitazone with either fluoxetine or lithium. Clemastine, fingolimod, and memantine benefit four of the cell types, and one chosen from those could be added to the two-drug combination to form a three-drug combination. Using low doses of chosen drugs will limit both toxicity and drug-drug interactions. A clinical trial is required to validate both the advocated concept and the choice of drugs.
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Affiliation(s)
- Jeffrey Fessel
- Department of Medicine, University of California, 2069 Filbert Street, San Francisco, CA 94123, USA
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33
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Thongrong S, Surapinit S, Promsrisuk T, Jittiwat J, Kongsui R. Pinostrobin alleviates chronic restraint stress‑induced cognitive impairment by modulating oxidative stress and the function of astrocytes in the hippocampus of rats. Biomed Rep 2023; 18:20. [PMID: 36798091 PMCID: PMC9922797 DOI: 10.3892/br.2023.1602] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 01/27/2023] [Indexed: 02/05/2023] Open
Abstract
Chronic stress has been recognized to induce the alterations of neuronal and glial cells in the hippocampus, and is thus implicated in cognitive dysfunction. There is increasing evidence to indicate that natural compounds capable of exerting neuroprotective and antioxidant activities, may function as potential therapeutic agents for cognitive impairment. The present study examined the neuroprotective effects of pinostrobin from Boesenbergia rotunda (L.) against chronic restraint stress (CRS)-induced cognitive impairment associated with the alterations of oxidative stress, neuronal density and glial fibrillary acidic protein (GFAP) of astrocytes in the hippocampus. For this purpose, male Wistar rats were administered once daily with pinostrobin (20 and 40 mg/kg, per os) prior to exposure to CRS (6 h/day) for 21 days. The cognitive behaviors, the concentration of malondialdehyde, and the activities of superoxide dismutase and catalase were determined. Histologically, the alterations in astrocytic GFAP and excitatory amino acid transporter 2 (EAAT2) in the hippocampus were examined. The results revealed that pinostrobin potentially attenuated cognitive impairment in the Y-maze and in novel object recognition tests, with a reduction in oxidative stress. Furthermore, pinostrobin effectively increased neuronal density, as well as the immunoreactivities of GFAP and EAAT2 in the hippocampus. Taken together, these findings indicate that treatment with pinostrobin alleviates chronic stress-induced cognitive impairment by exerting antioxidant effects, reducing neuronal cell damage, and improving the function of astrocytic GFAP and EAAT2. Thus, pinostrobin may have potential for use as a neuroprotective agent to protect against chronic stress-induced brain dysfunction and cognitive deficits.
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Affiliation(s)
- Sitthisak Thongrong
- Division of Anatomy, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand,Unit of Excellence in Translational Neurosciences Initiative, University of Phayao, Phayao 56000, Thailand
| | - Serm Surapinit
- Unit of Excellence in Translational Neurosciences Initiative, University of Phayao, Phayao 56000, Thailand,Department of Medical Technology, School of Allied Health Sciences, University of Phayao, Phayao 56000, Thailand
| | - Tichanon Promsrisuk
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Jinatta Jittiwat
- Faculty of Medicine, Mahasarakham University, Mahasarakham 44000, Thailand
| | - Ratchaniporn Kongsui
- Unit of Excellence in Translational Neurosciences Initiative, University of Phayao, Phayao 56000, Thailand,Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand,Correspondence to: Dr Ratchaniporn Kongsui, Division of Physiology, School of Medical Sciences, University of Phayao, 19 Moo 2 Phahonyothin Road, Maeka, Muang Phayao, Phayao 56000, Thailand
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34
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Fessel J. Formulating treatment of major psychiatric disorders: algorithm targets the dominantly affected brain cell-types. DISCOVER MENTAL HEALTH 2023; 3:3. [PMID: 37861813 PMCID: PMC10501034 DOI: 10.1007/s44192-022-00029-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 12/21/2022] [Indexed: 10/21/2023]
Abstract
BACKGROUND Pharmacotherapy for most psychiatric conditions was developed from serendipitous observations of benefit from drugs prescribed for different reasons. An algorithmic approach to formulating pharmacotherapy is proposed, based upon which combination of changed activities by brain cell-types is dominant for any particular condition, because those cell-types contain and surrogate for genetic, metabolic and environmental information, that has affected their function. The algorithm performs because functions of some or all the affected cell-types benefit from several available drugs: clemastine, dantrolene, erythropoietin, fingolimod, fluoxetine, lithium, memantine, minocycline, pioglitazone, piracetam, and riluzole PROCEDURES/FINDINGS: Bipolar disorder, major depressive disorder, schizophrenia, Alzheimer's disease, and post-traumatic stress disorder, illustrate the algorithm; for them, literature reviews show that no single combination of altered cell-types accounts for all cases; but they identify, for each condition, which combination occurs most frequently, i.e., dominates, as compared with other possible combinations. Knowing the dominant combination of altered cell-types in a particular condition, permits formulation of therapy with combinations of drugs taken from the above list. The percentage of patients who might benefit from that therapy, depends upon the frequency with which the dominant combination occurs in patients with that particular condition. CONCLUSIONS Knowing the dominant combination of changed cell types in psychiatric conditions, permits an algorithmically formulated, rationally-based treatment. Different studies of the same condition often produce discrepant results; all might be correct, because identical clinical phenotypes result from different combinations of impaired cell-types, thus producing different results. Clinical trials would validate both the proposed concept and choice of drugs.
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Affiliation(s)
- Jeffrey Fessel
- Department of Medicine, University of California, 2069 Filbert Street, San Francisco, CA, 94123, USA.
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Kruyer A, Kalivas PW, Scofield MD. Astrocyte regulation of synaptic signaling in psychiatric disorders. Neuropsychopharmacology 2023; 48:21-36. [PMID: 35577914 PMCID: PMC9700696 DOI: 10.1038/s41386-022-01338-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/27/2022] [Accepted: 05/01/2022] [Indexed: 02/07/2023]
Abstract
Over the last 15 years, the field of neuroscience has evolved toward recognizing the critical role of astroglia in shaping neuronal synaptic activity and along with the pre- and postsynapse is now considered an equal partner in tripartite synaptic transmission and plasticity. The relative youth of this recognition and a corresponding deficit in reagents and technologies for quantifying and manipulating astroglia relative to neurons continues to hamper advances in understanding tripartite synaptic physiology. Nonetheless, substantial advances have been made and are reviewed herein. We review the role of astroglia in synaptic function and regulation of behavior with an eye on how tripartite synapses figure into brain pathologies underlying behavioral impairments in psychiatric disorders, both from the perspective of measures in postmortem human brains and more subtle influences on tripartite synaptic regulation of behavior in animal models of psychiatric symptoms. Our goal is to provide the reader a well-referenced state-of-the-art understanding of current knowledge and predict what we may discover with deeper investigation of tripartite synapses using reagents and technologies not yet available.
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Affiliation(s)
- Anna Kruyer
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Peter W Kalivas
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA.
| | - Michael D Scofield
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
- Department of Anesthesia & Perioperative Medicine, Medical University of South Carolina, Charleston, SC, USA.
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36
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Uhlig M, Reinelt JD, Lauckner ME, Kumral D, Schaare HL, Mildner T, Babayan A, Möller HE, Engert V, Villringer A, Gaebler M. Rapid volumetric brain changes after acute psychosocial stress. Neuroimage 2023; 265:119760. [PMID: 36427754 DOI: 10.1016/j.neuroimage.2022.119760] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 11/14/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
Stress is an important trigger for brain plasticity: Acute stress can rapidly affect brain activity and functional connectivity, and chronic or pathological stress has been associated with structural brain changes. Measures of structural magnetic resonance imaging (MRI) can be modified by short-term motor learning or visual stimulation, suggesting that they also capture rapid brain changes. Here, we investigated volumetric brain changes (together with changes in T1 relaxation rate and cerebral blood flow) after acute stress in humans as well as their relation to psychophysiological stress measures. Sixty-seven healthy men (25.8±2.7 years) completed a standardized psychosocial laboratory stressor (Trier Social Stress Test) or a control version while blood, saliva, heart rate, and psychometrics were sampled. Structural MRI (T1 mapping / MP2RAGE sequence) at 3T was acquired 45 min before and 90 min after intervention onset. Grey matter volume (GMV) changes were analysed using voxel-based morphometry. Associations with endocrine, autonomic, and subjective stress measures were tested with linear models. We found significant group-by-time interactions in several brain clusters including anterior/mid-cingulate cortices and bilateral insula: GMV was increased in the stress group relative to the control group, in which several clusters showed a GMV decrease. We found a significant group-by-time interaction for cerebral blood flow, and a main effect of time for T1 values (longitudinal relaxation time). In addition, GMV changes were significantly associated with state anxiety and heart rate variability changes. Such rapid GMV changes assessed with VBM may be induced by local tissue adaptations to changes in energy demand following neural activity. Our findings suggest that endogenous brain changes are counteracted by acute psychosocial stress, which emphasizes the importance of considering homeodynamic processes and generally highlights the influence of stress on the brain.
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Affiliation(s)
- Marie Uhlig
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; International Max Planck Research School NeuroCom, Leipzig, Germany.
| | - Janis D Reinelt
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
| | - Mark E Lauckner
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Independent Research Group "Adaptive Memory", Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Medical Faculty of Leipzig University, Leipzig, Germany
| | - Deniz Kumral
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Institute of Psychology, Neuropsychology, University of Freiburg, Freiburg im Breisgau, Germany
| | - H Lina Schaare
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Otto Hahn Group "Cognitive Neurogenetics", Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; Institute of Neuroscience and Medicine (INM-7: Brain and Behaviour), Research Centre Jülich, Germany
| | - Toralf Mildner
- NMR Methods & Development Group, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
| | - Anahit Babayan
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; MindBrainBody Institute at the Berlin School of Mind and Brain, Faculty of Philosophy, Humboldt-Universität zu Berlin, Berlin, German
| | - Harald E Möller
- NMR Methods & Development Group, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
| | - Veronika Engert
- Institute of Psychosocial Medicine, Psychotherapy and Psychooncology, Jena University Hospital, Friedrich-Schiller University, Jena, Germany; Independent Research Group "Social Stress and Family Health", Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
| | - Arno Villringer
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; MindBrainBody Institute at the Berlin School of Mind and Brain, Faculty of Philosophy, Humboldt-Universität zu Berlin, Berlin, German
| | - Michael Gaebler
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; MindBrainBody Institute at the Berlin School of Mind and Brain, Faculty of Philosophy, Humboldt-Universität zu Berlin, Berlin, German
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37
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Juvenile social isolation affects the structure of the tanycyte-vascular interface in the hypophyseal portal system of the adult mice. Neurochem Int 2023; 162:105439. [PMID: 36356785 DOI: 10.1016/j.neuint.2022.105439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 10/26/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022]
Abstract
Accumulating evidence indicates that social stress in the juvenile period affects hypothalamic-pituitary-adrenal (HPA) axis activity in adulthood. The biological mechanisms underlying this phenomenon remain unclear. We aimed to elucidate them by comparing adult mice that had experienced social isolation from postnatal day 21-35 (juvenile social isolation (JSI) group) with those reared normally (control group). JSI group mice showed an attenuated HPA response to acute swim stress, while the control group had a normal response to this stress. Activity levels of the paraventricular nucleus in both groups were comparable, as shown by c-Fos immunoreactivities and mRNA expression of c-Fos, Corticotropin-releasing factor (CRF), Glucocorticoid receptor, and Mineralocorticoid receptor. We found greater vascular coverage by tanycytic endfeet in the median eminence of the JSI group mice than in that of the control group mice under basal condition and after acute swim stress. Moreover, CRF content after acute swim stress was greater in the median eminence of the JSI group mice than in that of the control group mice. The attenuated HPA response to acute swim stress was specific to JSI group mice, but not to control group mice. Although a direct link awaits further experiments, tanycyte morphological changes in the median eminence could be related to the HPA response.
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38
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Dolotov OV, Inozemtseva LS, Myasoedov NF, Grivennikov IA. Stress-Induced Depression and Alzheimer's Disease: Focus on Astrocytes. Int J Mol Sci 2022; 23:4999. [PMID: 35563389 PMCID: PMC9104432 DOI: 10.3390/ijms23094999] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/25/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative diseases and depression are multifactorial disorders with a complex and poorly understood physiopathology. Astrocytes play a key role in the functioning of neurons in norm and pathology. Stress is an important factor for the development of brain disorders. Here, we review data on the effects of stress on astrocyte function and evidence of the involvement of astrocyte dysfunction in depression and Alzheimer's disease (AD). Stressful life events are an important risk factor for depression; meanwhile, depression is an important risk factor for AD. Clinical data indicate atrophic changes in the same areas of the brain, the hippocampus and prefrontal cortex (PFC), in both pathologies. These brain regions play a key role in regulating the stress response and are most vulnerable to the action of glucocorticoids. PFC astrocytes are critically involved in the development of depression. Stress alters astrocyte function and can result in pyroptotic death of not only neurons, but also astrocytes. BDNF-TrkB system not only plays a key role in depression and in normalizing the stress response, but also appears to be an important factor in the functioning of astrocytes. Astrocytes, being a target for stress and glucocorticoids, are a promising target for the treatment of stress-dependent depression and AD.
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Affiliation(s)
- Oleg V. Dolotov
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (O.V.D.); (L.S.I.); (N.F.M.)
- Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory, 119234 Moscow, Russia
| | - Ludmila S. Inozemtseva
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (O.V.D.); (L.S.I.); (N.F.M.)
| | - Nikolay F. Myasoedov
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (O.V.D.); (L.S.I.); (N.F.M.)
| | - Igor A. Grivennikov
- Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia; (O.V.D.); (L.S.I.); (N.F.M.)
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Miguel-Hidalgo JJ. Astroglia in the Vulnerability to and Maintenance of Stress-Mediated Neuropathology and Depression. Front Cell Neurosci 2022; 16:869779. [PMID: 35530179 PMCID: PMC9074831 DOI: 10.3389/fncel.2022.869779] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 04/01/2022] [Indexed: 12/28/2022] Open
Abstract
Significant stress exposure and psychiatric depression are associated with morphological, biochemical, and physiological disturbances of astrocytes in specific brain regions relevant to the pathophysiology of those disorders, suggesting that astrocytes are involved in the mechanisms underlying the vulnerability to or maintenance of stress-related neuropathology and depression. To understand those mechanisms a variety of studies have probed the effect of various modalities of stress exposure on the metabolism, gene expression and plasticity of astrocytes. These studies have uncovered the participation of various cellular pathways, such as those for intracellular calcium regulation, neuroimmune responses, extracellular ionic regulation, gap junctions-based cellular communication, and regulation of neurotransmitter and gliotransmitter release and uptake. More recently epigenetic modifications resulting from exposure to chronic forms of stress or to early life adversity have been suggested to affect not only neuronal mechanisms but also gene expression and physiology of astrocytes and other glial cells. However, much remains to be learned to understand the specific role of those and other modifications in the astroglial contribution to the vulnerability to and maintenance of stress-related disorders and depression, and for leveraging that knowledge to achieve more effective psychiatric therapies.
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Cathomas F, Holt LM, Parise EM, Liu J, Murrough JW, Casaccia P, Nestler EJ, Russo SJ. Beyond the neuron: Role of non-neuronal cells in stress disorders. Neuron 2022; 110:1116-1138. [PMID: 35182484 PMCID: PMC8989648 DOI: 10.1016/j.neuron.2022.01.033] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/15/2021] [Accepted: 01/24/2022] [Indexed: 12/11/2022]
Abstract
Stress disorders are leading causes of disease burden in the U.S. and worldwide, yet available therapies are fully effective in less than half of all individuals with these disorders. Although to date, much of the focus has been on neuron-intrinsic mechanisms, emerging evidence suggests that chronic stress can affect a wide range of cell types in the brain and periphery, which are linked to maladaptive behavioral outcomes. Here, we synthesize emerging literature and discuss mechanisms of how non-neuronal cells in limbic regions of brain interface at synapses, the neurovascular unit, and other sites of intercellular communication to mediate the deleterious, or adaptive (i.e., pro-resilient), effects of chronic stress in rodent models and in human stress-related disorders. We believe that such an approach may one day allow us to adopt a holistic "whole body" approach to stress disorder research, which could lead to more precise diagnostic tests and personalized treatment strategies. Stress is a major risk factor for many psychiatric disorders. Cathomas et al. review new insight into how non-neuronal cells mediate the deleterious effects, as well as the adaptive, protective effects, of stress in rodent models and human stress-related disorders.
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Affiliation(s)
- Flurin Cathomas
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Leanne M Holt
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eric M Parise
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jia Liu
- Neuroscience Initiative, Advanced Science Research Center, Program in Biology and Biochemistry at The Graduate Center of The City University of New York, New York, NY, USA
| | - James W Murrough
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Patrizia Casaccia
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Neuroscience Initiative, Advanced Science Research Center, Program in Biology and Biochemistry at The Graduate Center of The City University of New York, New York, NY, USA
| | - Eric J Nestler
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Scott J Russo
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Li B, Zhang D, Verkhratsky A. Astrocytes in Post-traumatic Stress Disorder. Neurosci Bull 2022; 38:953-965. [PMID: 35349095 PMCID: PMC8960712 DOI: 10.1007/s12264-022-00845-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 01/07/2022] [Indexed: 01/15/2023] Open
Abstract
Although posttraumatic stress disorder (PTSD) is on the rise, traumatic events and their consequences are often hidden or minimized by patients for reasons linked to PTSD itself. Traumatic experiences can be broadly classified into mental stress (MS) and traumatic brain injury (TBI), but the cellular mechanisms of MS- or TBI-induced PTSD remain unknown. Recent evidence has shown that the morphological remodeling of astrocytes accompanies and arguably contributes to fearful memories and stress-related disorders. In this review, we summarize the roles of astrocytes in the pathogenesis of MS-PTSD and TBI-PTSD. Astrocytes synthesize and secrete neurotrophic, pro- and anti-inflammatory factors and regulate the microenvironment of the nervous tissue through metabolic pathways, ionostatic control, and homeostatic clearance of neurotransmitters. Stress or trauma-associated impairment of these vital astrocytic functions contribute to the pathophysiological evolution of PTSD and may present therapeutic targets.
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Affiliation(s)
- Baoman Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, 110122, China
| | - Dianjun Zhang
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, 110122, China
| | - Alexei Verkhratsky
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, 110122, China.
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK.
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, 01102, Vilnius, Lithuania.
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Gaspar R, Soares-Cunha C, Domingues AV, Coimbra B, Baptista FI, Pinto L, Ambrósio AF, Rodrigues AJ, Gomes CA. The Duration of Stress Determines Sex Specificities in the Vulnerability to Depression and in the Morphologic Remodeling of Neurons and Microglia. Front Behav Neurosci 2022; 16:834821. [PMID: 35330844 PMCID: PMC8940280 DOI: 10.3389/fnbeh.2022.834821] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/31/2022] [Indexed: 11/24/2022] Open
Abstract
Stress exposure has been shown to induce a variety of molecular and functional alterations associated with anxiety and depression. Some studies suggest that microglia, the immune cells of the brain, play a significant role in determining neuronal and behavioral responses to chronic stress and also contribute to the development of stress-related psychopathologies. However, little is known about the impact of the duration of stress exposure upon microglia and neurons morphology, particularly considering sex differences. This issue deserves particular investigation, considering that the process of morphologic remodeling of neurons and microglia is usually accompanied by functional changes with behavioral expression. Here, we examine the effects of short and long unpredictable chronic mild stress (uCMS) protocols on behavior, evaluating in parallel microglia and neurons morphology in the dorsal hippocampus (dHIP) and in the nucleus accumbens (NAc), two brain regions involved in the etiology of depression. We report that long-term uCMS induced more behavioral alterations in males, which present anxiety and depression-like phenotypes (anhedonia and helplessness behavior), while females only display anxiety-like behavior. After short-term uCMS, both sexes presented anxiety-like behavior. Microglia cells undergo a process of morphologic adaptation to short-term uCMS, dependent on sex, in the NAc: we observed a hypertrophy in males and an atrophy in females, transient effects that do not persist after long-term uCMS. In the dHIP, the morphologic adaptation of microglia is only observed in females (hypertrophy) and after the protocol of long uCMS. Interestingly, males are more vulnerable to neuronal morphological alterations in a region-specific manner: dendritic atrophy in granule neurons of the dHIP and hypertrophy in the medium spiny neurons of the NAc, both after short- or long-term uCMS. The morphology of neurons in these brain regions were not affected in females. These findings raise the possibility that, by differentially affecting neurons and microglia in dHIP and NAc, chronic stress may contribute for differences in the clinical presentation of stress-related disorders under the control of sex-specific mechanisms.
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Affiliation(s)
- Rita Gaspar
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Carina Soares-Cunha
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s –PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Ana Verónica Domingues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s –PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Bárbara Coimbra
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s –PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Filipa I. Baptista
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s –PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - António F. Ambrósio
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Ana João Rodrigues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s –PT Government Associate Laboratory, Braga/Guimarães, Portugal
- *Correspondence: Ana João Rodrigues,
| | - Catarina A. Gomes
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
- Catarina A. Gomes,
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Stress vulnerability shapes disruption of motor cortical neuroplasticity. Transl Psychiatry 2022; 12:91. [PMID: 35246507 PMCID: PMC8897461 DOI: 10.1038/s41398-022-01855-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 02/06/2022] [Accepted: 02/08/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic stress is a major cause of neuropsychiatric conditions such as depression. Stress vulnerability varies individually in mice and humans, measured by behavioral changes. In contrast to affective symptoms, motor retardation as a consequence of stress is not well understood. We repeatedly imaged dendritic spines of the motor cortex in Thy1-GFP M mice before and after chronic social defeat stress. Susceptible and resilient phenotypes were discriminated by symptom load and their motor learning abilities were assessed by a gross and fine motor task. Stress phenotypes presented individual short- and long-term changes in the hypothalamic-pituitary-adrenal axis as well as distinct patterns of altered motor learning. Importantly, stress was generally accompanied by a marked reduction of spine density in the motor cortex and spine dynamics depended on the stress phenotype. We found astrogliosis and altered microglia morphology along with increased microglia-neuron interaction in the motor cortex of susceptible mice. In cerebrospinal fluid, proteomic fingerprints link the behavioral changes and structural alterations in the brain to neurodegenerative disorders and dysregulated synaptic homeostasis. Our work emphasizes the importance of synaptic integrity and the risk of neurodegeneration within depression as a threat to brain health.
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Avalos MP, Guzman AS, Rigoni D, Gorostiza EA, Sanchez MA, Mongi-Bragato B, Garcia-Keller C, Perassi EM, Virgolini MB, Peralta Ramos JM, Iribarren P, Calfa GD, Bollati FA, Cancela LM. Minocycline prevents chronic restraint stress-induced vulnerability to developing cocaine self-administration and associated glutamatergic mechanisms: a potential role of microglia. Brain Behav Immun 2022; 101:359-376. [PMID: 35065197 DOI: 10.1016/j.bbi.2022.01.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 12/24/2021] [Accepted: 01/16/2022] [Indexed: 12/14/2022] Open
Abstract
Stressful experience-induced cocaine-related behaviors are associated with a significant impairment of glutamatergic mechanisms in the Nucleus Accumbens core (NAcore). The hallmarks of disrupted glutamate homeostasis following restraint stress are the enduring imbalance of glutamate efflux after a cocaine stimulus and increased basal concentrations of extracellular glutamate attributed to GLT-1 downregulation in the NAcore. Glutamate transmission is tightly linked to microglia functioning. However, the role of microglia in the biological basis of stress-induced addictive behaviors is still unknown. By using minocycline, a potent inhibitor of microglia activation with anti-inflammatory properties, we determined whether microglia could aid chronic restraint stress (CRS)-induced glutamate homeostasis disruption in the NAcore, underpinning stress-induced cocaine self-administration. In this study, adult male rats were restrained for 2 h/day for seven days (day 1-7). From day 16 until completing the experimental protocol, animals received a vehicle or minocycline treatment (30 mg/Kg/12h i.p.). On day 21, animals were assigned to microscopic, biochemical, neurochemical or behavioral studies. We confirm that the CRS-induced facilitation of cocaine self-administration is associated with enduring GLT-1 downregulation, an increase of basal extracellular glutamate and postsynaptic structural plasticity in the NAcore. These alterations were strongly related to the CRS-induced reactive microglia and increased TNF-α mRNA and protein expression, since by administering minocycline, the impaired glutamate homeostasis and the facilitation of cocaine self-administration were prevented. Our findings are the first to demonstrate that minocycline suppresses the CRS-induced facilitation of cocaine self-administration and glutamate homeostasis disruption in the NAcore. A role of microglia is proposed for the development of glutamatergic mechanisms underpinning stress-induced vulnerability to cocaine addiction.
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Affiliation(s)
- María Paula Avalos
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Andrea Susana Guzman
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Daiana Rigoni
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Ezequiel Axel Gorostiza
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Marianela Adela Sanchez
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Bethania Mongi-Bragato
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Constanza Garcia-Keller
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Eduardo Marcelo Perassi
- Instituto de Investigaciones en Fisicoquímica de Córdoba (INFIQC-CONICET), Departamento de Química Teórica y Computacional, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Miriam Beatriz Virgolini
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Javier María Peralta Ramos
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Pablo Iribarren
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Gastón Diego Calfa
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Flavia Andrea Bollati
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina.
| | - Liliana Marina Cancela
- Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina.
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Piras IS, Huentelman MJ, Pinna F, Paribello P, Solmi M, Murru A, Carpiniello B, Manchia M, Zai CC. A review and meta-analysis of gene expression profiles in suicide. Eur Neuropsychopharmacol 2022; 56:39-49. [PMID: 34923210 DOI: 10.1016/j.euroneuro.2021.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 11/30/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022]
Abstract
Suicide claims over 800,000 deaths worldwide, making it a serious public health problem. The etiopathophysiology of suicide remains unclear and is highly complex, and postmortem gene expression studies can offer insights into the molecular biological mechanism underlying suicide. In the current study, we conducted a meta-analysis of postmortem brain gene expression in relation to suicide. We identified five gene expression datasets for postmortem orbitofrontal, prefrontal, or dorsolateral prefrontal cortical brain regions from the Gene Expression Omnibus repository. After quality control, the total sample size was 380 (141 suicide deaths and 239 deaths from other causes). We performed the analyses using two meta-analytic approaches. We further performed pathway and cell-set enrichment analyses. We found reduced expression of the KCNJ2 (Potassium Inwardly Rectifying Channel Subfamily J Member 2), A2M (Alpha-2-Macroglobulin), AGT (Angiotensinogen), PMP2 (Peripheral Myelin Protein 2), and VEZF1 (Vascular Endothelial Zinc Finger 1) genes (FDR p<0.05). Our findings support the involvement of astrocytes, stress response, immune system, and microglia in suicide. These findings will require further validation in additional large datasets.
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Affiliation(s)
- Ignazio S Piras
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, United States
| | - Matthew J Huentelman
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, United States
| | - Federica Pinna
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
| | - Pasquale Paribello
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
| | - Marco Solmi
- Department of Psychiatry, University of Ottawa, Ontario, Canada; Department of Mental Health, The Ottawa Hospital, Ontario, Canada; Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program University of Ottawa Ottawa Ontario; Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, King's College London, London, United Kingdom
| | - Andrea Murru
- Bipolar and Depression Disorders Unit, Institute of Neuroscience, Hospital Clinic, IDIBAPS CIBERSAM, University of Barcelona, Barcelona, Catalonia, Spain
| | - Bernardo Carpiniello
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
| | - Mirko Manchia
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
| | - Clement C Zai
- Neurogenetics Section, Molecular Brain Science, Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, Institute of Medical Science, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, United States
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Elias E, Zhang AY, Manners MT. Novel Pharmacological Approaches to the Treatment of Depression. Life (Basel) 2022; 12:196. [PMID: 35207483 PMCID: PMC8879976 DOI: 10.3390/life12020196] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/19/2022] [Accepted: 01/23/2022] [Indexed: 12/18/2022] Open
Abstract
Major depressive disorder is one of the most prevalent mental health disorders. Monoamine-based antidepressants were the first drugs developed to treat major depressive disorder. More recently, ketamine and other analogues were introduced as fast-acting antidepressants. Unfortunately, currently available therapeutics are inadequate; lack of efficacy, adverse effects, and risks leave patients with limited treatment options. Efforts are now focused on understanding the etiology of depression and identifying novel targets for pharmacological treatment. In this review, we discuss promising novel pharmacological targets for the treatment of major depressive disorder. Targeting receptors including N-methyl-D-aspartate receptors, peroxisome proliferator-activated receptors, G-protein-coupled receptor 39, metabotropic glutamate receptors, galanin and opioid receptors has potential antidepressant effects. Compounds targeting biological processes: inflammation, the hypothalamic-pituitary-adrenal axis, the cholesterol biosynthesis pathway, and gut microbiota have also shown therapeutic potential. Additionally, natural products including plants, herbs, and fatty acids improved depressive symptoms and behaviors. In this review, a brief history of clinically available antidepressants will be provided, with a primary focus on novel pharmaceutical approaches with promising antidepressant effects in preclinical and clinical studies.
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Affiliation(s)
| | | | - Melissa T. Manners
- Department of Biological Sciences, University of the Sciences, 600 South 43rd Street, Philadelphia, PA 19104, USA; (E.E.); (A.Y.Z.)
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Machado-Santos AR, Loureiro-Campos E, Patrício P, Araújo B, Alves ND, Mateus-Pinheiro A, Correia JS, Morais M, Bessa JM, Sousa N, Rodrigues AJ, Oliveira JF, Pinto L. Beyond New Neurons in the Adult Hippocampus: Imipramine Acts as a Pro-Astrogliogenic Factor and Rescues Cognitive Impairments Induced by Stress Exposure. Cells 2022; 11:cells11030390. [PMID: 35159199 PMCID: PMC8834148 DOI: 10.3390/cells11030390] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023] Open
Abstract
Depression is a prevalent, socially burdensome disease. Different studies have demonstrated the important role of astrocytes in the pathophysiology of depression as modulators of neurotransmission and neurovascular coupling. This is evidenced by astrocyte impairments observed in brains of depressed patients and the appearance of depressive-like behaviors upon astrocytic dysfunctions in animal models. However, little is known about the importance of de novo generated astrocytes in the mammalian brain and in particular its possible involvement in the precipitation of depression and in the therapeutic actions of current antidepressants (ADs). Therefore, we studied the modulation of astrocytes and adult astrogliogenesis in the hippocampal dentate gyrus (DG) of rats exposed to an unpredictable chronic mild stress (uCMS) protocol, untreated and treated for two weeks with antidepressants—fluoxetine and imipramine. Our results show that adult astrogliogenesis in the DG is modulated by stress and imipramine. This study reveals that distinct classes of ADs impact differently in the astrogliogenic process, showing different cellular mechanisms relevant to the recovery from behavioral deficits induced by chronic stress exposure. As such, in addition to those resident, the newborn astrocytes in the hippocampal DG might also be promising therapeutic targets for future therapies in the neuropsychiatric field.
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Affiliation(s)
- Ana R Machado-Santos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Eduardo Loureiro-Campos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Patrícia Patrício
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Bruna Araújo
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Nuno Dinis Alves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - António Mateus-Pinheiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Joana Sofia Correia
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Mónica Morais
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - João M Bessa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Ana J Rodrigues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - João Filipe Oliveira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
- IPCA-EST-2Ai, Polytechnic Institute of Cávado and Ave, Applied Artificial Intelligence Laboratory, Campus of IPCA, 4750-810 Barcelos, Portugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
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Cheng Y, Wang Y, Wang X, Jiang Z, Zhu L, Fang S. Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Monocyte-to-Lymphocyte Ratio in Depression: An Updated Systematic Review and Meta-Analysis. Front Psychiatry 2022; 13:893097. [PMID: 35782448 PMCID: PMC9240476 DOI: 10.3389/fpsyt.2022.893097] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/10/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Research on neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in depression is still emerging and has increased 3-fold since the first meta-analysis. An updated meta-analysis with sufficient studies can provide more evidence for a potential relationship between NLR, PLR, MLR, and depression. METHODS We identified 18 studies from the PubMed, EMBASE, Cochrane library, and Web of Science databases. Meta-analyses were performed to generate pooled standardized mean differences (SMDs) and 95% confidence intervals (CIs) between patients with depression and controls. Sensitivity analysis, subgroup analysis, meta-regression, and publication bias were conducted. RESULTS A total of 18 studies including 2,264 depressed patients and 2,415 controls were included. Depressed patients had significantly higher NLR and PLR compared with controls (SMD = 0.33, 95% CI: 0.15-0.52, p < 0.001 and SMD = 0.24, 95% CI: 0.02-0.46, p < 0.05, respectively). MLR was slightly higher in depressed individuals compared to controls (SMD = 0.15, 95% CI: -0.26 to 0.55, p > 0.05), despite the absence of significance. Sensitivity analysis removing one study responsible for heterogeneity showed a higher and significant effect (SMD = 0.32, 95% CI: 0.20-0.44) of MLR. Three subgroup analyses of NLR, PLR, MLR, and depression revealed obvious differences in the inflammatory ratios between depressed patients and controls in China and the matched age and gender subgroup. Individuals with post-stroke depression (PSD) had higher NLR and MLR values as compared to non-PSD patients (SMD = 0.51, 95% CI: 0.36-0.67, p < 0.001 and SMD = 0.46, 95% CI: 0.12-0.79, p < 0.01, respectively). Meta-regression analyses showed that male proportion in the case group influenced the heterogeneity among studies that measured NLR values (p < 0.05). CONCLUSIONS Higher inflammatory ratios, especially NLR, were significantly associated with an increased risk of depression. In the subgroup of China and matched age and gender, NLR, PLR, and MLR were all elevated in depressed patients vs. controls. Individuals with PSD had higher NLR and MLR values as compared to non-PSD patients. Gender differences may have an effect on NLR values in patients with depression.
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Affiliation(s)
- Yanwei Cheng
- Department of Neurology, Neuroscience Centre, The First Hospital of Jilin University, Changchun, China
| | - Yiwen Wang
- Department of Neurology, Neuroscience Centre, The First Hospital of Jilin University, Changchun, China
| | - Xiangyi Wang
- Department of Neurology, Neuroscience Centre, The First Hospital of Jilin University, Changchun, China
| | - Zhuoya Jiang
- Department of Neurology, Neuroscience Centre, The First Hospital of Jilin University, Changchun, China
| | - Lijun Zhu
- China-Japan Union Hospital of Jilin University, Changchun, China
| | - Shaokuan Fang
- Department of Neurology, Neuroscience Centre, The First Hospital of Jilin University, Changchun, China
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49
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Roman C, Vivi E, Di Benedetto B. Morphological Features of Astrocytes in Health and Neuropsychiatric Disorders. ADVANCES IN NEUROBIOLOGY 2021; 26:75-92. [PMID: 34888831 DOI: 10.1007/978-3-030-77375-5_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Astroglial cells actively partner with several cell types to regulate the arrangement of neuronal circuits both in the developing and adult brain. Morphological features of astroglial cells strongly impact their functional interactions, thereby supporting the hypothesis that aberrancies in glial morphology may trigger the onset of neuropsychiatric disorders. Thus, understanding the factors which modulate astroglial shapes and the development of tools to examine them may help to gain valuable insights about the role of astroglia in physiological and pathological brain states.Here, we present a collection of representative review and original articles describing the major morphological features which define different subtypes of glial cells and emphasize a high degree of heterogeneity typical of these cell types, besides neurons. Furthermore, we offer an overview about first in vitro and in vivo evidences, which highlight an altered morphology of glial cells in brains of psychiatric patients and animal models of neuropsychiatric disorders.
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Affiliation(s)
- Celia Roman
- Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany
| | - Eugenia Vivi
- Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany
| | - Barbara Di Benedetto
- Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany. .,Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany.
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50
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Tran AA, De Smet M, Grant GD, Khoo TK, Pountney DL. Investigating the Convergent Mechanisms between Major Depressive Disorder and Parkinson's Disease. Complex Psychiatry 2021; 6:47-61. [PMID: 34883500 DOI: 10.1159/000512657] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 10/23/2020] [Indexed: 12/21/2022] Open
Abstract
Major depressive disorder (MDD) affects more than cognition, having a temporal relationship with neuroinflammatory pathways of Parkinson's disease (PD). Although this association is supported by epidemiological and clinical studies, the underlying mechanisms are unclear. Microglia and astrocytes play crucial roles in the pathophysiology of both MDD and PD. In PD, these cells can be activated by misfolded forms of the protein α-synuclein to release cytokines that can interact with multiple different physiological processes to produce depressive symptoms, including monoamine transport and availability, the hypothalamus-pituitary axis, and neurogenesis. In MDD, glial cell activation can be induced by peripheral inflammatory agents that cross the blood-brain barrier and/or c-Fos signalling from neurons. The resulting neuroinflammation can cause neurodegeneration due to oxidative stress and glutamate excitotoxicity, contributing to PD pathology. Astrocytes are another major link due to their recognized role in the glymphatic clearance mechanism. Research suggesting that MDD causes astrocytic destruction or structural atrophy highlights the possibility that accumulation of α-synuclein in the brain is facilitated as the brain cannot adequately clear the protein aggregates. This review examines research into the overlapping pathophysiology of MDD and PD with particular focus on the roles of glial cells and neuroinflammation.
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Affiliation(s)
- Angela A Tran
- School of Medical Science, Griffith University, Southport, Queensland, Australia.,School of Medicine, Griffith University, Southport, Queensland, Australia
| | - Myra De Smet
- School of Medical Science, Griffith University, Southport, Queensland, Australia
| | - Gary D Grant
- School of Pharmacy and Pharmacology, Griffith University, Southport, Queensland, Australia
| | - Tien K Khoo
- School of Medicine, Griffith University, Southport, Queensland, Australia.,Menzies Health Institute Queensland, Griffith University, Southport, Queensland, Australia.,School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia
| | - Dean L Pountney
- School of Medical Science, Griffith University, Southport, Queensland, Australia
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