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Yamaoka K, Nozaki K, Zhu M, Terai H, Kobayashi K, Ito H, Matsumata M, Takemoto H, Ikeda S, Sotomaru Y, Mori T, Aizawa H, Hashimoto K. Neuron-non-neuron electrical coupling networks are involved in chronic stress-induced electrophysiological changes in lateral habenular neurons. J Physiol 2025; 603:2713-2740. [PMID: 40168081 PMCID: PMC12072243 DOI: 10.1113/jp287286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 02/20/2025] [Indexed: 04/03/2025] Open
Abstract
The lateral habenula (LHb) is a key brain structure that receives input from higher brain regions and regulates monoaminergic activity. LHb hyperactivity has been implicated in the pathophysiology of depression, but the electrophysiological mechanisms underlying this hyperactivity remain poorly understood. To address this issue, we investigated how chronic stress alters the firing properties of LHb neurons in a mouse model of chronic social defeat. Whole-cell recordings were conducted from LHb neurons in the mouse acute brain slices. LHb neurons exhibited two types of rebound depolarizing potentials (RDPs) after the offset of hyperpolarization: short-RDPs (lasting <400 ms) and long-RDPs (order of seconds). Stress-susceptible mice showed a significantly reduced occurrence of long-RDPs, whereas spike firing in response to depolarizing current injections remained unchanged. Both short- and long-RDPs were triggered by T-type voltage-dependent Ca2+ channels and shortened by small-conductance Ca2+-activated K+ (SK) channels. The prolonged depolarizing phase of long-RDPs was mediated by cyclic nucleotide-gated (CNG) channels, which were activated via electrical coupling formed between neurons and non-neuronal cells. Whole-cell recording using an internal solution including a gap junction-permeable dye revealed that neurons formed dye coupling with non-neuronal cells, including oligodendrocytes and/or oligodendrocyte precursor cells. RNA-sequencing and genome editing experiments suggested that Cnga4, a CNG channel subtype, was the primary candidate for the long depolarizing phase of long-RDP, and its expression was decreased in the stress-susceptible mice. These findings suggest that stress-dependent changes in the firing activity of neurons are regulated by neuron-non-neuron networks formed in the LHb. KEY POINTS: Mouse lateral habenular (LHb) neurons exhibit short (<400 ms) rebound depolarizing potentials (short-RDPs) or long-RDPs (order of seconds) (long-RDPs) after the offset of hyperpolarization. The incidence of long-RDP neurons is significantly reduced in mice susceptible to chronic social defeat stress. The long depolarizing phase of long-RDPs is mediated by cyclic nucleotide-gated (CNG) channels, which are activated in non-neuronal cells via gap junctions. The expression of Cnga4, the gene encoding a subtype of the CNG channel, is decreased in the stress-susceptible mice. These results help us understand the mechanisms underlying stress-induced electrophysiological changes in LHb neurons and the functional roles of neuron-non-neuron networks for these neurons.
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Affiliation(s)
- Kenji Yamaoka
- Department of Neurophysiology, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Kanako Nozaki
- Department of Neurobiology, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Meina Zhu
- Department of Neurobiology, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Haruhi Terai
- Department of Neurobiology, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Kenta Kobayashi
- Section of Viral Vector DevelopmentNational Institute for Physiological SciencesOkazakiJapan
| | - Hikaru Ito
- Department of Neurobiology, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Miho Matsumata
- Department of Neurobiology, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Hidenori Takemoto
- Department of Neurobiology, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Shinya Ikeda
- Natural Science Center for Basic Research and DevelopmentHiroshima UniversityHiroshimaJapan
| | - Yusuke Sotomaru
- Natural Science Center for Basic Research and DevelopmentHiroshima UniversityHiroshimaJapan
| | - Tetsuji Mori
- Department of Biological Regulation, School of Health Science, Faculty of MedicineTottori UniversityYonagoJapan
| | - Hidenori Aizawa
- Department of Neurobiology, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Kouichi Hashimoto
- Department of Neurophysiology, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
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Xu N, He Y, Wei YN, Bai L, Wang L. Possible antidepressant mechanism of acupuncture: targeting neuroplasticity. Front Neurosci 2025; 19:1512073. [PMID: 40018358 PMCID: PMC11865234 DOI: 10.3389/fnins.2025.1512073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 02/03/2025] [Indexed: 03/01/2025] Open
Abstract
Major depressive disorder (MDD) is a highly prevalent and severely disabling psychiatric disorder that decreases quality of life and imposes substantial economic burden. Acupuncture has emerged as an effective adjunctive treatment for depression, it regulates neurotransmitters involved in mood regulation and modulates the activity of specific brain regions associated with emotional processing, as evidenced by neuroimaging and biochemical studies. Despite these insights, the precise neuroplastic mechanisms through which acupuncture exerts its antidepressant effects remain not fully elucidated. This review aims to summarize the current knowledge on acupuncture's modulation of neuroplasticity in depression, with a focus on the neuroplasticity-based targets associated with acupuncture's antidepressant effects. We encapsulate two decades of research into the neurobiological mechanisms underpinning the efficacy of acupuncture in treating depression. Additionally, we detail the acupoints and electroacupuncture parameters used in the treatment of depression to better serve clinical application.
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Affiliation(s)
- Ning Xu
- Department of First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yue He
- Department of First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yong-Nan Wei
- Department of First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lu Bai
- Department of First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Long Wang
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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Meng F, Wang J, Wang L, Zou W. Glucose metabolism impairment in major depressive disorder. Brain Res Bull 2025; 221:111191. [PMID: 39788458 DOI: 10.1016/j.brainresbull.2025.111191] [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: 10/14/2024] [Revised: 12/26/2024] [Accepted: 01/02/2025] [Indexed: 01/12/2025]
Abstract
Major depressive disorder (MDD) is a common mental disorder with chronic tendencies that seriously affect regular work, life, and study. However, its exact pathogenesis remains unclear. Patients with MDD experience systemic and localized impairments in glucose metabolism throughout the disease course, disrupting various processes such as glucose uptake, glycoprotein transport, glycolysis, the tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). These impairments may result from mechanisms including insulin resistance, hyperglycemia-induced damage, oxidative stress, astrocyte abnormalities, and mitochondrial dysfunction, leading to insufficient energy supply, altered synaptic plasticity, neuronal cell death, and functional and structural damage to reward networks. These mechanical changes contribute to the pathogenesis of MDD and severely interfere with the prognosis. Herein, we summarized the impairment of glucose metabolism and its pathophysiological mechanisms in patients with MDD. In addition, we briefly discussed potential pharmacological interventions for glucose metabolism to alleviate MDD, including glucagon-like peptide-1 receptor agonists, metformin, topical insulin, liraglutide, and pioglitazone, to encourage the development of new therapeutics.
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Affiliation(s)
- Fanhao Meng
- The Graduate School, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China
| | - Jing Wang
- The Graduate School, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China
| | - Long Wang
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China.
| | - Wei Zou
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China.
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Cheong E, Lee CJ. Gliotransmission in physiologic and pathologic conditions. HANDBOOK OF CLINICAL NEUROLOGY 2025; 209:93-116. [PMID: 40122634 DOI: 10.1016/b978-0-443-19104-6.00003-6] [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: 03/25/2025]
Abstract
This chapter explores the roles of gliotransmission in physiologic and pathologic conditions, including psychiatric and neurologic disorders. Gliotransmission, facilitated by astrocytes through the release of gliotransmitters such as glutamate, d-serine, and GABA, regulates neuronal activity and synaptic transmission. Under physiologic conditions, astrocytic gliotransmission maintains the balance of tonic excitation and inhibition, influencing synaptic plasticity and cognitive functions. In psychiatric disorders, the chapter examines how dysregulated gliotransmission contributes to major depression and schizophrenia. In major depression, changes in astrocytic glutamate and adenosine signaling impact mood regulation and cognitive functions. Schizophrenia involves complex astrocyte-neuron interactions, with dysregulated astrocytic activity affecting synaptic function and contributing to symptoms. The chapter also delves into neurologic disorders. In Alzheimer disease, aberrant GABA release from reactive astrocytes impairs memory and cognitive functions. Parkinson disease features alterations in glutamatergic and GABAergic systems, affecting motor and nonmotor symptoms. Epilepsy involves a disruption in the balance between excitatory and inhibitory neurotransmission, with astrocytic GABA accumulation helping to maintain neuronal stability. Autism spectrum disorder (ASD) is linked to imbalances in glutamatergic and GABAergic neurotransmission, underlying sensory, cognitive, and social impairments. Overall, the chapter underscores the pivotal role of gliotransmission in maintaining neural homeostasis and highlights its potential as a therapeutic target in various disorders.
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Affiliation(s)
- Eunji Cheong
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
| | - C Justin Lee
- Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea.
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Snijders GJLJ, Gigase FAJ. Neuroglia in mood disorders. HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:287-302. [PMID: 40148049 DOI: 10.1016/b978-0-443-19102-2.00010-7] [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
Multiple lines of evidence indicate that mood disorders, such as major depressive and bipolar disorder, are associated with abnormalities in neuroglial cells. This chapter discusses the existing literature investigating the potential role of astrocytes, oligodendrocytes, and microglia in mood pathology. We will describe evidence from in vivo imaging, postmortem, animal models based on (stress) paradigms that mimic depressive-like behavior, and biomarker studies in blood and cerebrospinal fluid in patients with mood disorders. The effect of medication used in the treatment of mood disorders, such as antidepressants and lithium, on glial function is discussed. Lastly, we highlight the most relevant findings about potential deficiencies in glia-glia crosstalk in mood disorders. Overall, decreased astrocyte and oligodendrocyte density and expression and microglial changes in homeostatic functions have frequently been put forward in MDD pathology. Studies of BD report similar findings to some extent; however, the evidence is less well established. Together, these findings are suggestive of reduced glial cell function leading to potential white matter abnormalities, glutamate dysregulation, disrupted neuronal functioning, and neurotransmission. However, more research is required to better understand the exact mechanisms underlying glial cell contributions to mood disorder development.
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Affiliation(s)
- Gijsje J L J Snijders
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
| | - Frederieke A J Gigase
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Fang Y, Pan H, Zhu H, Wang H, Ye M, Ren J, Peng J, Li J, Lu X, Huang C. Intranasal LAG3 antibody infusion induces a rapid antidepressant effect via the hippocampal ERK1/2-BDNF signaling pathway in chronically stressed mice. Neuropharmacology 2024; 259:110118. [PMID: 39153731 DOI: 10.1016/j.neuropharm.2024.110118] [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: 06/04/2024] [Revised: 08/05/2024] [Accepted: 08/14/2024] [Indexed: 08/19/2024]
Abstract
The decline of microglia in the dentate gyrus is a new phenomenon that may explain the pathogenesis of depression, and reversing this decline has an antidepressant effect. The development of strategies that restore the function of dentate gyrus microglia in under stressful conditions is becoming a new focus. Lymphocyte-activating gene-3 (LAG3) is an immune checkpoint expressed by immune cells including microglia. One of its functions is to suppress the expansion of immune cells. In a recent study, chronic systemic administration of a LAG3 antibody that readily penetrates the brain was reported to reverse chronic stress-induced hippocampal microglia decline and depression-like behaviors. We showed here that a single intranasal infusion of a LAG3 antibody (In-LAG3 Ab) reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in a dose-dependent manner, which was accompanied by an increase in brain-derived neurotrophic factor (BDNF) in the dentate gyrus. Infusion of an anti-BDNF antibody into the dentate gyrus, construction of knock-in mice with the BDNF Val68Met allele, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of In-LAG3 Ab. Activation of extracellular signal-regulated kinase1/2 (ERK1/2) is required for the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and BDNF decrease in the dentate gyrus. Moreover, both inhibition and depletion of microglia prevented the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and impairment of ERK1/2-BDNF signaling in the dentate gyrus. These results suggest that In-LAG3 Ab exhibits an antidepressant effect through microglia-mediated activation of ERK1/2 and synthesis of BDNF in the dentate gyrus.
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Affiliation(s)
- Yunli Fang
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Hainan Pan
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Haojie Zhu
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Hanxiao Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Minxiu Ye
- Department of Pharmacy, Kunshan Hospital of Traditional Chinese Medicine, #388 Zuchongzhi South Road, Kunshan, Suzhou, 215300, China
| | - Jie Ren
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Jie Peng
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Jinxin Li
- Department of Pharmacy, Changzhou Geriatric Hospital Affiliated to Soochow University, Changzhou No. 7 People's Hospital, #288 Yanling East Road, Changzhou 223000, Jiangsu, China
| | - Xu Lu
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China.
| | - Chao Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China.
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Pan Y, Xiang L, Zhu T, Wang H, Xu Q, Liao F, He J, Wang Y. Prefrontal cortex astrocytes in major depressive disorder: exploring pathogenic mechanisms and potential therapeutic targets. J Mol Med (Berl) 2024; 102:1355-1369. [PMID: 39276178 DOI: 10.1007/s00109-024-02487-9] [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: 04/14/2024] [Revised: 08/20/2024] [Accepted: 09/06/2024] [Indexed: 09/16/2024]
Abstract
Major depressive disorder (MDD) is a prevalent mental health condition characterized by persistent feelings of sadness and hopelessness, affecting millions globally. The precise molecular mechanisms underlying MDD remain elusive, necessitating comprehensive investigations. Our study integrates transcriptomic analysis, functional assays, and computational modeling to explore the molecular landscape of MDD, focusing on the DLPFC. We identify key genomic alterations and co-expression modules associated with MDD, highlighting potential therapeutic targets. Functional enrichment and protein-protein interaction analyses emphasize the role of astrocytes in MDD progression. Machine learning is employed to develop a predictive model for MDD risk assessment. Single-cell and spatial transcriptomic analyses provide insights into cell type-specific expression patterns, particularly regarding astrocytes. We have identified significant genomic alterations and co-expression modules associated with MDD in the DLPFC. Key genes involved in neuroactive ligand-receptor interaction pathways, notably in astrocytes, have been highlighted. Additionally, we developed a predictive model for MDD risk assessment based on selected key genes. Single-cell and spatial transcriptomic analyses underscored the role of astrocytes in MDD. Virtual screening of compounds targeting GPR37L1, KCNJ10, and PPP1R3C proteins has identified potential therapeutic candidates. In summary, our comprehensive approach enhances the understanding of MDD's molecular underpinnings and offers promising opportunities for advancing therapeutic interventions, ultimately aiming to alleviate the burden of this debilitating mental health condition. KEY MESSAGES: Our investigation furnishes insightful revelations concerning the dysregulation of astrocyte-associated processes in MDD. We have pinpointed specific genes, namely KCNJ10, PPP1R3C, and GPR37L1, as potential candidates warranting further exploration and therapeutic intervention. We incorporate a virtual screening of small molecule compounds targeting KCNJ10, PPP1R3C, and GPR37L1, presenting a promising trajectory for drug discovery in MDD.
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Affiliation(s)
- Yarui Pan
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Lan Xiang
- Department of Gynecology, Anhui Maternal and Child Health Hospital, Hefei, 230012, China
| | - Tingting Zhu
- Department of Gynecology, Anhui Maternal and Child Health Hospital, Hefei, 230012, China
| | - Haiyan Wang
- Department of Gynecology, Anhui Maternal and Child Health Hospital, Hefei, 230012, China
| | - Qi Xu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Faxue Liao
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, 230000, China.
- Anhui Public Health Clinical Center, The First Affiliated Hospital of Anhui Medical University, Xinzhan District, No. 100 Huaihai Avenue, Hefei, 230000, China.
| | - Juan He
- Department of Gynecology, Anhui Maternal and Child Health Hospital, Hefei, 230012, China.
| | - Yongquan Wang
- Anhui Public Health Clinical Center, The First Affiliated Hospital of Anhui Medical University, Xinzhan District, No. 100 Huaihai Avenue, Hefei, 230000, China.
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Liu Y, Fu X, Zhao X, Cui R, Yang W. The role of exercise-related FNDC5/irisin in depression. Front Pharmacol 2024; 15:1461995. [PMID: 39484160 PMCID: PMC11524886 DOI: 10.3389/fphar.2024.1461995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 10/03/2024] [Indexed: 11/03/2024] Open
Abstract
The complexity of depression presents a significant challenge to traditional treatment methods, such as medication and psychotherapy. Recent studies have shown that exercise can effectively reduce depressive symptoms, offering a new alternative for treating depression. However, some depressed patients are unable to engage in regular physical activity due to age, physical limitations, and other factors. Therefore, pharmacological agents that mimic the effects of exercise become a potential treatment option. A newly discovered myokine, irisin, which is produced during exercise via cleavage of its precursor protein fibronectin type III domain-containing protein 5 (FNDC5), plays a key role in regulating energy metabolism, promoting adipose tissue browning, and improving insulin resistance. Importantly, FNDC5 can promote neural stem cell differentiation, enhance neuroplasticity, and improve mood and cognitive function. This review systematically reviews the mechanisms of action of exercise in the treatment of depression, outlines the physiology of exercise-related irisin, explores possible mechanisms of irisin's antidepressant effects. The aim of this review is to encourage future research and clinical applications of irisin in the prevention and treatment of depression.
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Affiliation(s)
- Yaqi Liu
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Xiying Fu
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin, China
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Xing Zhao
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Yang
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin, China
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Zhang AY, Elias E, Manners MT. Sex-dependent astrocyte reactivity: Unveiling chronic stress-induced morphological changes across multiple brain regions. Neurobiol Dis 2024; 200:106610. [PMID: 39032799 PMCID: PMC11500746 DOI: 10.1016/j.nbd.2024.106610] [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: 05/28/2024] [Revised: 07/08/2024] [Accepted: 07/16/2024] [Indexed: 07/23/2024] Open
Abstract
Chronic stress is a major precursor to various neuropsychiatric disorders and is linked with increased inflammation in the brain. However, the bidirectional association between inflammation and chronic stress has yet to be fully understood. Astrocytes are one of the key inflammatory regulators in the brain, and the morphological change in reactive astrocytes serves as an important indicator of inflammation. In this study, we evaluated the sex-specific astrocyte response to chronic stress or systemic inflammation in key brain regions associated with mood disorders. We conducted the unpredictable chronic mild stress (UCMS) paradigm to model chronic stress, or lipopolysaccharide (LPS) injection to model systemic inflammation. To evaluate stress-induced morphological changes in astrocyte complexity, we measured GFAP fluorescent intensity for astrocyte expression, branch bifurcation by quantifying branch points and terminal points, branch arborization by conducting Sholl analysis, and calculated the ramification index. Our analysis indicated that chronic stress-induced morphological changes in astrocytes in all brain regions investigated. The effects of chronic stress were region and sex specific. Notably, females had greater stress or inflammation-induced astrocyte activation in the hypothalamus (HYPO), CA1, CA3, and amygdala (AMY) than males. These findings indicate that chronic stress induces astrocyte activation that may drive sex and region-specific effects in females, potentially contributing to sex-dependent mechanisms of disease.
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Affiliation(s)
- Ariel Y Zhang
- Department of Biological and Biomedical Sciences, Rowan University, Glassboro, NJ 08028, USA.
| | - Elias Elias
- Department of Biological and Biomedical Sciences, Rowan University, Glassboro, NJ 08028, USA.
| | - Melissa T Manners
- Department of Biological and Biomedical Sciences, Rowan University, Glassboro, NJ 08028, USA.
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Wang JY, Ren P, Cui LY, Duan JY, Chen HL, Zeng ZR, Li YF. Astrocyte-specific activation of sigma-1 receptors in mPFC mediates the faster onset antidepressant effect by inhibiting NF-κB-induced neuroinflammation. Brain Behav Immun 2024; 120:256-274. [PMID: 38852761 DOI: 10.1016/j.bbi.2024.06.008] [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: 04/01/2024] [Revised: 05/29/2024] [Accepted: 06/06/2024] [Indexed: 06/11/2024] Open
Abstract
Major depressive disorder (MDD) is a global health burden characterized by persistent low mood, deprivation of pleasure, recurrent thoughts of death, and physical and cognitive deficits. The current understanding of the pathophysiology of MDD is lacking, resulting in few rapid and effective antidepressant therapies. Recent studies have pointed to the sigma-1 (σ-1) receptor as a potential rapid antidepressant target; σ-1 agonists have shown promise in a variety of preclinical depression models. Hypidone hydrochloride (YL-0919), an independently developed antidepressant by our institute with faster onset of action and low rate of side effects, has recently emerged as a highly selective σ-1 receptor agonist; however, its underlying astrocyte-specific mechanism is unknown. In this study, we investigated the effect of YL-0919 treatment on gene expression in the prefrontal cortex of depressive-like mice by single-cell RNA sequencing. Furthermore, we knocked down σ-1 receptors on astrocytes in the medial prefrontal cortex of mice to explore the effects of YL-0919 on depressive-like behavior and neuroinflammation in mice. Our results demonstrated that astrocyte-specific knockdown of σ-1 receptor resulted in depressive-like behavior in mice, which was reversed by YL-0919 administration. In addition, astrocytic σ-1 receptor deficiency led to activation of the NF-κB inflammatory pathway, and crosstalk between reactive astrocytes and activated microglia amplified neuroinflammation, exacerbating stress-induced neuronal apoptosis. Furthermore, the depressive-like behavior induced by astrocyte-specific knockdown of the σ-1 receptor was improved by a selective NF-κB inhibitor, JSH-23, in mice. Our study not only reaffirms the σ-1 receptor as a key target of the faster antidepressant effect of YL-0919, but also contributes to the development of astrocytic σ-1 receptor-based novel drugs.
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Affiliation(s)
- Jing-Ya Wang
- Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Peng Ren
- Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
| | - Lin-Yu Cui
- Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing, 100850, China
| | - Jing-Yao Duan
- Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing, 100850, China
| | - Hong-Lei Chen
- Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Zhi-Rui Zeng
- Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 561113, China
| | - Yun-Feng Li
- Beijing Institute of Basic Medical Sciences, Beijing, 100850, China; Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing, 100850, China.
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Rasheed M, Tahir A, Maazouzi M, Wang H, Li Y, Chen Z, Deng Y. Interplay of miRNAs and molecular pathways in spaceflight-induced depression: Insights from a rat model using simulated complex space environment. FASEB J 2024; 38:e23831. [PMID: 39037540 DOI: 10.1096/fj.202400420rr] [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: 02/26/2024] [Revised: 06/30/2024] [Accepted: 07/08/2024] [Indexed: 07/23/2024]
Abstract
Depression is a significant concern among astronauts, yet the molecular mechanisms underlying spaceflight-induced depression remain poorly understood. MicroRNAs (miRNAs) have emerged as potential regulators of neuropsychiatric disorders, including depression, but their specific role in space-induced depression remains unexplored. This study aimed to elucidate the involvement of candidate miRNAs (miR-455-3p, miR-206-3p, miR-132-3p, miR-16-5p, miR-124-3p, and miR-145-3p) and their interaction with differentially expressed genes (DEGs) in the neurobiology of spaceflight-induced depressive behavior. Using a simulated space environmental model (SCSE) for 21 days, depressive behavior was induced in rats, and candidate miRNA expressions and DEGs in the cortex region were analyzed through qRT-PCR and HPLC, respectively. Results showed that SCSE-exposed rats exhibited depressive behaviors, including anhedonia, increased immobility, and anxiousness compared to controls. Further analysis revealed increased hydrogen peroxide levels and decreased superoxide dismutase levels in the SCSE group, indicating abnormal oxidative stress in the cerebral cortex. Moreover, miRNA analysis demonstrated significant upregulation of miR-455-3p, miR-206-3p, miR-132-3p, and miR-16-5p expression. Among the DEGs identified, the in silico analysis highlighted their involvement in crucial pathways such as glutamatergic signaling, GABA synaptic pathway, and calcium signaling, implicating their role in spaceflight-induced depression. Protein-protein interaction analysis identified hub genes, including DLG4, DLG3, GRIN1, GRIN2B, GRIN2A, SYNGAP1, DLGAP1, GRIK2, and GRIN3A, impacting neuronal dysfunction functions in the cortex region of SCSE depressive rats. DLG4 emerged as a core gene regulated by miR-455-3p and miR-206-3p. Overall, this study underscores the potential of miRNAs as biomarkers for mood disorders and neurological abnormalities associated with spaceflight, advancing health sciences, and space health care.
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Affiliation(s)
- Madiha Rasheed
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing, People's Republic of China
| | - Adnan Tahir
- Department of Biology, College of Science, Sultan Qaboos University, Muscat, Oman
| | - Mohamed Maazouzi
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing, People's Republic of China
| | - Han Wang
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing, People's Republic of China
| | - Yumeng Li
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing, People's Republic of China
| | - Zixuan Chen
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing, People's Republic of China
| | - Yulin Deng
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Medical Technology, Beijing Institute of Technology, Beijing, People's Republic of China
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12
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Li C, Shao X, Zhang S, Wang Y, Jin K, Yang P, Lu X, Fan X, Wang Y. scRank infers drug-responsive cell types from untreated scRNA-seq data using a target-perturbed gene regulatory network. Cell Rep Med 2024; 5:101568. [PMID: 38754419 PMCID: PMC11228399 DOI: 10.1016/j.xcrm.2024.101568] [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: 05/05/2023] [Revised: 12/27/2023] [Accepted: 04/21/2024] [Indexed: 05/18/2024]
Abstract
Cells respond divergently to drugs due to the heterogeneity among cell populations. Thus, it is crucial to identify drug-responsive cell populations in order to accurately elucidate the mechanism of drug action, which is still a great challenge. Here, we address this problem with scRank, which employs a target-perturbed gene regulatory network to rank drug-responsive cell populations via in silico drug perturbations using untreated single-cell transcriptomic data. We benchmark scRank on simulated and real datasets, which shows the superior performance of scRank over existing methods. When applied to medulloblastoma and major depressive disorder datasets, scRank identifies drug-responsive cell types that are consistent with the literature. Moreover, scRank accurately uncovers the macrophage subpopulation responsive to tanshinone IIA and its potential targets in myocardial infarction, with experimental validation. In conclusion, scRank enables the inference of drug-responsive cell types using untreated single-cell data, thus providing insights into the cellular-level impacts of therapeutic interventions.
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Affiliation(s)
- Chengyu Li
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314103, China
| | - Xin Shao
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314103, China.
| | - Shujing Zhang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Yingchao Wang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Kaiyu Jin
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314103, China
| | - Penghui Yang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314103, China
| | - Xiaoyan Lu
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Xiaohui Fan
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314103, China; Jinhua Institute of Zhejiang University, Jinhua 321299, China; Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
| | - Yi Wang
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; National Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314103, China.
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13
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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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14
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Engler-Chiurazzi E. B cells and the stressed brain: emerging evidence of neuroimmune interactions in the context of psychosocial stress and major depression. Front Cell Neurosci 2024; 18:1360242. [PMID: 38650657 PMCID: PMC11033448 DOI: 10.3389/fncel.2024.1360242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/25/2024] [Indexed: 04/25/2024] Open
Abstract
The immune system has emerged as a key regulator of central nervous system (CNS) function in health and in disease. Importantly, improved understanding of immune contributions to mood disorders has provided novel opportunities for the treatment of debilitating stress-related mental health conditions such as major depressive disorder (MDD). Yet, the impact to, and involvement of, B lymphocytes in the response to stress is not well-understood, leaving a fundamental gap in our knowledge underlying the immune theory of depression. Several emerging clinical and preclinical findings highlight pronounced consequences for B cells in stress and MDD and may indicate key roles for B cells in modulating mood. This review will describe the clinical and foundational observations implicating B cell-psychological stress interactions, discuss potential mechanisms by which B cells may impact brain function in the context of stress and mood disorders, describe research tools that support the investigation of their neurobiological impacts, and highlight remaining research questions. The goal here is for this discussion to illuminate both the scope and limitations of our current understanding regarding the role of B cells, stress, mood, and depression.
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Affiliation(s)
- Elizabeth Engler-Chiurazzi
- Department of Neurosurgery and Neurology, Clinical Neuroscience Research Center, Tulane Brain Institute, Tulane University School of Medicine, New Orleans, LA, United States
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15
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Ciubuc-Batcu MT, Stapelberg NJC, Headrick JP, Renshaw GMC. A mitochondrial nexus in major depressive disorder: Integration with the psycho-immune-neuroendocrine network. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166920. [PMID: 37913835 DOI: 10.1016/j.bbadis.2023.166920] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/06/2023] [Accepted: 10/09/2023] [Indexed: 11/03/2023]
Abstract
Nervous system processes, including cognition and affective state, fundamentally rely on mitochondria. Impaired mitochondrial function is evident in major depressive disorder (MDD), reflecting cumulative detrimental influences of both extrinsic and intrinsic stressors, genetic predisposition, and mutation. Glucocorticoid 'stress' pathways converge on mitochondria; oxidative and nitrosative stresses in MDD are largely mitochondrial in origin; both initiate cascades promoting mitochondrial DNA (mtDNA) damage with disruptions to mitochondrial biogenesis and tryptophan catabolism. Mitochondrial dysfunction facilitates proinflammatory dysbiosis while directly triggering immuno-inflammatory activation via released mtDNA, mitochondrial lipids and mitochondria associated membranes (MAMs), further disrupting mitochondrial function and mitochondrial quality control, promoting the accumulation of abnormal mitochondria (confirmed in autopsy studies). Established and putative mechanisms highlight a mitochondrial nexus within the psycho-immune neuroendocrine (PINE) network implicated in MDD. Whether lowering neuronal resilience and thresholds for disease, or linking mechanistic nodes within the MDD pathogenic network, impaired mitochondrial function emerges as an important risk, a functional biomarker, providing a therapeutic target in MDD. Several treatment modalities have been demonstrated to reset mitochondrial function, which could benefit those with MDD.
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Affiliation(s)
- M T Ciubuc-Batcu
- Griffith University School of Medicine and Dentistry, Australia; Gold Coast Health, Queensland, Australia
| | - N J C Stapelberg
- Bond University Faculty of Health Sciences and Medicine, Australia; Gold Coast Health, Queensland, Australia
| | - J P Headrick
- Griffith University School of Pharmacy and Medical Science, Australia
| | - G M C Renshaw
- Hypoxia and Ischemia Research Unit, Griffith University, School of Health Sciences and Social Work, Australia.
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16
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Tani H, Moxon-Emre I, Forde NJ, Neufeld NH, Bingham KS, Whyte EM, Meyers BS, Alexopoulos GS, Hoptman MJ, Rothschild AJ, Uchida H, Flint AJ, Mulsant BH, Voineskos AN. Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication. Brain Imaging Behav 2024; 18:117-129. [PMID: 37917311 PMCID: PMC10844359 DOI: 10.1007/s11682-023-00807-0] [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] [Accepted: 10/01/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites. METHODS Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups. RESULTS Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25-1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71-2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate. CONCLUSIONS Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.
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Affiliation(s)
- Hideaki Tani
- Centre for Addiction and Mental Health and Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Iska Moxon-Emre
- Centre for Addiction and Mental Health and Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Natalie J Forde
- Centre for Addiction and Mental Health and Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
| | - Nicholas H Neufeld
- Centre for Addiction and Mental Health and Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Kathleen S Bingham
- University Health Network and Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Ellen M Whyte
- Department of Psychiatry, University of Pittsburgh School of Medicine and UPMC Western Psychiatric Hospital, Pittsburgh, PA, USA
| | - Barnett S Meyers
- Department of Psychiatry, Weill Medical College of Cornell University and New York Presbyterian Hospital, White Plains, NY, USA
| | - George S Alexopoulos
- Department of Psychiatry, Weill Medical College of Cornell University and New York Presbyterian Hospital, White Plains, NY, USA
| | - Matthew J Hoptman
- Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA
- Department of Psychiatry, New York University School of Medicine, New York, NY, USA
| | - Anthony J Rothschild
- University of Massachusetts Medical School and UMass Memorial Health Care, Worcester, MA, USA
| | - Hiroyuki Uchida
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Alastair J Flint
- University Health Network and Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Benoit H Mulsant
- Centre for Addiction and Mental Health and Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Aristotle N Voineskos
- Centre for Addiction and Mental Health and Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada.
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17
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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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18
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Réus GZ, Manosso LM, Quevedo J, Carvalho AF. Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities. Neurosci Biobehav Rev 2023; 155:105425. [PMID: 37852343 DOI: 10.1016/j.neubiorev.2023.105425] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/16/2023] [Accepted: 10/12/2023] [Indexed: 10/20/2023]
Abstract
Notwithstanding advances in understanding the pathophysiology of major depressive disorder (MDD), no single mechanism can explain all facets of this disorder. An expanding body of evidence indicates a putative role for the inflammatory response. Several meta-analyses showed an increase in systemic peripheral inflammatory markers in individuals with MDD. Numerous conditions and circumstances in the modern world may promote chronic systemic inflammation through mechanisms, including alterations in the gut microbiota. Peripheral cytokines may reach the brain and contribute to neuroinflammation through cellular, humoral, and neural pathways. On the other hand, antidepressant drugs may decrease peripheral levels of inflammatory markers. Anti-inflammatory drugs and nutritional strategies that reduce inflammation also could improve depressive symptoms. The present study provides a critical review of recent advances in the role of inflammation in the pathophysiology of MDD. Furthermore, this review discusses the role of glial cells and the main drivers of changes associated with neuroinflammation. Finally, we highlight possible novel neurotherapeutic targets for MDD that could exert antidepressant effects by modulating inflammation.
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Affiliation(s)
- Gislaine Z Réus
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil.
| | - Luana M Manosso
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - João Quevedo
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil; Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - André F Carvalho
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
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19
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Verkhratsky A, Butt A, Li B, Illes P, Zorec R, Semyanov A, Tang Y, Sofroniew MV. Astrocytes in human central nervous system diseases: a frontier for new therapies. Signal Transduct Target Ther 2023; 8:396. [PMID: 37828019 PMCID: PMC10570367 DOI: 10.1038/s41392-023-01628-9] [Citation(s) in RCA: 127] [Impact Index Per Article: 63.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 08/15/2023] [Accepted: 08/22/2023] [Indexed: 10/14/2023] Open
Abstract
Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.
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Affiliation(s)
- Alexei Verkhratsky
- International Joint Research Centre on Purinergic Signalling/School of 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.
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, LT-01102, Vilnius, Lithuania.
| | - Arthur Butt
- Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | - 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/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, 04109, Leipzig, Germany
| | - Robert Zorec
- Celica Biomedical, Lab Cell Engineering, Technology Park, 1000, Ljubljana, Slovenia
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
| | - Alexey Semyanov
- Department of Physiology, Jiaxing University College of Medicine, 314033, Jiaxing, China
| | - Yong Tang
- International Joint Research Centre on Purinergic Signalling/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
- Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, China.
| | - Michael V Sofroniew
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
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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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Deng Q, Gupta A, Jeon H, Nam JH, Yilmaz AS, Chang W, Pietrzak M, Li L, Kim HJ, Chung D. graph-GPA 2.0: improving multi-disease genetic analysis with integration of functional annotation data. Front Genet 2023; 14:1079198. [PMID: 37501720 PMCID: PMC10370274 DOI: 10.3389/fgene.2023.1079198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 06/21/2023] [Indexed: 07/29/2023] Open
Abstract
Genome-wide association studies (GWAS) have successfully identified a large number of genetic variants associated with traits and diseases. However, it still remains challenging to fully understand the functional mechanisms underlying many associated variants. This is especially the case when we are interested in variants shared across multiple phenotypes. To address this challenge, we propose graph-GPA 2.0 (GGPA 2.0), a statistical framework to integrate GWAS datasets for multiple phenotypes and incorporate functional annotations within a unified framework. Our simulation studies showed that incorporating functional annotation data using GGPA 2.0 not only improves the detection of disease-associated variants, but also provides a more accurate estimation of relationships among diseases. Next, we analyzed five autoimmune diseases and five psychiatric disorders with the functional annotations derived from GenoSkyline and GenoSkyline-Plus, along with the prior disease graph generated by biomedical literature mining. For autoimmune diseases, GGPA 2.0 identified enrichment for blood-related epigenetic marks, especially B cells and regulatory T cells, across multiple diseases. Psychiatric disorders were enriched for brain-related epigenetic marks, especially the prefrontal cortex and the inferior temporal lobe for bipolar disorder and schizophrenia, respectively. In addition, the pleiotropy between bipolar disorder and schizophrenia was also detected. Finally, we found that GGPA 2.0 is robust to the use of irrelevant and/or incorrect functional annotations. These results demonstrate that GGPA 2.0 can be a powerful tool to identify genetic variants associated with each phenotype or those shared across multiple phenotypes, while also promoting an understanding of functional mechanisms underlying the associated variants.
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Affiliation(s)
- Qiaolan Deng
- The Interdisciplinary PhD Program in Biostatistics, The Ohio State University, Columbus, OH, United States
| | - Arkobrato Gupta
- The Interdisciplinary PhD Program in Biostatistics, The Ohio State University, Columbus, OH, United States
| | - Hyeongseon Jeon
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Jin Hyun Nam
- Division of Big Data Science, Korea University Sejong Campus, Sejong, Republic of Korea
| | - Ayse Selen Yilmaz
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, United States
| | - Won Chang
- Division of Statistics and Data Science, University of Cincinnati, Cincinnati, OH, United States
| | - Maciej Pietrzak
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, United States
| | - Lang Li
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, United States
| | - Hang J. Kim
- Division of Statistics and Data Science, University of Cincinnati, Cincinnati, OH, United States
| | - Dongjun Chung
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
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22
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Corrigan M, O'Rourke A, Moran B, Fletcher J, Harkin A. Inflammation in the pathogenesis of depression: a disorder of neuroimmune origin. Neuronal Signal 2023; 7:NS20220054. [PMID: 37457896 PMCID: PMC10345431 DOI: 10.1042/ns20220054] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 06/22/2023] [Accepted: 06/23/2023] [Indexed: 07/18/2023] Open
Abstract
There are several hypotheses concerning the underlying pathophysiological mechanisms of major depression, which centre largely around adaptive changes in neuronal transmission and plasticity, neurogenesis, and circuit and regional connectivity. The immune and endocrine systems are commonly implicated in driving these changes. An intricate interaction of stress hormones, innate immune cells and the actions of soluble mediators of immunity within the nervous system is described as being associated with the symptoms of depression. Bridging endocrine and immune processes to neurotransmission and signalling within key cortical and limbic brain circuits are critical to understanding depression as a disorder of neuroimmune origins. Emergent areas of research include a growing recognition of the adaptive immune system, advances in neuroimaging techniques and mechanistic insights gained from transgenic animals. Elucidation of glial-neuronal interactions is providing additional avenues into promising areas of research, the development of clinically relevant disease models and the discovery of novel therapies. This narrative review focuses on molecular and cellular mechanisms that are influenced by inflammation and stress. The aim of this review is to provide an overview of our current understanding of depression as a disorder of neuroimmune origin, focusing on neuroendocrine and neuroimmune dysregulation in depression pathophysiology. Advances in current understanding lie in pursuit of relevant biomarkers, as the potential of biomarker signatures to improve clinical outcomes is yet to be fully realised. Further investigations to expand biomarker panels including integration with neuroimaging, utilising individual symptoms to stratify patients into more homogenous subpopulations and targeting the immune system for new treatment approaches will help to address current unmet clinical need.
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Affiliation(s)
- Myles Corrigan
- Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences and Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
- Transpharmation Ireland, Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
| | - Aoife M. O'Rourke
- School of Biochemistry and Immunology, Trinity Biosciences Institute, Trinity College, Dublin, Ireland
| | - Barry Moran
- School of Biochemistry and Immunology, Trinity Biosciences Institute, Trinity College, Dublin, Ireland
| | - Jean M. Fletcher
- School of Biochemistry and Immunology, Trinity Biosciences Institute, Trinity College, Dublin, Ireland
| | - Andrew Harkin
- Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences and Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
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23
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Maitra M, Mitsuhashi H, Rahimian R, Chawla A, Yang J, Fiori LM, Davoli MA, Perlman K, Aouabed Z, Mash DC, Suderman M, Mechawar N, Turecki G, Nagy C. Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes. Nat Commun 2023; 14:2912. [PMID: 37217515 PMCID: PMC10203145 DOI: 10.1038/s41467-023-38530-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 05/05/2023] [Indexed: 05/24/2023] Open
Abstract
Major depressive disorder (MDD) is a common, heterogenous, and potentially serious psychiatric illness. Diverse brain cell types have been implicated in MDD etiology. Significant sexual differences exist in MDD clinical presentation and outcome, and recent evidence suggests different molecular bases for male and female MDD. We evaluated over 160,000 nuclei from 71 female and male donors, leveraging new and pre-existing single-nucleus RNA-sequencing data from the dorsolateral prefrontal cortex. Cell type specific transcriptome-wide threshold-free MDD-associated gene expression patterns were similar between the sexes, but significant differentially expressed genes (DEGs) diverged. Among 7 broad cell types and 41 clusters evaluated, microglia and parvalbumin interneurons contributed the most DEGs in females, while deep layer excitatory neurons, astrocytes, and oligodendrocyte precursors were the major contributors in males. Further, the Mic1 cluster with 38% of female DEGs and the ExN10_L46 cluster with 53% of male DEGs, stood out in the meta-analysis of both sexes.
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Affiliation(s)
- Malosree Maitra
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Haruka Mitsuhashi
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Reza Rahimian
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Anjali Chawla
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Jennie Yang
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Laura M Fiori
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Maria Antonietta Davoli
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Kelly Perlman
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Zahia Aouabed
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Deborah C Mash
- Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Matthew Suderman
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Naguib Mechawar
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada.
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada.
| | - Corina Nagy
- McGill Group for Suicide Studies, Douglas Institute, Verdun, QC, Canada.
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
- Douglas Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada.
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24
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Gao SQ, Chen JQ, Zhou HY, Luo L, Zhang BY, Li MT, He HY, Chen C, Guo Y. Thrombospondin1 mimics rapidly relieve depression via Shank3 dependent uncoupling between dopamine D1 and D2 receptors. iScience 2023; 26:106488. [PMID: 37091229 PMCID: PMC10119609 DOI: 10.1016/j.isci.2023.106488] [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: 12/10/2020] [Revised: 06/17/2022] [Accepted: 03/18/2023] [Indexed: 04/25/2023] Open
Abstract
Deficits in astrocyte function contribute to major depressive disorder (MDD) and suicide, but the therapeutic effect of directly reactivating astrocytes for depression remains unclear. Here, specific gains and losses of astrocytic cell functions in the medial prefrontal cortex (mPFC) bidirectionally regulate depression-like symptoms. Remarkably, recombinant human Thrombospondin-1 (rhTSP1), an astrocyte-secreted protein, exerted rapidly antidepressant-like actions through tyrosine hydroxylase (Th)/dopamine (DA)/dopamine D2 receptors (D2Rs) pathways, but not dopamine D1 receptors (D1Rs), which was dependent on SH3 and multiple ankyrin repeat domains 3 (Shank3) in the mPFC. TSP1 in the mPFC might have potential as a target for treating clinical depression.
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Affiliation(s)
- Shuang-Qi Gao
- Departments of Neurosurgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China
- Corresponding author
| | - Jun-Quan Chen
- Departments of Neurosurgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China
| | - Hai-Yun Zhou
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lun Luo
- Departments of Neurosurgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China
| | - Bao-Yu Zhang
- Departments of Neurosurgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China
| | - Man-Ting Li
- Departments of Neurosurgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China
| | - Hai-Yong He
- Departments of Neurosurgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China
| | - Chuan Chen
- Departments of Neurosurgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China
- Corresponding author
| | - Ying Guo
- Departments of Neurosurgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China
- Corresponding author
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25
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Battistella I, Cutarelli A, Zasso J, Clerici M, Sala C, Marcatili M, Conti L. Cortical Astrocyte Progenitors and Astrocytes from Human Pluripotent Stem Cells. J Pers Med 2023; 13:jpm13030538. [PMID: 36983719 PMCID: PMC10051695 DOI: 10.3390/jpm13030538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/12/2023] [Accepted: 03/16/2023] [Indexed: 03/19/2023] Open
Abstract
Astrocytes coordinate several homeostatic processes of the central nervous system and play essential roles for normal brain development and response to disease conditions. Protocols for the conversion of human induced pluripotent stem cells (hiPSCs) into mature astrocytes have opened to the generation of in vitro systems to explore astrocytes’ functions in living human cell contexts and patient-specific settings. In this study, we present an optimized monolayer procedure to commit hiPSC-derived cortical progenitors into enriched populations of cortical astrocyte progenitor cells (CX APCs) that can be further amplified and efficiently differentiated into mature astrocytes. Our optimized system provides a valid tool to explore the role of these cells in neurodevelopmental and neuropsychiatric diseases, opening it up to applications in drug development and biomarkers discovery/validation.
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Affiliation(s)
- Ingrid Battistella
- Laboratory of Stem Cell Biology, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123 Trento, Italy
| | - Alessandro Cutarelli
- Laboratory of Stem Cell Biology, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123 Trento, Italy
| | - Jacopo Zasso
- Laboratory of Stem Cell Biology, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123 Trento, Italy
| | - Massimo Clerici
- Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy
- Department of Mental Health, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Carlo Sala
- National Research Council Neuroscience Institute, 20100 Milan, Italy
| | - Matteo Marcatili
- Department of Mental Health, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Luciano Conti
- Laboratory of Stem Cell Biology, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123 Trento, Italy
- Correspondence: ; Tel.: +39-0461-285216
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26
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Sharma S, Ma W, Ressler KJ, Anderson T, Li DC, Jin P, Gourley SL, Qin Z. Dysregulation of Prefrontal Oligodendrocyte Lineage Cells Across Mouse Models of Adversity and Human Major Depressive Disorder Oligodendrocyte dysregulation in mouse models of stress and MDD. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.09.531989. [PMID: 36945653 PMCID: PMC10028961 DOI: 10.1101/2023.03.09.531989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
Animal models of adversity have yielded few molecular mechanisms that translate to human stress-related diseases like major depressive disorder (MDD). We congruently analyze publicly available bulk-tissue transcriptomic data from prefrontal cortex (PFC) in multiple mouse models of adversity and in MDD. We apply strategies, to quantify cell-type specific enrichment from bulk-tissue transcriptomics, utilizing reference single cell RNA sequencing datasets. These analyses reveal conserved patterns of oligodendrocyte (OL) dysregulation across animal experiments, including susceptibility to social defeat, acute cocaine withdrawal, chronic unpredictable stress, early life stress, and adolescent social isolation. Using unbiased methodologies, we further identify a dysregulation of layer 6 neurons that associate with deficits in goal-directed behavior after social isolation. Human post-mortem brains with MDD show similar OL transcriptome changes in Brodmann Areas 8/9 in both male and female patients. This work assesses cell type involvement in an unbiased manner from differential expression analyses across animal models of adversity and human MDD and finds a common signature of OL dysfunction in the frontal cortex.
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Affiliation(s)
- Sumeet Sharma
- Department of Psychiatry and Behavioral Sciences, Emory University
| | - Wenjing Ma
- Department of Computer Science, Emory University
| | | | | | - Dan. C. Li
- Graduate Program in Neuroscience, Emory University
| | - Peng Jin
- Department of Human Genetics, Emory University
| | - Shannon L. Gourley
- Graduate Program in Neuroscience, Emory University
- Department of Pediatrics, Emory University School of Medicine; Yerkes National Primate Research Center
- Children’s Healthcare of Atlanta
| | - Zhaohui Qin
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University
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27
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Hyper-inflammation of astrocytes in patients of major depressive disorder: Evidence from serum astrocyte-derived extracellular vesicles. Brain Behav Immun 2023; 109:51-62. [PMID: 36587855 DOI: 10.1016/j.bbi.2022.12.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 12/03/2022] [Accepted: 12/16/2022] [Indexed: 12/31/2022] Open
Abstract
Astrocyte-derived extracellular vesicles (ADEs) allow the in vivo probing of the inflammatory status of astrocytes practical. Serum sample and ADEs were used to test the inflammatory hypothesis in 70 patients with major depressive disorder (MDD) and 70 matched healthy controls (HCs). In serum, tumor necrosis factor α (TNF-α) and interleukin (IL)-17A were significantly increased, where as IL-12p70 was significantly reduced in the MDD patients compared with HCs. In ADEs, all inflammatory markers (Interferon-γ, IL-12p70, IL-1β, IL-2, IL-4, IL-6, TNF-α, and IL-17A) except IL-10 were significantly increased in the MDD patients, the Hedge's g values of elevated inflammatory markers varied from 0.48 to 1.07. However, there were no differences of all inflammatory markers whether in serum or ADEs between MDD-drug free and medicated subgroups. The association of inflammatory biomarkers between ADEs and serum did not reach statistically significance after multi-comparison correction neither in the HCs nor MDD patients. The spearman coefficients between inflammatory factors and clinical characteristics in the MDD patients, such as onset age, disease course, current episode duration, and severity of depression, were nonsignificant after multi-comparison correction. In the receiver operating characteristic curves analysis, the corrected partial area under the curve (pAUC) of each inflammatory markers in ADEs ranged from 0.522 to 0.696, and the combination of these inflammatory factors achieved a high pAUC (>0.9). Our findings support the inflammatory glial hypothesis of depression, and suggests that in human ADEs could be a useful tool to probe the in vivo astrocyte status.
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28
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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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29
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Zeb S, Ye H, Liu Y, Du HP, Guo Y, Zhu YM, Ni Y, Zhang HL, Xu Y. Necroptotic kinases are involved in the reduction of depression-induced astrocytes and fluoxetine's inhibitory effects on necroptotic kinases. Front Pharmacol 2023; 13:1060954. [PMID: 36686688 PMCID: PMC9847570 DOI: 10.3389/fphar.2022.1060954] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/29/2022] [Indexed: 01/06/2023] Open
Abstract
The role of astrocytes in major depressive disorder has received great attention. Increasing evidence indicates that decreased astrocyte numbers in the hippocampus may be associated with depression, but the role of necroptosis in depression is unknown. Here, in a chronic unpredictable mild stress (CUMS) mouse model and a corticosterone (Cort)-induced human astrocyte injury model in vitro, we found that mice treated with chronic unpredictable mild stress for 3-5 weeks presented depressive-like behaviors and reduced body weight gain, accompanied by a reduction in astrocytes and a decrease in astrocytic brain-derived neurotropic factors (BDNF), by activation of necroptotic kinases, including RIPK1 (receptor-interacting protein kinase 1)/p-RIPK1, RIPK3 (receptor-interacting protein kinase 3)/p-RIPK3 and MLKL (mixed lineage kinase domain-like protein)/p-MLKL, and by upregulation of inflammatory cytokines in astrocytes of the mouse hippocampus. In contrast, necroptotic kinase inhibitors suppressed Cort-induced necroptotic kinase activation, reduced astrocytes, astrocytic necroptosis and dysfunction, and decreased Cort-mediated inflammatory cytokines in astrocytes. Treatment with fluoxetine (FLX) for 5 weeks improved chronic unpredictable mild stress-induced mouse depressive-like behaviors; simultaneously, fluoxetine inhibited depression-induced necroptotic kinase activation, reversed the reduction in astrocytes and astrocytic necroptosis and dysfunction, decreased inflammatory cytokines and upregulated brain-derived neurotropic factors and 5-HT1A levels. Furthermore, fluoxetine had no direct inhibitory effect on receptor-interacting protein kinase 1 phosphorylation. The combined administration of fluoxetine and necroptotic kinase inhibitors further reduced corticosterone-induced astrocyte injury. In conclusion, the reduction in astrocytes caused by depressive-like models in vivo and in vitro may be associated with the activation of necroptotic kinases and astrocytic necroptosis, and fluoxetine exerts an antidepressive effect by indirectly inhibiting receptor-interacting protein kinase 1-mediated astrocytic necroptosis.
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Affiliation(s)
- Salman Zeb
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China,Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou, China,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China
| | - Huan Ye
- Department of Neurology, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Yuan Liu
- Department of Neurology, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Hua-Ping Du
- Department of Neurology, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China
| | - Yi Guo
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China,Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou, China,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China
| | - Yong-Ming Zhu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China,Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou, China,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China
| | - Yong Ni
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China,Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou, China,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China,Pain Department, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Hui-Ling Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China,Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou, China,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China,*Correspondence: Hui-Ling Zhang, ; Yuan Xu,
| | - Yuan Xu
- Department of Neurology, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, China,*Correspondence: Hui-Ling Zhang, ; Yuan Xu,
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30
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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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Tallarico M, Pisano M, Leo A, Russo E, Citraro R, De Sarro G. Antidepressant Drugs for Seizures and Epilepsy: Where do we Stand? Curr Neuropharmacol 2023; 21:1691-1713. [PMID: 35761500 PMCID: PMC10514547 DOI: 10.2174/1570159x20666220627160048] [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: 02/26/2022] [Revised: 06/13/2022] [Accepted: 06/18/2022] [Indexed: 11/22/2022] Open
Abstract
People with epilepsy (PWE) are more likely to develop depression and both these complex chronic diseases greatly affect health-related quality of life (QOL). This comorbidity contributes to the deterioration of the QOL further than increasing the severity of epilepsy worsening prognosis. Strong scientific evidence suggests the presence of shared pathogenic mechanisms. The correct identification and management of these factors are crucial in order to improve patients' QOL. This review article discusses recent original research on the most common pathogenic mechanisms of depression in PWE and highlights the effects of antidepressant drugs (ADs) against seizures in PWE and animal models of seizures and epilepsy. Newer ADs, such as selective serotonin reuptake inhibitors (SRRI) or serotonin-noradrenaline reuptake inhibitors (SNRI), particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine may lead to improvements in epilepsy severity whereas the use of older tricyclic antidepressant (TCAs) can increase the occurrence of seizures. Most of the data demonstrate the acute effects of ADs in animal models of epilepsy while there is a limited number of studies about the chronic antidepressant effects in epilepsy and epileptogenesis or on clinical efficacy. Much longer treatments are needed in order to validate the effectiveness of these new alternatives in the treatment and the development of epilepsy, while further clinical studies with appropriate protocols are warranted in order to understand the real potential contribution of these drugs in the management of PWE (besides their effects on mood).
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Affiliation(s)
- Martina Tallarico
- System and Applied Pharmacology, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Maria Pisano
- System and Applied Pharmacology, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Antonio Leo
- System and Applied Pharmacology, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Emilio Russo
- System and Applied Pharmacology, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Rita Citraro
- System and Applied Pharmacology, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Giovambattista De Sarro
- System and Applied Pharmacology, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
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Jiang J, Li L, Lin J, Hu X, Zhao Y, Sweeney JA, Gong Q. A voxel-based meta-analysis comparing medication-naive patients of major depression with treated longer-term ill cases. Neurosci Biobehav Rev 2023; 144:104991. [PMID: 36476776 DOI: 10.1016/j.neubiorev.2022.104991] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 11/19/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
Structural neuroimaging studies have identified brain areas implicated in the pathogenesis of major depressive disorder (MDD). However, findings have been inconsistent, potentially due to variable illness duration and effects of antidepressant treatment. Using a meta-analytic approach, we compared gray matter (GM) volumes in patients grouped by medication status (naïve and treated) and illness duration (early course and long-term ill) to identify potential treatment and illness duration effects on brain structure. A total of 70 studies were included, including 3682 patients and 3469 controls. The pooled analysis found frontal, temporal and limbic regions with decreased GM volume in MDD patients. Additional analyses indicated that larger GM volume in the right striatum and smaller GM volume in the right precuneus are likely to be associated with drug effects, while smaller GM volume in the right temporal gyrus may correlate with longer illness duration. Similar GM decreases in bilateral medial frontal cortex between patient subgroups suggest that this alteration may persist over the course of illness and drug treatment.
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Affiliation(s)
- Jing Jiang
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China; Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, Sichuan, China
| | - Lei Li
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China; Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Jinping Lin
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China; Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, Sichuan, China
| | - Xinyu Hu
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Youjin Zhao
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China; Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - John A Sweeney
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China; Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA
| | - Qiyong Gong
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China; Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen 361021, Fujian, China.
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Asnakew S, Legas G, Belete A, Admasu FT, Yitbarek GY, Aytenew TM, Demise B, Alemu EM, Alemu MA, Bayih WA, Feleke DG, Chanie ES, Birhane BM, Kefale D. Cognitive adverse effects of epilepsy and its predictors attending outpatient department of South Gondar zone hospitals, Amhara Region, Ethiopia 2020 /2021. PLoS One 2022; 17:e0278908. [PMID: 36490273 PMCID: PMC9733840 DOI: 10.1371/journal.pone.0278908] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Epilepsy is the most common neurologic disorder which is further complicated by neurobehavioral co-morbidities, cognitive impairment, psychiatric disorders, and social problems. However, assessments of cognitive status of epileptic patients are far too low during clinical visits. This calls for early neuropsychological assessment soon after the diagnosis of epilepsy for a better treatment plan and outcome for epileptic patients. OBJECTIVE This study aimed to assess the cognitive adverse effects of epilepsy and its predictors attending outpatient departments of South Gondar Zone hospitals Amhara region Ethiopia 2020/2021. METHODS A multi-center institutional-based cross-sectional study was conducted. A total of 509 respondents were included with a response rate of 93.9%. Previously adapted pretested structured questionnaire was used containing, socio-demographic, clinical, and seizure related factors. Mini-Mental State Examination (MMSE) was used to measure cognitive impairment. A systematic random sampling technique was applied. Data were entered into Epi data version 4.4.2 then exported to SPSS version 24 for analysis. Descriptive statistics, bivariable and multivariable binary logistic regressions with odds ratios and 95% confidence interval were employed. The level of significance of association was determined at a p-value < 0.05. RESULTS Prevalence of cognitive impairment in this study was 69.2% (95%CI; 65.4, 73.1). Rural residents (AOR = 4.16,95%CI, 1.99,8.67), respondents who couldn't read and write (AOR = 2.62, 95%CI; 1.24, 5.5,) longer duration of seizure disorder (AOR = 4.59,95%CI; 2.01,10.52), taking combined Phenobarbital and Phenytoin (AOR = 4.69,95%CI; 1.88,11.69), having history of head injury (AOR = 3.29,95%CI;1.30,8.32), having depression (AOR = 4.76,95%CI;2.83,7.98), and anxiety (AOR = 3.11,95%CI; 1.58,6.12) were significantly associated with cognitive impairment. CONCLUSIONS Prevalence of cognitive impairment in this study was high. Regular neuropsychiatric assessment of patients with epilepsy should be encouraged especially for those participants with longer durations of illness, who are rural residents, who take combined Phenobarbital and Phenytoin, participants who had a history of head injury, depression, and anxiety.
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Affiliation(s)
- Sintayehu Asnakew
- Department of Psychiatry, School of Medicine, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
- * E-mail:
| | - Getasew Legas
- Department of Psychiatry, School of Medicine, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Amsalu Belete
- Department of Psychiatry, School of Medicine, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Fitalew Tadele Admasu
- Department of Biomedical Sciences, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Getachew Yideg Yitbarek
- Department of Biomedical Sciences, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Tigabu Munye Aytenew
- Department of Nursing, College of Health Science Debre Tabor University, Debre Tabor, Ethiopia
| | - Biruk Demise
- Departments of Social and Population Health, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Eshetie Molla Alemu
- Departments of Social and Population Health, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Muluken Adela Alemu
- Departemnt of Pharmacy, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Wubet Alebachew Bayih
- Department of Pediatrics and Child Health and Neonatal Nursing, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Dejen Getaneh Feleke
- Department of Pediatrics and Child Health and Neonatal Nursing, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Ermias Sisay Chanie
- Department of Pediatrics and Child Health and Neonatal Nursing, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Binyam Munye Birhane
- Department of Pediatrics and Child Health and Neonatal Nursing, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Demewoz Kefale
- Department of Pediatrics and Child Health and Neonatal Nursing, College of Health Science, Debre Tabor University, Debre Tabor, Ethiopia
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Carrier M, Dolhan K, Bobotis BC, Desjardins M, Tremblay MÈ. The implication of a diversity of non-neuronal cells in disorders affecting brain networks. Front Cell Neurosci 2022; 16:1015556. [PMID: 36439206 PMCID: PMC9693782 DOI: 10.3389/fncel.2022.1015556] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 10/07/2022] [Indexed: 11/13/2022] Open
Abstract
In the central nervous system (CNS) neurons are classically considered the functional unit of the brain. Analysis of the physical connections and co-activation of neurons, referred to as structural and functional connectivity, respectively, is a metric used to understand their interplay at a higher level. A myriad of glial cell types throughout the brain composed of microglia, astrocytes and oligodendrocytes are key players in the maintenance and regulation of neuronal network dynamics. Microglia are the central immune cells of the CNS, able to affect neuronal populations in number and connectivity, allowing for maturation and plasticity of the CNS. Microglia and astrocytes are part of the neurovascular unit, and together they are essential to protect and supply nutrients to the CNS. Oligodendrocytes are known for their canonical role in axonal myelination, but also contribute, with microglia and astrocytes, to CNS energy metabolism. Glial cells can achieve this variety of roles because of their heterogeneous populations comprised of different states. The neuroglial relationship can be compromised in various manners in case of pathologies affecting development and plasticity of the CNS, but also consciousness and mood. This review covers structural and functional connectivity alterations in schizophrenia, major depressive disorder, and disorder of consciousness, as well as their correlation with vascular connectivity. These networks are further explored at the cellular scale by integrating the role of glial cell diversity across the CNS to explain how these networks are affected in pathology.
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Affiliation(s)
- Micaël Carrier
- Neurosciences Axis, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Kira Dolhan
- Department of Psychology, University of Victoria, Victoria, BC, Canada
- Department of Biology, University of Victoria, Victoria, BC, Canada
| | | | - Michèle Desjardins
- Department of Physics, Physical Engineering and Optics, Université Laval, Québec City, QC, Canada
- Oncology Axis, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
| | - Marie-Ève Tremblay
- Neurosciences Axis, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
- *Correspondence: Marie-Ève Tremblay,
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Alnafisah RS, Reigle J, Eladawi MA, O'Donovan SM, Funk AJ, Meller J, Mccullumsmith RE, Shukla R. Assessing the effects of antipsychotic medications on schizophrenia functional analysis: a postmortem proteome study. Neuropsychopharmacology 2022; 47:2033-2041. [PMID: 35354897 PMCID: PMC9556610 DOI: 10.1038/s41386-022-01310-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/01/2022] [Accepted: 03/11/2022] [Indexed: 12/15/2022]
Abstract
Antipsychotic drugs (APDs) are effective in treating positive symptoms of schizophrenia (SCZ). However, they have a substantial impact on postmortem studies. As most cohorts lack samples from drug-naive patients, many studies, rather than understanding SCZ pathophysiology, are analyzing the drug effects. We hypothesized that comparing SCZ-altered and APD-influenced signatures derived from the same cohort can provide better insight into SCZ pathophysiology. For this, we performed LCMS-based proteomics on dorsolateral prefrontal cortex (DLPFC) samples from control and SCZ subjects and used statistical approaches to identify SCZ-altered and APD-influenced proteomes, validated experimentally using independent cohorts and published datasets. Functional analysis of both proteomes was contrasted at the biological-pathway, cell-type, subcellular-synaptic, and drug-target levels. In silico validation revealed that the SCZ-altered proteome was conserved across several studies from the DLPFC and other brain areas. At the pathway level, SCZ influenced changes in homeostasis, signal-transduction, cytoskeleton, and dendrites, whereas APD influenced changes in synaptic-signaling, neurotransmitter-regulation, and immune-system processes. At the cell-type level, the SCZ-altered and APD-influenced proteomes were associated with two distinct striatum-projecting layer-5 pyramidal neurons regulating dopaminergic-secretion. At the subcellular synaptic level, compensatory pre- and postsynaptic events were observed. At the drug-target level, dopaminergic processes influenced the SCZ-altered upregulated-proteome, whereas nondopaminergic and a diverse array of non-neuromodulatory mechanisms influenced the downregulated-proteome. Previous findings were not independent of the APD effect and thus require re-evaluation. We identified a hyperdopaminergic cortex and drugs targeting the cognitive SCZ-symptoms and discussed their influence on SCZ pathology in the context of the cortico-striatal pathway.
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Affiliation(s)
- Rawan S Alnafisah
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - James Reigle
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA
| | | | - Sinead M O'Donovan
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Adam J Funk
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Jaroslaw Meller
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA
- Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH, USA
| | - Robert E Mccullumsmith
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
- Neurosciences Institute, ProMedica, Toledo, OH, USA
| | - Rammohan Shukla
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
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36
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Zhang X, Wolfinger A, Wu X, Alnafisah R, Imami A, Hamoud AR, Lundh A, Parpura V, McCullumsmith RE, Shukla R, O’Donovan SM. Gene Enrichment Analysis of Astrocyte Subtypes in Psychiatric Disorders and Psychotropic Medication Datasets. Cells 2022; 11:3315. [PMID: 36291180 PMCID: PMC9600295 DOI: 10.3390/cells11203315] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/17/2022] [Accepted: 10/20/2022] [Indexed: 11/26/2022] Open
Abstract
Astrocytes have many important functions in the brain, but their roles in psychiatric disorders and their responses to psychotropic medications are still being elucidated. Here, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, psychiatric diseases, and psychotropic medications (antipsychotics, antidepressants and mood stabilizers). We also carried out qPCR analyses and "look-up" studies to assess the chronic effects of these drugs on astrocyte marker gene expression. Our bioinformatic analysis identified gene enrichment of different astrocyte subtypes in psychiatric disorders. The highest level of enrichment was found in schizophrenia, supporting a role for astrocytes in this disorder. We also found differential enrichment of astrocyte subtypes associated with specific biological processes, highlighting the complex responses of astrocytes under pathological conditions. Enrichment of protein phosphorylation in astrocytes and disease was confirmed by biochemical analysis. Analysis of LINCS chemical perturbagen gene signatures also found that kinase inhibitors were highly discordant with astrocyte-SCZ associated gene signatures. However, we found that common gene enrichment of different psychotropic medications and astrocyte subtypes was limited. These results were confirmed by "look-up" studies and qPCR analysis, which also reported little effect of psychotropic medications on common astrocyte marker gene expression, suggesting that astrocytes are not a primary target of these medications. Conversely, antipsychotic medication does affect astrocyte gene marker expression in postmortem schizophrenia brain tissue, supporting specific astrocyte responses in different pathological conditions. Overall, this study provides a unique view of astrocyte subtypes and the effect of medications on astrocytes in disease, which will contribute to our understanding of their role in psychiatric disorders and offers insights into targeting astrocytes therapeutically.
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Affiliation(s)
- Xiaolu Zhang
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Alyssa Wolfinger
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Xiaojun Wu
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Rawan Alnafisah
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Ali Imami
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Abdul-rizaq Hamoud
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Anna Lundh
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
| | - Vladimir Parpura
- Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Robert E. McCullumsmith
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
- Promedica Neurosciences Institute, Toledo, OH 43606, USA
| | - Rammohan Shukla
- Department of Neurosciences, University of Toledo, Toledo, OH 43614, USA
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Prenatal SAMe Treatment Induces Changes in Brain Monoamines and in the Expression of Genes Related to Monoamine Metabolism in a Mouse Model of Social Hierarchy and Depression, Probably via an Epigenetic Mechanism. Int J Mol Sci 2022; 23:ijms231911898. [PMID: 36233200 PMCID: PMC9569718 DOI: 10.3390/ijms231911898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/25/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open
Abstract
Reduction in the levels of monoamines, such as serotonin and dopamine in the brain, were reported in patients and animals with depression. SAMe, a universal methyl donor and an epigenetic modulator, is successfully used as an adjunct treatment of depression. We previously found that prenatal treatment with SAMe of Submissive (Sub) mice that serve as a model for depression alleviated many of the behavioral depressive symptoms. In the present study, we treated pregnant Sub mice with 20 mg/kg of SAMe on days 12–15 of gestation and studied the levels of monoamines and the expression of genes related to monoamines metabolism in their prefrontal cortex (PFC) at the age of 3 months. The data were compared to normal saline-treated Sub mice that exhibit depressive-like symptoms. SAMe increased the levels of serotonin in the PFC of female Sub mice but not in males. The levels of 5-HIAA were not changed. SAMe increased the levels of dopamine and of DOPAC in males and females but increased the levels of HVA only in females. The levels of norepinephrine and its metabolite MHPG were unchanged. SAMe treatment changed the expression of several genes involved in the metabolism of these monoamines, also in a sex-related manner. The increase in several monoamines induced by SAMe in the PFC may explain the alleviation of depressive-like symptoms. Moreover, these changes in gene expression more than 3 months after treatment probably reflect the beneficial effects of SAMe as an epigenetic modulator in the treatment of depression.
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Smail MA, Chandrasena SS, Zhang X, Reddy V, Kelley C, Herman JP, Sherif M, McCullumsmith RE, Shukla R. Differential vulnerability of anterior cingulate cortex cell types to diseases and drugs. Mol Psychiatry 2022; 27:4023-4034. [PMID: 35754044 PMCID: PMC9875728 DOI: 10.1038/s41380-022-01657-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 05/29/2022] [Accepted: 06/01/2022] [Indexed: 02/07/2023]
Abstract
In psychiatric disorders, mismatches between disease states and therapeutic strategies are highly pronounced, largely because of unanswered questions regarding specific vulnerabilities of different cell types and therapeutic responses. Which cellular events (housekeeping or salient) are most affected? Which cell types succumb first to challenges, and which exhibit the strongest response to drugs? Are these events coordinated between cell types? How does disease and drug effect this coordination? To address these questions, we analyzed single-nucleus-RNAseq (sn-RNAseq) data from the human anterior cingulate cortex-a region involved in many psychiatric disorders. Density index, a metric for quantifying similarities and dissimilarities across functional profiles, was employed to identify common or salient functional themes across cell types. Cell-specific signatures were integrated with existing disease and drug-specific signatures to determine cell-type-specific vulnerabilities, druggabilities, and responsiveness. Clustering of functional profiles revealed cell types jointly participating in these events. SST and VIP interneurons were found to be most vulnerable, whereas pyramidal neurons were least. Overall, the disease state is superficial layer-centric, influences cell-specific salient themes, strongly impacts disinhibitory neurons, and influences astrocyte interaction with a subset of deep-layer pyramidal neurons. In absence of disease, drugs profiles largely recapitulate disease profiles, offering a possible explanation for drug side effects. However, in presence of disease, drug activities, are deep layer-centric and involve activating a distinct subset of deep-layer pyramidal neurons to circumvent the disease state's disinhibitory circuit malfunction. These findings demonstrate a novel application of sn-RNAseq data to explain drug and disease action at a systems level.
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Affiliation(s)
- Marissa A Smail
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA
- Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH, USA
| | | | - Xiaolu Zhang
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Vineet Reddy
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Craig Kelley
- Program in Biomedical Engineering, SUNY Downstate Health Science University, Brooklyn, NY, USA
| | - James P Herman
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA
- Veterans Affairs Medical Center, Cincinnati, OH, USA
- Department of Neurology, University of Cincinnati, Cincinnati, OH, USA
| | - Mohamed Sherif
- Department of Psychiatry and Human Behavior, Carney Institute for Brain Science, Brown University, Providence, RI, USA
| | - Robert E McCullumsmith
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
- Neurosciences Institute, ProMedica, Toledo, OH, USA
| | - Rammohan Shukla
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
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Zlomuzica A, Plank L, Dere E. A new path to mental disorders: Through gap junction channels and hemichannels. Neurosci Biobehav Rev 2022; 142:104877. [PMID: 36116574 DOI: 10.1016/j.neubiorev.2022.104877] [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: 01/31/2022] [Revised: 08/20/2022] [Accepted: 09/13/2022] [Indexed: 11/18/2022]
Abstract
Behavioral disturbances related to emotional regulation, reward processing, cognition, sleep-wake regulation and activity/movement represent core symptoms of most common mental disorders. Increasing empirical and theoretical evidence suggests that normal functioning of these behavioral domains relies on fine graded coordination of neural and glial networks which are maintained and modulated by intercellular gap junction channels and unapposed pannexin or connexin hemichannels. Dysfunctions in these networks might contribute to the development and maintenance of psychopathological and neurobiological features associated with mental disorders. Here we review and discuss the evidence indicating a prominent role of gap junction channel and hemichannel dysfunction in core symptoms of mental disorders. We further discuss how the increasing knowledge on intercellular gap junction channels and unapposed pannexin or connexin hemichannels in the brain might lead to deeper mechanistic insight in common mental disorders and to the development of novel treatment approaches. We further attempt to exemplify what type of future research on this topic could be integrated into multidimensional approaches to understand and cure mental disorders.
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Affiliation(s)
- Armin Zlomuzica
- Department of Behavioral and Clinical Neuroscience, Ruhr-University Bochum (RUB), Massenbergstraße 9-13, D-44787 Bochum, Germany.
| | - Laurin Plank
- Department of Behavioral and Clinical Neuroscience, Ruhr-University Bochum (RUB), Massenbergstraße 9-13, D-44787 Bochum, Germany
| | - Ekrem Dere
- Department of Behavioral and Clinical Neuroscience, Ruhr-University Bochum (RUB), Massenbergstraße 9-13, D-44787 Bochum, Germany; Sorbonne Université. Institut de Biologie Paris-Seine, (IBPS), Département UMR 8256: Adaptation Biologique et Vieillissement, UFR des Sciences de la Vie, Campus Pierre et Marie Curie, Bâtiment B, 9 quai Saint Bernard, F-75005 Paris, France.
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40
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Larsen NY, Vihrs N, Møller J, Sporring J, Tan X, Li X, Ji G, Rajkowska G, Sun F, Nyengaard JR. Layer III pyramidal cells in the prefrontal cortex reveal morphological changes in subjects with depression, schizophrenia, and suicide. Transl Psychiatry 2022; 12:363. [PMID: 36064829 PMCID: PMC9445178 DOI: 10.1038/s41398-022-02128-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 11/09/2022] Open
Abstract
Brodmann Area 46 (BA46) has long been regarded as a hotspot of disease pathology in individuals with schizophrenia (SCH) and major depressive disorder (MDD). Pyramidal neurons in layer III of the Brodmann Area 46 (BA46) project to other cortical regions and play a fundamental role in corticocortical and thalamocortical circuits. The AutoCUTS-LM pipeline was used to study the 3-dimensional structural morphology and spatial organization of pyramidal cells. Using quantitative light microscopy, we used stereology to calculate the entire volume of layer III in BA46 and the total number and density of pyramidal cells. Volume tensors estimated by the planar rotator quantified the volume, shape, and nucleus displacement of pyramidal cells. All of these assessments were carried out in four groups of subjects: controls (C, n = 10), SCH (n = 10), MDD (n = 8), and suicide subjects with a history of depression (SU, n = 11). SCH subjects had a significantly lower somal volume, total number, and density of pyramidal neurons when compared to C and tended to show a volume reduction in layer III of BA46. When comparing MDD subjects with C, the measured parameters were inclined to follow SCH, although there was only a significant reduction in pyramidal total cell number. While no morphometric differences were observed between SU and MDD, SU had a significantly higher total number of pyramidal cells and nucleus displacement than SCH. Finally, no differences in the spatial organization of pyramidal cells were found among groups. These results suggest that despite significant morphological alterations in layer III of BA46, which may impair prefrontal connections in people with SCH and MDD, the spatial organization of pyramidal cells remains the same across the four groups and suggests no defects in neuronal migration. The increased understanding of pyramidal cell biology may provide the cellular basis for symptoms and neuroimaging observations in SCH and MDD patients.
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Affiliation(s)
- Nick Y. Larsen
- grid.7048.b0000 0001 1956 2722Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark ,grid.7048.b0000 0001 1956 2722Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark ,Sino-Danish Center for Education and Research, Aarhus, Denmark ,grid.410726.60000 0004 1797 8419University of the Chinese Academy of Sciences, Beijing, China ,grid.5117.20000 0001 0742 471XCentre for Stochastic Geometry and Advanced Bioimaging, Aalborg University, Aarhus University and University of Copenhagen, Aarhus, Denmark
| | - Ninna Vihrs
- grid.5117.20000 0001 0742 471XDepartment of Mathematical Sciences, Aalborg University, Aalborg, Denmark
| | - Jesper Møller
- grid.5117.20000 0001 0742 471XCentre for Stochastic Geometry and Advanced Bioimaging, Aalborg University, Aarhus University and University of Copenhagen, Aarhus, Denmark ,grid.5117.20000 0001 0742 471XDepartment of Mathematical Sciences, Aalborg University, Aalborg, Denmark
| | - Jon Sporring
- grid.5117.20000 0001 0742 471XCentre for Stochastic Geometry and Advanced Bioimaging, Aalborg University, Aarhus University and University of Copenhagen, Aarhus, Denmark ,grid.5254.60000 0001 0674 042XDepartment of Computer Science, University of Copenhagen, Copenhagen, Denmark
| | - Xueke Tan
- grid.418856.60000 0004 1792 5640National Key Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China ,grid.418856.60000 0004 1792 5640Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xixia Li
- grid.5254.60000 0001 0674 042XDepartment of Computer Science, University of Copenhagen, Copenhagen, Denmark ,grid.418856.60000 0004 1792 5640National Key Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Gang Ji
- grid.5254.60000 0001 0674 042XDepartment of Computer Science, University of Copenhagen, Copenhagen, Denmark ,grid.418856.60000 0004 1792 5640National Key Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Grazyna Rajkowska
- grid.410721.10000 0004 1937 0407Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS USA
| | - Fei Sun
- Sino-Danish Center for Education and Research, Aarhus, Denmark ,grid.410726.60000 0004 1797 8419University of the Chinese Academy of Sciences, Beijing, China ,grid.418856.60000 0004 1792 5640National Key Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China ,grid.418856.60000 0004 1792 5640Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jens R. Nyengaard
- grid.7048.b0000 0001 1956 2722Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark ,Sino-Danish Center for Education and Research, Aarhus, Denmark ,grid.5117.20000 0001 0742 471XCentre for Stochastic Geometry and Advanced Bioimaging, Aalborg University, Aarhus University and University of Copenhagen, Aarhus, Denmark ,grid.154185.c0000 0004 0512 597XDepartment of Pathology, Aarhus University Hospital, Aarhus, Denmark
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Almasabi F, Alosaimi F, Corrales-Terrón M, Wolters A, Strikwerda D, Smit JV, Temel Y, Janssen MLF, Jahanshahi A. Post-Mortem Analysis of Neuropathological Changes in Human Tinnitus. Brain Sci 2022; 12:brainsci12081024. [PMID: 36009087 PMCID: PMC9406157 DOI: 10.3390/brainsci12081024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/26/2022] [Accepted: 07/28/2022] [Indexed: 12/04/2022] Open
Abstract
Tinnitus is the phantom perception of a sound, often accompanied by increased anxiety and depressive symptoms. Degenerative or inflammatory processes, as well as changes in monoaminergic systems, have been suggested as potential underlying mechanisms. Herein, we conducted the first post-mortem histopathological assessment to reveal detailed structural changes in tinnitus patients’ auditory and non-auditory brain regions. Tissue blocks containing the medial geniculate body (MGB), thalamic reticular nucleus (TRN), central part of the inferior colliculus (CIC), and dorsal and obscurus raphe nuclei (DRN and ROb) were obtained from tinnitus patients and matched controls. Cell density and size were assessed in Nissl-stained sections. Astrocytes and microglia were assessed using immunohistochemistry. The DRN was stained using antibodies raised against phenylalanine hydroxylase-8 (PH8) and tyrosine-hydroxylase (TH) to visualize serotonergic and dopaminergic cells, respectively. Cell density in the MGB and CIC of tinnitus patients was reduced, accompanied by a reduction in the number of astrocytes in the CIC only. Quantification of cell surface size did not reveal any significant difference in any of the investigated brain regions between groups. The number of PH8-positive cells was reduced in the DRN and ROb of tinnitus patients compared to controls, while the number of TH-positive cells remained unchanged in the DRN. These findings suggest that both neurodegenerative and inflammatory processes in the MGB and CIC underlie the neuropathology of tinnitus. Moreover, the reduced number of serotonergic cell bodies in tinnitus cases points toward a potential role of the raphe serotonergic system in tinnitus.
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Affiliation(s)
- Faris Almasabi
- Department of Neurosurgery, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands; (F.A.); (F.A.); (Y.T.)
- School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (M.C.-T.); (A.W.); (D.S.); (J.V.S.); (M.L.F.J.)
- Department of Physiology, Faculty of Medicine, King Khalid University, Abha 62529, Saudi Arabia
| | - Faisal Alosaimi
- Department of Neurosurgery, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands; (F.A.); (F.A.); (Y.T.)
- School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (M.C.-T.); (A.W.); (D.S.); (J.V.S.); (M.L.F.J.)
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Rabigh 25732, Saudi Arabia
| | - Minerva Corrales-Terrón
- School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (M.C.-T.); (A.W.); (D.S.); (J.V.S.); (M.L.F.J.)
| | - Anouk Wolters
- School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (M.C.-T.); (A.W.); (D.S.); (J.V.S.); (M.L.F.J.)
| | - Dario Strikwerda
- School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (M.C.-T.); (A.W.); (D.S.); (J.V.S.); (M.L.F.J.)
| | - Jasper V. Smit
- School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (M.C.-T.); (A.W.); (D.S.); (J.V.S.); (M.L.F.J.)
- Department of Ear, Nose, Throat, Head and Neck Surgery, Zuyderland Medical Center, 6419 PC Heerlen, The Netherlands
| | - Yasin Temel
- Department of Neurosurgery, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands; (F.A.); (F.A.); (Y.T.)
- School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (M.C.-T.); (A.W.); (D.S.); (J.V.S.); (M.L.F.J.)
| | - Marcus L. F. Janssen
- School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (M.C.-T.); (A.W.); (D.S.); (J.V.S.); (M.L.F.J.)
- Department of Clinical Neurophysiology, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands
| | - Ali Jahanshahi
- Department of Neurosurgery, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands; (F.A.); (F.A.); (Y.T.)
- School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (M.C.-T.); (A.W.); (D.S.); (J.V.S.); (M.L.F.J.)
- Correspondence:
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Liu J, Yang L, Li H, Cai Y, Feng J, Hu Z. Conditional ablation of protein tyrosine phosphatase receptor U in midbrain dopaminergic neurons results in reduced neuronal size. J Chem Neuroanat 2022; 124:102135. [DOI: 10.1016/j.jchemneu.2022.102135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 06/17/2022] [Accepted: 07/01/2022] [Indexed: 11/30/2022]
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Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway. Int J Mol Sci 2022; 23:ijms23137191. [PMID: 35806192 PMCID: PMC9266916 DOI: 10.3390/ijms23137191] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 02/05/2023] Open
Abstract
The neuroimmune mechanism underlying neuropathic pain has been extensively studied. Tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine that drives cytokine storm and stimulates a cascade of other cytokines in pain-related pathways, induces and modulates neuropathic pain by facilitating peripheral (primary afferents) and central (spinal cord) sensitization. Functionally, TNF-α controls the balance between cell survival and death by inducing an inflammatory response and two programmed cell death mechanisms (apoptosis and necroptosis). Necroptosis, a novel form of programmed cell death, is receiving increasing attraction and may trigger neuroinflammation to promote neuropathic pain. Chronic pain is often accompanied by adverse pain-associated emotional reactions and cognitive disorders. Overproduction of TNF-α in supraspinal structures such as the anterior cingulate cortex (ACC) and hippocampus plays an important role in pain-associated emotional disorders and memory deficits and also participates in the modulation of pain transduction. At present, studies reporting on the role of the TNF-α–necroptosis pathway in pain-related disorders are lacking. This review indicates the important research prospects of this pathway in pain modulation based on its role in anxiety, depression and memory deficits associated with other neurodegenerative diseases. In addition, we have summarized studies related to the underlying mechanisms of neuropathic pain mediated by TNF-α and discussed the role of the TNF-α–necroptosis pathway in detail, which may represent an avenue for future therapeutic intervention.
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44
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Transcriptome Profiling of the Dorsomedial Prefrontal Cortex in Suicide Victims. Int J Mol Sci 2022; 23:ijms23137067. [PMID: 35806070 PMCID: PMC9266666 DOI: 10.3390/ijms23137067] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/20/2022] [Accepted: 06/23/2022] [Indexed: 01/27/2023] Open
Abstract
The default mode network (DMN) plays an outstanding role in psychiatric disorders. Still, gene expressional changes in its major component, the dorsomedial prefrontal cortex (DMPFC), have not been characterized. We used RNA sequencing in postmortem DMPFC samples to investigate suicide victims compared to control subjects. 1400 genes differed using log2FC > ±1 and adjusted p-value < 0.05 criteria between groups. Genes associated with depressive disorder, schizophrenia and impaired cognition were strongly overexpressed in top differentially expressed genes. Protein−protein interaction and co-expressional networks coupled with gene set enrichment analysis revealed that pathways related to cytokine receptor signaling were enriched in downregulated, while glutamatergic synaptic signaling upregulated genes in suicidal individuals. A validated differentially expressed gene, which is known to be associated with mGluR5, was the N-terminal EF-hand calcium-binding protein 2 (NECAB2). In situ hybridization histochemistry and immunohistochemistry proved that NECAB2 is expressed in two different types of inhibitory neurons located in layers II-IV and VI, respectively. Our results imply extensive gene expressional alterations in the DMPFC related to suicidal behavior. Some of these genes may contribute to the altered mental state and behavior of suicide victims.
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45
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Ma X, Yang S, Zhang Z, Liu L, Shi W, Yang S, Li S, Cai X, Zhou Q. Rapid and sustained restoration of astrocytic functions by ketamine in depression model mice. Biochem Biophys Res Commun 2022; 616:89-94. [DOI: 10.1016/j.bbrc.2022.03.068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/14/2022] [Indexed: 11/16/2022]
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46
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Leung E, Lau EW, Liang A, de Dios C, Suchting R, Östlundh L, Masdeu JC, Fujita M, Sanches M, Soares JC, Selvaraj S. Alterations in brain synaptic proteins and mRNAs in mood disorders: a systematic review and meta-analysis of postmortem brain studies. Mol Psychiatry 2022; 27:1362-1372. [PMID: 35022529 DOI: 10.1038/s41380-021-01410-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 11/19/2021] [Accepted: 11/26/2021] [Indexed: 11/09/2022]
Abstract
The pathophysiological mechanisms underlying bipolar (BD) and major depressive disorders (MDD) are multifactorial but likely involve synaptic dysfunction and dysregulation. There are multiple synaptic proteins but three synaptic proteins, namely SNAP-25, PSD-95, and synaptophysin, have been widely studied for their role in synaptic function in human brain postmortem studies in BD and MDD. These studies have yielded contradictory results, possibly due to the small sample size and sourcing material from different cortical regions of the brain. We performed a systematic review and meta-analysis to understand the role of these three synaptic proteins and other synaptic proteins, messenger RNA (mRNA) and their regional localizations in BD and MDD. A systematic literature search was conducted and the review is reported in accordance with the MOOSE Guidelines. Meta-analysis was performed to compare synaptic marker levels between BD/MDD groups and controls separately. 1811 papers were identified in the literature search and screened against the preset inclusion and exclusion criteria. A total of 72 studies were screened in the full text, of which 47 were identified as eligible to be included in the systematic review. 24 of these 47 papers were included in the meta-analysis. The meta-analysis indicated that SNAP-25 protein levels were significantly lower in BD. On average, PSD-95 mRNA levels were lower in BD, and protein levels of SNAP-25, PSD-95, and syntaxin were lower in MDD. Localization analysis showed decreased levels of PSD-95 protein in the frontal cortex. We found specific alterations in synaptic proteins and RNAs in both BD and MDD. The review was prospectively registered online in PROSPERO international prospective register of systematic reviews, registration no. CRD42020196932.
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Affiliation(s)
- Edison Leung
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ethan W Lau
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Andi Liang
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Constanza de Dios
- Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Robert Suchting
- Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Linda Östlundh
- The National Medical Library, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Joseph C Masdeu
- Houston Methodist Neurological Institute, Houston, TX, USA.,Weill Cornell Medicine, New York, NY, USA
| | - Masahiro Fujita
- Weill Cornell Medicine, New York, NY, USA.,PET Core Facility, Houston Methodist Research Insitute, Houston, TX, USA
| | - Marsal Sanches
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jair C Soares
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Sudhakar Selvaraj
- McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA. .,Depression Research Program, Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
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47
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KILINÇ Ö, HIZAL M, ARISOY Ö, ÖZGEDİK N, KALAYCIOĞLU O. Alteration of cerebral perfusion and cortical thickness in depression episodes: a comparative MRI study. JOURNAL OF HEALTH SCIENCES AND MEDICINE 2022. [DOI: 10.32322/jhsm.993848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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48
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Glial Cell Abnormalities in Major Psychiatric Diseases: A Systematic Review of Postmortem Brain Studies. Mol Neurobiol 2022; 59:1665-1692. [PMID: 35013935 DOI: 10.1007/s12035-021-02672-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/25/2021] [Indexed: 10/19/2022]
Abstract
There have been a large number of reports about glial cell dysfunction being related to major psychiatric diseases such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). In this review, we provide an overview of postmortem studies analyzing the structural changes of glial cells in these three major psychiatric diseases, including the density, number and size of glial cells, and the expression of related markers. Up to May 1, 2021, 108 articles that met the inclusion criteria were identified by searching PubMed and Web of Science. Although most studies evaluating total glial cells did not show abnormalities in the brains of postmortem patients, astrocytes, microglial cells, and oligodendrocytes seem to have specific patterns of changes in each disease. For example, out of 20 studies that evaluated astrocyte markers in MDD, 11 studies found decreased astrocyte marker expression in MDD patients. Similarly, out of 25 studies evaluating oligodendrocyte markers in SCZ, 15 studies showed decreased expression of oligodendrocyte markers in different brain regions of SCZ patients. In addition, activated microglial cells were observed in patients with SCZ, BD, and MDD, but suicide may be a confounding factor for the observed effects. Although the data from the included studies were heterogeneous and this cannot be fully explained at present, it is likely that there are a variety of contributing factors, including the measured brain regions, methods of measurement, gender, age at time of death, and medications.
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49
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Bidirectional Relations Among Depression, Migraine, and Epilepsy: Do They Have an Impact on Their Response to Treatment? Curr Top Behav Neurosci 2021; 55:251-265. [PMID: 34964936 DOI: 10.1007/7854_2021_286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The evaluation and treatment of patients with epilepsy is not limited to the type of epilepsy, but it must incorporate the common comorbid neurologic, psychiatric, and medical disorders, as the latter can bare an impact on the course and response to treatment of the seizure disorder and vice versa. In this article we review the bidirectional relations among epilepsy and two of its most common comorbidities, mood disorders and migraine and examine the implications of these relations on the selection of therapies of these three disorders and their response to treatment. We also review the most salient common pathogenic mechanisms that may explain such relations.
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50
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Stenovec M, Li B, Verkhratsky A, Zorec R. Ketamine Action on Astrocytes Provides New Insights into Rapid Antidepressant Mechanisms. ADVANCES IN NEUROBIOLOGY 2021; 26:349-365. [PMID: 34888841 DOI: 10.1007/978-3-030-77375-5_14] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, exerts rapid, potent and long-lasting antidepressant effect already after a single administration of a low dose into depressed individuals. Apart from targeting neuronal NMDARs essential for synaptic transmission, ketamine also interacts with astrocytes, the principal homoeostatic cells of the central nervous system. The cellular mechanisms underlying astrocyte-based rapid antidepressant effect are incompletely understood. Here we overview recent data that describe ketamine-dependent changes in astrocyte cytosolic cAMP activity ([cAMP]i) and ketamine-induced modifications of stimulus-evoked Ca2+ signalling. The latter regulates exocytotic release of gliosignalling molecules and stabilizes the vesicle fusion pore in a narrow configuration that obstructs cargo discharge or vesicle membrane recycling. Ketamine also instigates rapid redistribution of cholesterol in the astrocyte plasmalemma that may alter flux of cholesterol to neurones, where it is required for changes in synaptic plasticity. Finally, ketamine attenuates mobility of vesicles carrying the inward rectifying potassium channel (Kir4.1) and reduces the surface density of Kir4.1 channels that control extracellular K+ concentration, which tunes the pattern of action potential firing in neurones of lateral habenula as demonstrated in a rat model of depression. Thus, diverse, but not mutually exclusive, mechanisms act synergistically to evoke changes in synaptic plasticity leading to sustained strengthening of excitatory synapses necessary for rapid antidepressant effect of ketamine.
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Affiliation(s)
- Matjaž Stenovec
- Celica BIOMEDICAL, Ljubljana, Slovenia.,Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Baoman Li
- Practical Teaching Centre, School of Forensic Medicine, China Medical University, Shenyang, China.,Department of Poison Analysis, School of Forensic Medicine, China Medical University, Shenyang, China
| | - Alexei Verkhratsky
- Celica BIOMEDICAL, Ljubljana, Slovenia.,Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,Achucarro Center for Neuroscience, IKERBASQUE, Bilbao, Spain
| | - Robert Zorec
- Celica BIOMEDICAL, Ljubljana, Slovenia. .,Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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