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Merz EC, Morys F, Hansen M, Strack J, Jacobs L, Vainik U, Shishikura M, Myers B. Socioeconomic factors, brain-derived neurotrophic factor Val66Met polymorphism, and cortical structure in children and adolescents. Sci Rep 2025; 15:18953. [PMID: 40442425 PMCID: PMC12122700 DOI: 10.1038/s41598-025-04081-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 05/26/2025] [Indexed: 06/02/2025] Open
Abstract
Variability in associations between socioeconomic status and cortical gray matter may be due in part to the common, functional brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, which alters BDNF signaling. In this study, we examined whether BDNF Val66Met genotype moderated the associations between socioeconomic factors (family income, parental education) and cortical surface area (SA) and thickness (CT) in two large independent samples of typically-developing children and adolescents. Participants were 3- to 21-year-olds (N = 383; 47% female) from the Pediatric Imaging, Neurocognition, and Genetics (PING) study and 11- to 14-year-olds (N = 2566; 46% female) in the Adolescent Brain Cognitive Development (ABCD) study. High-resolution, T1-weighted magnetic resonance imaging data were acquired in both studies. Analyses were conducted on global and regional SA and CT. In the PING sample, BDNF Val66Met genotype significantly moderated the association between family income and total SA and SA in the left fusiform gyrus. In the ABCD sample, there were no significant interactions for global or regional SA or CT. Collectively, these results suggest that BDNF Val66Met genotype may not explain variability in associations between socioeconomic factors and SA or CT in children and adolescents.
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Affiliation(s)
- Emily C Merz
- Department of Psychology, Colorado State University, Fort Collins, CO, USA.
| | - Filip Morys
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Melissa Hansen
- Department of Psychology, Colorado State University, Fort Collins, CO, USA
| | - Jordan Strack
- Department of Psychology, Colorado State University, Fort Collins, CO, USA
| | - Lydia Jacobs
- Department of Psychology, Colorado State University, Fort Collins, CO, USA
| | - Uku Vainik
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- University of Tartu, Tartu, Estonia
| | - Mari Shishikura
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Brent Myers
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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2
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Qiu Y, Zhu L, Cai W, Zhu L. Research Progress on BDNF and Depression. ACS Chem Neurosci 2025. [PMID: 40359301 DOI: 10.1021/acschemneuro.5c00193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025] Open
Abstract
Depression is a potentially life-threatening psychiatric disorder that affects the physical and mental health of millions of individuals worldwide. It can manifest at any stage of life, inducing profound emotional despondency, negative cognitions, and, in severe cases, suicidal ideation, often accompanied by physical symptoms, bringing a significant burden on both families and society. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, is widely expressed in the central nervous system (CNS), particularly in regions, such as the hippocampus and cortex. Numerous studies have shown that an imbalance or inadequate conversion of pro-brain-derived neurotrophic factor (proBDNF) into its mature form, mature BDNF (mBDNF), may impair neuronal plasticity, which is crucial to the pathogenesis of depression. This paper provides a comprehensive review of the neurotrophic mechanisms implicated in depression, covering the location, expression, and release of BDNF; the relationship between proBDNF, mBDNF, and depression; and the downstream signaling pathways triggered by BNDF binding to its receptors. This review aims to provide a theoretical foundation for understanding the pathogenesis and clinical treatment of depression.
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Affiliation(s)
- Yahong Qiu
- The Key Laboratory of Developmental Genes and Human Disease, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Lixia Zhu
- Patent Examination Cooperation (JIANGSU) Center of the Patent Office, China National Intellectual Property Administration (CNIPA), Suzhou, Jiangsu 215163, China
| | - Wenyan Cai
- The Key Laboratory of Developmental Genes and Human Disease, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Lijuan Zhu
- The Key Laboratory of Developmental Genes and Human Disease, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
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3
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Bollinger JL, Johnsamuel S, Vollmer LL, Kuhn AM, Wohleb ES. Stress-induced dysfunction of neurovascular astrocytes in the prefrontal cortex contributes to sex-dependent deficits in cognition and behavior. Mol Psychiatry 2025:10.1038/s41380-025-02993-3. [PMID: 40185903 DOI: 10.1038/s41380-025-02993-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 03/14/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
Astrocytes form an integral component of the neurovascular unit, ensheathing brain blood vessels with endfeet high in aquaporin-4 (AQP4) expression. These AQP4-rich endfeet facilitate interaction between the vascular endothelium, astrocytes, and neurons, and help stabilize vascular morphology. Studies using preclinical models of psychological stress and post-mortem tissue from patients with major depressive disorder (MDD) have reported reductions in AQP4, loss of astrocytic structures, and vascular impairment in the prefrontal cortex (PFC). Though compelling, the role of AQP4 in mediating stress-induced alterations in neurovascular function and behavior remains unclear. Here, we address this, alongside potential sex differences in chronic unpredictable stress (CUS) effects on astrocyte phenotype, blood-brain barrier integrity, and behavior. CUS led to more pronounced shifts in stress-coping behavior and working memory deficits in male- as compared to female mice. Following behavioral testing, astrocytes from the frontal cortex were isolated for gene expression analyses. We found that CUS increased transcripts associated with blood vessel maintenance in males, but either had no effect on- or decreased- these transcripts in females. Furthermore, CUS caused a reduction in vascular-localized AQP4 and elevated extravasation of a small fluorescent reporter (Dextran) in the PFC in males but not females. Studies showed that knockdown of AQP4 in the PFC is sufficient to disrupt astrocyte phenotype and increase behavioral susceptibility to a sub-chronic stressor in males yet has little effect on stress susceptibility in females. Our findings provide evidence that sex-specific alterations in astrocyte phenotype and neurovascular integrity in the PFC contribute to cognitive-behavioral consequences following stress.
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Affiliation(s)
- Justin L Bollinger
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Shobha Johnsamuel
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lauren L Vollmer
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Alexander M Kuhn
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Eric S Wohleb
- Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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4
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Giesler LP, Mychasiuk R, Shultz SR, McDonald SJ. BDNF: New Views of an Old Player in Traumatic Brain Injury. Neuroscientist 2024; 30:560-573. [PMID: 37067029 PMCID: PMC11423547 DOI: 10.1177/10738584231164918] [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] [Indexed: 04/18/2023]
Abstract
Traumatic brain injury is a common health problem affecting millions of people each year. BDNF has been investigated in the context of traumatic brain injury due to its crucial role in maintaining brain homeostasis. Val66Met is a functional single-nucleotide polymorphism that results in a valine-to-methionine amino acid substitution at codon 66 in the BDNF prodomain, which ultimately reduces secretion of BDNF. Here, we review experimental animal models as well as clinical studies investigating the role of the Val66Met single-nucleotide polymorphism in traumatic brain injury outcomes, including cognitive function, motor function, neuropsychiatric symptoms, and nociception. We also review studies investigating the role of BDNF on traumatic brain injury pathophysiology as well as circulating BDNF as a biomarker of traumatic brain injury.
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Affiliation(s)
| | - Richelle Mychasiuk
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, The Alfred Hospital, Melbourne, Australia
| | - Sandy R. Shultz
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, The Alfred Hospital, Melbourne, Australia
| | - Stuart J. McDonald
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, The Alfred Hospital, Melbourne, Australia
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Cao J, Gorwood P, Ramoz N, Viltart O. The Role of Central and Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker of Anorexia Nervosa Reconceptualized as a Metabo-Psychiatric Disorder. Nutrients 2024; 16:2617. [PMID: 39203753 PMCID: PMC11357464 DOI: 10.3390/nu16162617] [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: 06/12/2024] [Revised: 07/26/2024] [Accepted: 08/04/2024] [Indexed: 09/03/2024] Open
Abstract
Neurotrophic factors play pivotal roles in shaping brain development and function, with brain-derived neurotrophic factor (BDNF) emerging as a key regulator in various physiological processes. This review explores the intricate relationship between BDNF and anorexia nervosa (AN), a complex psychiatric disorder characterized by disordered eating behaviors and severe medical consequences. Beginning with an overview of BDNF's fundamental functions in neurodevelopment and synaptic plasticity, the review delves into recent clinical and preclinical evidence implicating BDNF in the pathophysiology of AN. Specifically, it examines the impact of BDNF polymorphisms, such as the Val66Met variant, on AN susceptibility, prognosis, and treatment response. Furthermore, the review discusses the interplay between BDNF and stress-related mood disorders, shedding light on the mechanisms underlying AN vulnerability to stress events. Additionally, it explores the involvement of BDNF in metabolic regulation, highlighting its potential implications for understanding the metabolic disturbances observed in AN. Through a comprehensive analysis of clinical data and animal studies, the review elucidates the nuanced role of BDNF in AN etiology and prognosis, emphasizing its potential as a diagnostic and prognostic biomarker. Finally, the review discusses limitations and future directions in BDNF research, underscoring the need for further investigations to elucidate the complex interplay between BDNF signaling and AN pathology.
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Affiliation(s)
- Jingxian Cao
- Institute of Psychiatry and Neuroscience of Paris (IPNP), Université Paris Cité, INSERM UMR-S 1266, F-75014 Paris, France (O.V.)
| | - Philip Gorwood
- Institute of Psychiatry and Neuroscience of Paris (IPNP), Université Paris Cité, INSERM UMR-S 1266, F-75014 Paris, France (O.V.)
- GHU Paris Psychiatrie et Neurosciences, CMME, Hôpital Sainte Anne, F-75014 Paris, France
| | - Nicolas Ramoz
- Institute of Psychiatry and Neuroscience of Paris (IPNP), Université Paris Cité, INSERM UMR-S 1266, F-75014 Paris, France (O.V.)
- GHU Paris Psychiatrie et Neurosciences, CMME, Hôpital Sainte Anne, F-75014 Paris, France
| | - Odile Viltart
- Institute of Psychiatry and Neuroscience of Paris (IPNP), Université Paris Cité, INSERM UMR-S 1266, F-75014 Paris, France (O.V.)
- SCALab Laboratory, PsySEF Faculty, Université de Lille, UMR CNRS 9193, F-59650 Villeneuve d’Ascq, France
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Yu H, Li X, Zhang Q, Geng L, Su B, Wang Y. miR-143-3p modulates depressive-like behaviors via Lasp1 in the mouse ventral hippocampus. Commun Biol 2024; 7:944. [PMID: 39098885 PMCID: PMC11298515 DOI: 10.1038/s42003-024-06639-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 07/26/2024] [Indexed: 08/06/2024] Open
Abstract
Depression is a prevalent and intricate mental disorder. The involvement of small RNA molecules, such as microRNAs in the pathogenesis and neuronal mechanisms underlying the depression have been documented. Previous studies have demonstrated the involvement of microRNA-143-3p (miR-143-3p) in the process of fear memory and pathogenesis of ischemia; however, the relationship between miR-143-3p and depression remains poorly understood. Here we utilized two kinds of mouse models to investigate the role of miR-143-3p in the pathogenesis of depression. Our findings reveal that the expression of miR-143-3p is upregulated in the ventral hippocampus (VH) of mice subjected to chronic restraint stress (CRS) or acute Lipopolysaccharide (LPS) treatment. Inhibiting the expression of miR-143-3p in the VH effectively alleviates depressive-like behaviors in CRS and LPS-treated mice. Furthermore, we identify Lasp1 as one of the downstream target genes regulated by miR-143-3p. The miR-143-3p/Lasp1 axis primarily affects the occurrence of depressive-like behaviors in mice by modulating synapse numbers in the VH. Finally, miR-143-3p/Lasp1-induced F-actin change is responsible for the synaptic number variations in the VH. In conclusion, this study enhances our understanding of microRNA-mediated depression pathogenesis and provides novel prospects for developing therapeutic approaches for this intractable mood disorder.
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Affiliation(s)
- Hui Yu
- Department of Cell Biology, Shandong Provincial Key Laboratory of Mental Disorders, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Xiaobing Li
- Medical Experimental Center, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, 250000, Jinan, China
- Department of Human Anatomy Histology and Embryology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117, Jinan, China
| | - Qiyao Zhang
- Medical Experimental Center, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, 250000, Jinan, China
| | - Lian Geng
- Department of Cell Biology, Shandong Provincial Key Laboratory of Mental Disorders, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Bo Su
- Department of Cell Biology, Shandong Provincial Key Laboratory of Mental Disorders, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China.
| | - Yue Wang
- Medical Experimental Center, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, 250000, Jinan, China.
- Department of Human Anatomy Histology and Embryology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117, Jinan, China.
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Martins LA, Schiavo A, Paz LV, Xavier LL, Mestriner RG. Neural underpinnings of fine motor skills under stress and anxiety: A review. Physiol Behav 2024; 282:114593. [PMID: 38782244 DOI: 10.1016/j.physbeh.2024.114593] [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: 03/05/2024] [Revised: 05/17/2024] [Accepted: 05/21/2024] [Indexed: 05/25/2024]
Abstract
This review offers a comprehensive examination of how stress and anxiety affect motor behavior, particularly focusing on fine motor skills and gait adaptability. We explore the role of several neurochemicals, including brain-derived neurotrophic factor (BDNF) and dopamine, in modulating neural plasticity and motor control under these affective states. The review highlights the importance of developing therapeutic strategies that enhance motor performance by leveraging the interactions between key neurochemicals. Additionally, we investigate the complex interplay between emotional-cognitive states and sensorimotor behaviors, showing how stress and anxiety disrupt neural integration, leading to impairments in skilled movements and negatively impacting quality of life. Synthesizing evidence from human and rodent studies, we provide a detailed understanding of the relationships among stress, anxiety, and motor behavior. Our findings reveal neurophysiological pathways, behavioral outcomes, and potential therapeutic targets, emphasizing the intricate connections between neurobiological mechanisms, environmental factors, and motor performance.
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Affiliation(s)
- Lucas Athaydes Martins
- Pontifical Catholic University of Rio Grande do Sul (PUCRS). Graduate Program in Biomedical Gerontology, Av. Ipiranga, 6681, Porto Alegre, Brazil; Pontifical Catholic University of Rio Grande do Sul (PUCRS). Neuroscience, Motor Behavior, and Rehabilitation Research Group (NECORE-CNPq), Av. Ipiranga, 6681, Porto Alegre, Brazil
| | - Aniuska Schiavo
- Pontifical Catholic University of Rio Grande do Sul (PUCRS). Graduate Program in Biomedical Gerontology, Av. Ipiranga, 6681, Porto Alegre, Brazil; Pontifical Catholic University of Rio Grande do Sul (PUCRS). Neuroscience, Motor Behavior, and Rehabilitation Research Group (NECORE-CNPq), Av. Ipiranga, 6681, Porto Alegre, Brazil
| | - Lisiê Valéria Paz
- Pontifical Catholic University of Rio Grande do Sul (PUCRS). Graduate Program in Cellular and Molecular Biology, Av. Ipiranga, 6681, Porto Alegre, Brazil
| | - Léder Leal Xavier
- Pontifical Catholic University of Rio Grande do Sul (PUCRS). Neuroscience, Motor Behavior, and Rehabilitation Research Group (NECORE-CNPq), Av. Ipiranga, 6681, Porto Alegre, Brazil; Pontifical Catholic University of Rio Grande do Sul (PUCRS). Graduate Program in Cellular and Molecular Biology, Av. Ipiranga, 6681, Porto Alegre, Brazil
| | - Régis Gemerasca Mestriner
- Pontifical Catholic University of Rio Grande do Sul (PUCRS). Graduate Program in Biomedical Gerontology, Av. Ipiranga, 6681, Porto Alegre, Brazil; Pontifical Catholic University of Rio Grande do Sul (PUCRS). Neuroscience, Motor Behavior, and Rehabilitation Research Group (NECORE-CNPq), Av. Ipiranga, 6681, Porto Alegre, Brazil; Pontifical Catholic University of Rio Grande do Sul (PUCRS). Graduate Program in Cellular and Molecular Biology, Av. Ipiranga, 6681, Porto Alegre, Brazil.
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Harada H, Mori M, Murata Y, Kohno Y, Terada K, Ohe K, Enjoji M. Divergent effects of chronic continuous and intermittent social defeat stress on emotional behaviors: Impact on phosphorylated CREB and BDNF protein levels in the rat hippocampus. Neurosci Lett 2024; 835:137851. [PMID: 38838971 DOI: 10.1016/j.neulet.2024.137851] [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: 03/19/2024] [Revised: 05/06/2024] [Accepted: 06/02/2024] [Indexed: 06/07/2024]
Abstract
Chronic psychosocial stress stands as a significant heterogeneous risk factor for psychiatric disorders. The brain's physiological response to such stress varies based on the frequency and intensity of stress episodes. However, whether stress episodes divergently could affect hippocampal cyclic AMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling remains unclear, a key regulator of psychiatric symptoms. We aimed to assess how two distinct patterns of social defeat stress exposure impact anxiety- and depression-like behaviors, fear, and hippocampal CREB-BDNF signaling in adult male rats. To explore this, adult male Sprague-Dawley rats were subjected to psychosocial stress using a Resident/Intruder paradigm for ten consecutive days (continuous social defeat stress: [CS]) or ten social defeat stress over the course of 21 days (intermittent social defeat stress [IS]). Behavioral tests (including novelty-suppressed feeding test, forced swimming test, and contextually conditioned fear) were conducted. Protein expression levels of phosphorylated CREB and BDNF in the dorsal and ventral hippocampi were examined. CS led to heightened anxiety-like behavior, fear, and increased levels of phosphorylated CREB in both the dorsal and ventral hippocampi. Conversely, IS resulted in increased anxiety-like behavior and behavioral despair alongside decreased levels of phosphorylated CREB and BDNF, particularly in the dorsal hippocampus. These findings indicate that chronic psychosocial stress divergently affects hippocampal CREB-BDNF signaling and emotional regulation depending on the stress episode. Such insights could enhance our understanding of the molecular basis of the heterogeneity of psychiatric disorders and facilitate the development of innovative treatment approaches to patients with psychiatric disorders.
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Affiliation(s)
- Hiroyoshi Harada
- Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
| | - Masayoshi Mori
- Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Yusuke Murata
- Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
| | - Yuri Kohno
- Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
| | - Kazuki Terada
- Department of Human Physiology and Pathology, Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Kenji Ohe
- Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
| | - Munechika Enjoji
- Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
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9
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Bollinger JL, Johnsamuel S, Vollmer LL, Kuhn AM, Wohleb ES. Stress-induced dysfunction of neurovascular astrocytes contributes to sex-specific behavioral deficits. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.14.594147. [PMID: 38798398 PMCID: PMC11118421 DOI: 10.1101/2024.05.14.594147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Astrocytes form an integral component of the neurovascular unit, ensheathing brain blood vessels with projections high in aquaporin-4 (AQP4) expression. These AQP4-rich projections facilitate interaction between the vascular endothelium, astrocytes, and neurons, and help stabilize vascular morphology. Studies using preclinical models of psychological stress and post-mortem tissue from patients with major depressive disorder (MDD) have reported reductions in AQP4, loss of astrocytic structures, and vascular impairment in the prefrontal cortex (PFC). Though compelling, the role of AQP4 in mediating stress-induced alterations in blood vessel function and behavior remains unclear. Here, we address this, alongside potential sex differences in chronic unpredictable stress (CUS) effects on astrocyte phenotype, blood-brain barrier integrity, and behavior. CUS led to pronounced shifts in stress-coping behavior and working memory deficits in male -but not female- mice. Following behavioral testing, astrocytes from the frontal cortex were isolated for gene expression analyses. We found that CUS increased various transcripts associated with blood vessel maintenance in astrocytes from males, but either had no effect on- or decreased- these genes in females. Furthermore, CUS caused a reduction in vascular-localized AQP4 and elevated extravasation of a small molecule fluorescent reporter (Dextran) in the PFC in males but not females. Studies showed that knockdown of AQP4 in the PFC in males is sufficient to disrupt astrocyte phenotype and increase behavioral susceptibility to a sub-chronic stressor. Collectively, these findings provide initial evidence that sex-specific alterations in astrocyte phenotype and neurovascular integrity in the PFC contribute to behavioral and cognitive consequences following chronic stress.
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Affiliation(s)
- Justin L Bollinger
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Shobha Johnsamuel
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Lauren L Vollmer
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Alexander M Kuhn
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Eric S Wohleb
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH
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10
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Merighi A. Brain-Derived Neurotrophic Factor, Nociception, and Pain. Biomolecules 2024; 14:539. [PMID: 38785946 PMCID: PMC11118093 DOI: 10.3390/biom14050539] [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: 02/08/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/25/2024] Open
Abstract
This article examines the involvement of the brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin known for its essential role in neuronal survival and plasticity, has garnered significant attention for its potential implications as a modulator of synaptic transmission. This comprehensive review aims to provide insights into the multifaceted interactions between BDNF and pain pathways, encompassing both physiological and pathological pain conditions. I delve into the molecular mechanisms underlying BDNF's involvement in pain processing and discuss potential therapeutic applications of BDNF and its mimetics in managing pain. Furthermore, I highlight recent advancements and challenges in translating BDNF-related research into clinical practice.
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Affiliation(s)
- Adalberto Merighi
- Department of Veterinary Sciences, University of Turin, 10095 Turin, Italy
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11
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Xavier FAC, Barbieri SS, Popoli M, Ieraci A. Short- and Long-Term Effects of Subchronic Stress Exposure in Male and Female Brain-Derived Neurotrophic Factor Knock-In Val66Met Mice. BIOLOGY 2024; 13:303. [PMID: 38785785 PMCID: PMC11118886 DOI: 10.3390/biology13050303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/19/2024] [Accepted: 04/24/2024] [Indexed: 05/25/2024]
Abstract
Stress is an important risk factor for the onset of anxiety and depression. The ability to cope with stressful events varies among different subjects, probably depending on different genetic variants, sex and previous life experiences. The Val66Met variant of Brain-Derived Neurotrophic Factor (BDNF), which impairs the activity-dependent secretion of BDNF, has been associated with increased susceptibility to the development of various neuropsychiatric disorders. Adult male and female wild-type Val/Val (BDNFV/V) and heterozygous Val/Met (BDNFV/M) mice were exposed to two sessions of forced swimming stress (FSS) per day for two consecutive days. The mice were behaviorally tested 1 day (short-term effect) or 11 days (long-term effect) after the last stress session. Protein and mRNA levels were measured in the hippocampus 16 days after the end of stress exposure. Stressed mice showed a higher anxiety-like phenotype compared to non-stressed mice, regardless of the sex and genotype, when analyzed following the short period of stress. In the prolonged period, anxiety-like behavior persisted only in male BDNFV/M mice (p < 0.0001). Interestingly, recovery in male BDNFV/V mice was accompanied by an increase in pCREB (p < 0.001) and Bdnf4 (p < 0.01) transcript and a decrease in HDAC1 (p < 0.05) and Dnmt3a (p = 0.01) in the hippocampus. Overall, our results show that male and female BDNF Val66Met knock-in mice can recover from subchronic stress in different ways.
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Affiliation(s)
- Fernando Antonio Costa Xavier
- Laboratory of Molecular and Cellular Biology, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90619-900, Brazil;
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, 20133 Milano, Italy;
| | - Silvia Stella Barbieri
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy;
| | - Maurizio Popoli
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, 20133 Milano, Italy;
| | - Alessandro Ieraci
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
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Homberg JR, Brivio P, Greven CU, Calabrese F. Individuals being high in their sensitivity to the environment: Are sensitive period changes in play? Neurosci Biobehav Rev 2024; 159:105605. [PMID: 38417743 DOI: 10.1016/j.neubiorev.2024.105605] [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: 10/11/2023] [Revised: 02/13/2024] [Accepted: 02/25/2024] [Indexed: 03/01/2024]
Abstract
All individuals on planet earth are sensitive to the environment, but some more than others. These individual differences in sensitivity to environments are seen across many animal species including humans, and can influence personalities as well as vulnerability and resilience to mental disorders. Yet, little is known about the underlying brain mechanisms. Key genes that contribute to individual differences in environmental sensitivity are the serotonin transporter, dopamine D4 receptor and brain-derived neurotrophic factor genes. By synthesizing neurodevelopmental findings of these genetic factors, and discussing them through the lens of mechanisms related to sensitive periods, which are phases of heightened neuronal plasticity during which a certain network is being finetuned by experiences, we propose that these genetic factors delay but extend postnatal sensitive periods. This may explain why sensitive individuals show behavioral features that are characteristic of a young brain state at the level of sensory information processing, such as reduced filtering or blockade of irrelevant information, resulting in a sensory processing system that 'keeps all options open'.
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Affiliation(s)
- Judith R Homberg
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
| | - Paola Brivio
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy
| | - Corina U Greven
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands; King's College London, Institute of Psychiatry, Psychology and Neuroscience, Social, Genetic and Developmental Psychiatry Center, London, United Kingdom
| | - Francesca Calabrese
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy
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13
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Yasuda T, Kashima Y. A soy protein enzymatic digest mitigates Nrf2-related oxidative stress and attenuates depression-like behavior in a mouse model of sub-chronic restraint stress. Heliyon 2024; 10:e27826. [PMID: 38524573 PMCID: PMC10958348 DOI: 10.1016/j.heliyon.2024.e27826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 03/26/2024] Open
Abstract
Continuous oxidative stress conditions have been identified as a major cause of various neuropsychiatric disorders, including depression. The present study investigated the potential antidepressant-like effects of a soy protein enzymatic digest (SPD) containing soy-deprestatin, which is a soy-derived peptide with reported antidepressant-like effects, as well as its ability to mitigate oxidative stress in the brain caused by sub-chronic restraint stress. Mice were divided into two groups: a control group and restraint stress group. The restraint stress group was further divided into two groups administered water or SPD. After repeated short-time restraints over five days, we evaluated immobility times in the tail suspension test, and antioxidant enzyme activities, glutathione levels, oxidative stress maker levels, and the gene expression levels of Nrf2 and antioxidant enzymes in the brain. The results obtained showed that the oral administration of SPD reduced immobility times in mice exposed to restraint stress. In comparisons with the water-treated restraint group, the administration of SPD restored superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities and glutathione levels and prevented restraint stress-induced increases in malondialdehyde, carbonyl protein, and 8-OHdG levels in the restraint stress group. In addition, high expression levels of Nrf2, HO-1, NQO-1 and GCLC were observed in the SPD-treated restraint group. These results suggest that SPD attenuated repeated restraint stress-induced depression-like behaviors by mitigating oxidative stress through the activation of the Nrf2 signaling pathway.
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Affiliation(s)
- Takuwa Yasuda
- Global Healthcare Research Laboratory, UHA Mikakuto Co., Ltd., Osaka, Japan
| | - Yasuhiro Kashima
- Global Healthcare Research Laboratory, UHA Mikakuto Co., Ltd., Osaka, Japan
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14
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Vahid-Ansari F, Zahrai A, Daigle M, Albert PR. Chronic Desipramine Reverses Deficits in Cell Activity, Norepinephrine Innervation, and Anxiety-Depression Phenotypes in Fluoxetine-Resistant cF1ko Mice. J Neurosci 2024; 44:e1147232023. [PMID: 38050173 PMCID: PMC10860653 DOI: 10.1523/jneurosci.1147-23.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 11/09/2023] [Accepted: 11/20/2023] [Indexed: 12/06/2023] Open
Abstract
Selective serotonin (5-HT) reuptake inhibitors are only 30% effective for remission in subjects with major depression, and the best treatments for SSRI-resistant patients remain unclear. To model SSRI resistance, we used cF1ko mice with conditional deletion of the repressor Freud-1/CC2D1A in adult 5-HT neurons. Within weeks, this deletion leads to overexpression of 5-HT1A autoreceptors, reduced serotonergic activity, and fluoxetine-resistant anxiety-depression phenotype. We hypothesized that desipramine (DES), which targets norepinephrine (NE), may be effective in cF1ko mice. The actions of chronic DES treatment on behavior, chronic cellular activation, and NE projections were examined in both sexes of cF1ko and WT mice. In contrast to fluoxetine, chronic DES reversed the behavioral phenotypes in cF1ko mice, while in WT littermates DES slightly increased anxiety and depression-like behaviors. Deficits in FosB+ cell counts were seen in the entorhinal cortex, hippocampal CA2/3 layer, and BLA of cF1ko mice and were reversed by chronic DES treatment, especially in GABAergic neurons. In cF1ko mice, widespread reductions were seen in NE axons, varicosities, and especially 30-60% reductions in NE synaptic and triadic contacts, particularly to inhibitory gephyrin-positive sites. DES treatment also reversed these reductions in NE innervation. These results indicate the dynamic plasticity of the adult noradrenergic system within weeks of altering serotonergic function that can be normalized by DES treatment. Accompanying these changes, DES but not fluoxetine reversed the behavioral alterations in cF1ko mice, suggesting a key role for noradrenergic plasticity in antidepressant response in this model of reduced serotonin activity.
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Affiliation(s)
- Faranak Vahid-Ansari
- Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, Ontario K1H-8M5, Canada
| | - Amin Zahrai
- Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, Ontario K1H-8M5, Canada
| | - Mireille Daigle
- Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, Ontario K1H-8M5, Canada
| | - Paul R Albert
- Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, Ontario K1H-8M5, Canada
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15
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Cai CY, Liang HY, Zhou T, Yang C, Yin JJ, Yao MH, Gu QX, Liu D, Ni HY. High-intensity interval training ameliorates chronic unpredictable mild stress-induced depressive behaviors via HDAC2-BDNF signaling in the ventral hippocampus. Brain Res 2023; 1816:148480. [PMID: 37429454 DOI: 10.1016/j.brainres.2023.148480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/03/2023] [Accepted: 07/07/2023] [Indexed: 07/12/2023]
Abstract
Major depressive disorder (MDD) is a devastating psychiatric disease, and current therapies could not well meet the demand for MDD treatment. Exercise benefits mental illness, and notably, exercise has been recommended as an alternative option for MDD treatment in some countries. However, the paradigm and intensity of exercise for MDD treatment has yet to be determined. High-intensity interval training (HIIT) is a potent and time-efficient type of exercise training and has gained popularity in recent years. In this study, we exposed the mice to chronic unpredictable mild stress (CUMS) and found HIIT exerted substantial antidepressant effect. Moreover, HIIT further enhanced the antidepressant effect of fluoxetine, a classic antidepressant in the clinic, confirming the antidepressant role of HIIT. HIIT significantly reversed the CUMS-induced upregulations in HDAC2 mRNA and protein level in the ventral hippocampus. We also found HIIT rescued the CUMS-induced downregulation in the expression of brain-derived neurotrophic factor (BDNF) and HDAC2 overexpression counteracted the HIIT-induced increase in BDNF level. More importantly, both virus-mediated HDAC2 overexpression and microinfusion of TrkB-Fc, a BDNF scavenger, in the ventral hippocampus abolished the antidepressant effect of HIIT. Together, our results strongly demonstrate that HIIT attenuates depressive behaviors, probably via HDAC2-BDNF signaling pathway and reveal that HIIT may serve as an alternative option for MDD treatment.
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Affiliation(s)
- Cheng-Yun Cai
- Co-innovation Center of Neuroregeneration, School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China
| | - Hai-Ying Liang
- Department of Pharmacy, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, China
| | - Ting Zhou
- Co-innovation Center of Neuroregeneration, School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China
| | - Chao Yang
- Co-innovation Center of Neuroregeneration, School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China
| | - Jia-Jie Yin
- Co-innovation Center of Neuroregeneration, School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China
| | - Meng-Han Yao
- Co-innovation Center of Neuroregeneration, School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China
| | - Qiu-Xiang Gu
- Co-innovation Center of Neuroregeneration, School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China.
| | - Dong Liu
- Co-innovation Center of Neuroregeneration, School of Life Sciences, Nantong Laboratory of Development and Diseases, Nantong University, Nantong, China.
| | - Huan-Yu Ni
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China; Nanjing Medical Center for Clinical Pharmacy, Nanjing, Jiangsu, China.
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16
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Corrone M, Nanev A, Amato I, Bicknell R, Piantella S, Maruff P, van den Buuse M, Wright BJ. The brain-derived neurotrophic factor Val66met polymorphism is associated with better attention and working memory performance and resilience to mild chronic stress. Eur J Neurosci 2023; 58:3903-3916. [PMID: 37740693 DOI: 10.1111/ejn.16153] [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: 05/15/2023] [Revised: 09/07/2023] [Accepted: 09/10/2023] [Indexed: 09/25/2023]
Abstract
The val66met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has been identified as a potential moderator for the relationship between chronic stress and executive functioning. However, whether the presence of the met allele increases cognitive vulnerability or resilience to stress has yet to be determined. Given the established effects of autonomic activity and psychological arousal on executive functioning, in the present study, 56 healthy university students completed self-report measures of chronic stress, positive arousal (vigour) and negative arousal (anxiety) and measured heart-rate variability to quantify autonomic activity. Participants then completed a cognitive test battery that measured attention, decision-making, visual learning and working memory. Regression analyses demonstrated that Val/met participants performed better on attention and working memory tasks than Val/val participants, but no differences were seen in decision-making and visual learning. Further, Val/met participants were protected from stress-related differences in attention seen in Val/val participants. Val66met was not associated with physiological or psychological arousal. This study demonstrates that val66met plays an important but selective role in cognitive performance.
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Affiliation(s)
- Michelle Corrone
- School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Aleshia Nanev
- School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Isabella Amato
- School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Rowena Bicknell
- School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Stefan Piantella
- School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Paul Maruff
- Cogstate Ltd, Melbourne, Victoria, Australia
| | - Maarten van den Buuse
- School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Bradley J Wright
- School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia
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17
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Madjid N, Lidell V, Nordvall G, Lindskog M, Ögren SO, Forsell P, Sandin J. Antidepressant effects of novel positive allosteric modulators of Trk-receptor mediated signaling - a potential therapeutic concept? Psychopharmacology (Berl) 2023; 240:1789-1804. [PMID: 37394539 PMCID: PMC10349764 DOI: 10.1007/s00213-023-06410-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 06/20/2023] [Indexed: 07/04/2023]
Abstract
BACKGROUND Major depressive disorder (MDD) is defined as a complex mental disorder which is characterized by a pervasive low mood and aversion to activity. Several types of neurotransmitter systems e.g. serotonergic, glutamatergic and noradrenergic systems have been suggested to play an important role in the origination of depression, but neurotrophins such as brain derived neurotrophic factor (BDNF) have also been implicated in the disease process. OBJECTIVES The purpose of this study was to examine the effects of a newly developed class of molecules, characterized as positive allosteric modulators of neurotrophin/Trk receptor mediated signaling (Trk-PAM), on neurotransmitter release and depression-like behavior in vivo. METHODS The effect of and possible interaction of neurotrophin/Trk signaling pathways with serotonergic and glutamatergic systems in the modulation of depression-related responses was studied using newly developed Trk-PAM compounds (ACD855, ACD856 and AC26845), as well as ketamine and fluoxetine in the forced swim test (FST) in rodents. Moreover, in vivo microdialysis in freely moving rats was used to assess changes in neurotransmitter levels in the rat. RESULTS The results from the study show that several different compounds, which all potentiate Trk-receptor mediated signaling, display antidepressant-like activity in the FST. Moreover, the data also indicate that the effects of both fluoxetine and ketamine in the FST, both used in clinical practice, are mediated via BDNF/TrkB signaling, which could have implications for novel therapies in MDD. CONCLUSIONS Trk-PAMs could provide an interesting avenue for the development of novel therapeutics in this area.
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Affiliation(s)
- Nather Madjid
- AlzeCure Pharma AB, Hälsovägen 7, 141 57, Huddinge, Sweden
| | | | - Gunnar Nordvall
- AlzeCure Pharma AB, Hälsovägen 7, 141 57, Huddinge, Sweden
- Division of Neuroscience, Care and Society, Department of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden
| | - Maria Lindskog
- Division of Neuroscience, Care and Society, Department of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden
| | - Sven-Ove Ögren
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Pontus Forsell
- AlzeCure Pharma AB, Hälsovägen 7, 141 57, Huddinge, Sweden
- Division of Neuroscience, Care and Society, Department of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden
| | - Johan Sandin
- AlzeCure Pharma AB, Hälsovägen 7, 141 57, Huddinge, Sweden.
- Division of Neuroscience, Care and Society, Department of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.
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18
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Li X, Teng T, Yan W, Fan L, Liu X, Clarke G, Zhu D, Jiang Y, Xiang Y, Yu Y, Zhang Y, Yin B, Lu L, Zhou X, Xie P. AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models. Transl Psychiatry 2023; 13:200. [PMID: 37308476 DOI: 10.1038/s41398-023-02486-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 05/06/2023] [Accepted: 05/26/2023] [Indexed: 06/14/2023] Open
Abstract
Major depressive disorder (MDD) is a highly heterogeneous psychiatric disorder. The pathogenesis of MDD remained unclear, and it may be associated with exposure to different stressors. Most previous studies have focused on molecular changes in a single stress-induced depression model, which limited the identification of the pathogenesis of MDD. The depressive-like behaviors were induced by four well-validated stress models in rats, including chronic unpredictable mild stress, learned helplessness stress, chronic restraint stress and social defeat stress. We applied proteomic and metabolomic to investigate molecular changes in the hippocampus of those four models and revealed 529 proteins and 98 metabolites. Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified differentially regulated canonical pathways, and then we presented a schematic model that simulates AKT and MAPK signaling pathways network and their interactions and revealed the cascade reactions. Further, the western blot confirmed that p-AKT, p-ERK12, GluA1, p-MEK1, p-MEK2, p-P38, Syn1, and TrkB, which were changed in at least one depression model. Importantly, p-AKT, p-ERK12, p-MEK1 and p-P38 were identified as common alterations in four depression models. The molecular level changes caused by different stressors may be dramatically different, and even opposite, between four depression models. However, the different molecular alterations converge on a common AKT and MAPK molecular pathway. Further studies of these pathways could contribute to a better understanding of the pathogenesis of depression, with the ultimate goal of helping to develop or select more effective treatment strategies for MDD.
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Affiliation(s)
- Xuemei Li
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Teng Teng
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Yan
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Li Fan
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xueer Liu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Gerard Clarke
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Dan Zhu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuanliang Jiang
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yajie Xiang
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ying Yu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuqing Zhang
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bangmin Yin
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Lu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China.
| | - Xinyu Zhou
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Peng Xie
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Li J, Zhang M, Pei Y, Yang Q, Zheng L, Wang G, Sun Y, Yang W, Liu L. The total alkaloids of Sophora alopecuroides L. improve depression-like behavior in mice via BDNF-mediated AKT/mTOR signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023:116723. [PMID: 37271329 DOI: 10.1016/j.jep.2023.116723] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 04/02/2023] [Accepted: 06/01/2023] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Depression has become a global public health problem and the development of new highly effective, low-toxicity antidepressants is imminent. Sophora alopecuroides L. is a common medicinal plant, which has therapeutic effect on central nervous system diseases. AIM OF THE STUDY In this study, the antidepressant effect of total alkaloids (ALK) isolated from Sophora alopecuroides L. was explored and the mechanism was further elucidated. MATERIALS AND METHODS A primary neuronal injury model was established in vitro by corticosterone. ICR mice were then selected to construct an in vivo model of chronic unpredictable mild stress (CUMS)-induced depression, and the ameliorative effects of ALK on depression were examined by various behavioral tests. The antidepressant molecular mechanism of ALK was subsequently revealed by ELISA, Western blot, immunohistochemistry and Golgi staining. RESULTS BDNF secretion as well as TrkB and ERK phosphorylated protein levels were found to be improved in primary cortical neurons, along with improved dendritic complexity of neurons. The results of in vivo showed that the depression-like behavior of CUMS-induced mice was reversed after 2 weeks of continuous gavage administration of ALK, and the neurotransmitter levels in the plasma of mice were increased. Moreover, the expression levels of key proteins of BDNF-AKT-mTOR pathway and the complexity of neuronal dendrites were improved in the prefrontal cortex of mice. CONCLUSIONS These findings indicate that ALK of Sophora alopecuroides L. can effectively improve the depressive phenotype of mice, possibly by promoting the expression of BDNF in prefrontal cortex, activating the downstream AKT/mTOR signal pathway, and ultimately enhancing neuronal dendritic complexity.
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Affiliation(s)
- Jingyi Li
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China
| | - Ming Zhang
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, China
| | - Yiying Pei
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China
| | - Qifang Yang
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China
| | - Lihua Zheng
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China
| | - Guannan Wang
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China
| | - Ying Sun
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China
| | - Wei Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China.
| | - Lei Liu
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China.
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20
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Yoon S, Iqbal H, Kim SM, Jin M. Phytochemicals That Act on Synaptic Plasticity as Potential Prophylaxis against Stress-Induced Depressive Disorder. Biomol Ther (Seoul) 2023; 31:148-160. [PMID: 36694423 PMCID: PMC9970837 DOI: 10.4062/biomolther.2022.116] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/06/2022] [Accepted: 12/20/2022] [Indexed: 01/26/2023] Open
Abstract
Depression is a neuropsychiatric disorder associated with persistent stress and disruption of neuronal function. Persistent stress causes neuronal atrophy, including loss of synapses and reduced size of the hippocampus and prefrontal cortex. These alterations are associated with neural dysfunction, including mood disturbances, cognitive impairment, and behavioral changes. Synaptic plasticity is the fundamental function of neural networks in response to various stimuli and acts by reorganizing neuronal structure, function, and connections from the molecular to the behavioral level. In this review, we describe the alterations in synaptic plasticity as underlying pathological mechanisms for depression in animal models and humans. We further elaborate on the significance of phytochemicals as bioactive agents that can positively modulate stress-induced, aberrant synaptic activity. Bioactive agents, including flavonoids, terpenes, saponins, and lignans, have been reported to upregulate brain-derived neurotrophic factor expression and release, suppress neuronal loss, and activate the relevant signaling pathways, including TrkB, ERK, Akt, and mTOR pathways, resulting in increased spine maturation and synaptic numbers in the neuronal cells and in the brains of stressed animals. In clinical trials, phytochemical usage is regarded as safe and well-tolerated for suppressing stress-related parameters in patients with depression. Thus, intake of phytochemicals with safe and active effects on synaptic plasticity may be a strategy for preventing neuronal damage and alleviating depression in a stressful life.
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Affiliation(s)
- Soojung Yoon
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea
| | - Hamid Iqbal
- Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Sun Mi Kim
- Department of Psychiatry, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea,Department of Psychiatry, Chung-Ang University Hospital, Seoul 06973, Republic of Korea
| | - Mirim Jin
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea,Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea,Corresponding Author E-mail: , Tel: +82-32-899-6080, Fax: +82-32-899-6029
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21
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Woodburn SC, Asrat HS, Flurer JK, Schwierling HC, Bollinger JL, Vollmer LL, Wohleb ES. Depletion of microglial BDNF increases susceptibility to the behavioral and synaptic effects of chronic unpredictable stress. Brain Behav Immun 2023; 109:127-138. [PMID: 36681359 PMCID: PMC10023455 DOI: 10.1016/j.bbi.2023.01.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 12/22/2022] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
In the medial prefrontal cortex (PFC), chronic stress reduces synaptic expression of glutamate receptors, leading to decreased excitatory signaling from layer V pyramidal neurons and working memory deficits. One key element driving these changes is a reduction in brain-derived neurotrophic factor (BDNF) signaling. BDNF is a potent mediator of synaptic growth and deficient BDNF signaling has been linked to stress susceptibility. Prior studies indicated that neurons are the primary source of BDNF, but more recent work suggests that microglia are also an important source of BDNF. Adding to this, our work showed that 14 days of chronic unpredictable stress (CUS) reduced Bdnf transcript in PFC microglia, evincing its relevance in the effects of stress. To explore this further, we utilized transgenic mice with microglia-specific depletion of BDNF (Cx3cr1Cre/+:Bdnffl/fl) and genotype controls (Cx3cr1Cre/+:Bdnf+/+). In the following experiments, mice were exposed to a shortened CUS paradigm (7 days) to determine if microglial Bdnf depletion promotes stress susceptibility. Analyses of PFC microglia revealed that Cx3cr1Cre/+:Bdnffl/fl mice had shifts in phenotypic markers and gene expression. In a separate cohort, synaptoneurosomes were collected from the PFC and western blotting was performed for synaptic markers. These experiments showed that Cx3cr1Cre/+:Bdnffl/fl mice had baseline deficits in GluN2B, and that 7 days of CUS additionally reduced GluN2A levels in Cx3cr1Cre/+:Bdnffl/fl mice, but not genotype controls. Behavioral and cognitive testing showed that this coincided with exacerbated stress effects on temporal object recognition in Cx3cr1Cre/+:Bdnffl/fl mice. These results indicate that microglial BDNF promotes glutamate receptor expression in the PFC. As such, mice with deficient microglial BDNF had increased susceptibility to the behavioral and cognitive consequences of stress.
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Affiliation(s)
- Samuel C Woodburn
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Helina S Asrat
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - James K Flurer
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Hana C Schwierling
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Justin L Bollinger
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lauren L Vollmer
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Eric S Wohleb
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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22
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Deyama S, Kaneda K. Role of neurotrophic and growth factors in the rapid and sustained antidepressant actions of ketamine. Neuropharmacology 2023; 224:109335. [PMID: 36403852 DOI: 10.1016/j.neuropharm.2022.109335] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/10/2022] [Accepted: 11/12/2022] [Indexed: 11/18/2022]
Abstract
The neurotrophic hypothesis of depression proposes that reduced levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) contribute to neuronal atrophy or loss in the prefrontal cortex (PFC) and hippocampus and impaired hippocampal adult neurogenesis, which are associated with depressive symptoms. Chronic, but acute, treatment with typical monoaminergic antidepressants can at least partially reverse these deficits, in part via induction of BDNF and/or VEGF expression, consistent with their delayed onset of action. Ketamine, an N-methyl-d-aspartate receptor antagonist, exerts rapid and sustained antidepressant effects. Rodent studies have revealed that ketamine rapidly increases BDNF and VEGF release and/or expression in the PFC and hippocampus, which in turn increases the number and function of spine synapses in the PFC and hippocampal neurogenesis. Ketamine also induces the persistent release of insulin-like growth factor 1 (IGF-1) in the PFC of male mice. These neurotrophic effects of ketamine are associated with its rapid and sustained antidepressant effects. In this review, we first provide an overview of the neurotrophic hypothesis of depression and then discuss the role of BDNF, VEGF, IGF-1, and other growth factors (IGF-2 and transforming growth factor-β1) in the antidepressant effects of ketamine and its enantiomers. This article is part of the Special Issue on 'Ketamine and its Metabolites'.
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Affiliation(s)
- Satoshi Deyama
- Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
| | - Katsuyuki Kaneda
- Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
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23
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Islas-Preciado D, Splinter TFL, Ibrahim M, Black N, Wong S, Lieblich SE, Liu-Ambrose T, Barha CK, Galea LAM. Sex and BDNF Val66Met polymorphism matter for exercise-induced increase in neurogenesis and cognition in middle-aged mice. Horm Behav 2023; 148:105297. [PMID: 36623432 DOI: 10.1016/j.yhbeh.2022.105297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 11/23/2022] [Accepted: 12/15/2022] [Indexed: 01/09/2023]
Abstract
Females show greater benefits of exercise on cognition in both humans and rodents, which may be related to brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP), the Val66Met polymorphism, within the human BDNF gene, causes impaired activity-dependent secretion of neuronal BDNF and impairments to some forms of memory. We evaluated whether sex and BDNF genotype (Val66Met polymorphism (Met/Met) versus wild-type (Val/Val)) influenced the ability of voluntary running to enhance cognition and hippocampal neurogenesis in mice. Middle-aged C57BL/6J (13 months) mice were randomly assigned to either a control or an aerobic training (AT) group (running disk access). Mice were trained on the visual discrimination and reversal paradigm in a touchscreen-based technology to evaluate cognitive flexibility. BDNF Met/Met mice had fewer correct responses compared to BDNF Val/Val mice on both cognitive tasks. Female BDNF Val/Val mice showed greater cognitive flexibility compared to male mice regardless of AT. Despite running less than BDNF Val/Val mice, AT improved performance in both cognitive tasks in BDNF Met/Met mice. AT increased neurogenesis in the ventral hippocampus of BDNF Val/Val mice of both sexes and increased the proportion of mature type 3 doublecortin-expressing cells in the dorsal hippocampus of female mice only. Our results indicate AT improved cognitive performance in BDNF Met/Met mice and increased hippocampal neurogenesis in BDNF Val/Val mice in middle age. Furthermore, middle-aged female mice may benefit more from AT than males in terms of neuroplasticity, an effect that was influenced by the BDNF Val66Met polymorphism.
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Affiliation(s)
- Dannia Islas-Preciado
- Department of Psychology, University of British Columbia, Canada; Dajavad Mowifaghian Centre for Brain Health, University of British Columbia, Canada; Lab de Neuropsicofarmacología, Dirección de Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 14370, México
| | | | - Muna Ibrahim
- Department of Psychology, University of British Columbia, Canada
| | - Natasha Black
- Department of Psychology, University of British Columbia, Canada
| | - Sarah Wong
- Department of Psychology, University of British Columbia, Canada
| | | | - Teresa Liu-Ambrose
- Department of Physical Therapy, University of British Columbia, Canada; Dajavad Mowifaghian Centre for Brain Health, University of British Columbia, Canada
| | - Cindy K Barha
- Department of Physical Therapy, University of British Columbia, Canada; Dajavad Mowifaghian Centre for Brain Health, University of British Columbia, Canada.
| | - Liisa A M Galea
- Department of Psychology, University of British Columbia, Canada; Dajavad Mowifaghian Centre for Brain Health, University of British Columbia, Canada.
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24
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Mansour HM, El-Khatib AS. Repositioning of receptor tyrosine kinase inhibitors. RECEPTOR TYROSINE KINASES IN NEURODEGENERATIVE AND PSYCHIATRIC DISORDERS 2023:353-401. [DOI: 10.1016/b978-0-443-18677-6.00010-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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25
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Lu X, Liu H, Cai Z, Hu Z, Ye M, Gu Y, Wang Y, Wang D, Lu Q, Shen Z, Shen X, Huang C. ERK1/2-dependent BDNF synthesis and signaling is required for the antidepressant effect of microglia stimulation. Brain Behav Immun 2022; 106:147-160. [PMID: 35995236 DOI: 10.1016/j.bbi.2022.08.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/27/2022] [Accepted: 08/13/2022] [Indexed: 10/31/2022] Open
Abstract
Depressed mice have lower numbers of microglia in the dentate gyrus (DG). Reversal of this decline by a single low dose of lipopolysaccharide (LPS) may have antidepressant effects, but there is little information on the molecular mechanisms underlying this effect. It is known that impairment of brain-derived neurotrophic factor (BDNF) signaling is involved in the development of depression. Here, we used a combination of neutralizing antibodies, mutant mice, and pharmacological approaches to test the role of BDNF-tyrosine kinase receptor B (TrkB) signaling in the DG in the effect of microglial stimulation. Our results suggest that inhibition of BDNF signaling by infusion of an anti-BDNF antibody, the BDNF receptor antagonist K252a, or knock-in of the mutant BDNF Val68Met allele abolished the antidepressant effect of LPS in chronically stressed mice. Increased BDNF synthesis in DG, mediated by extracellular signal-regulated kinase1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling, was essential for the antidepressant effect of microglial stimulation. These results suggest that increased BDNF synthesis through activation of ERK1/2 caused by a single LPS injection and subsequent TrkB signaling are required for the antidepressant effect of hippocampal microglial stimulation.
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Affiliation(s)
- Xu Lu
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Huijun Liu
- Department of Pharmacy, Yancheng First Hospital, the Fourth Affiliated Hospital of Nantong University, #66 Renmin South Road, Yancheng 224006, Jiangsu, China
| | - Zixuan Cai
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Zhichao Hu
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Minxiu Ye
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Yue Gu
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Yue Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Dan Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China
| | - Qun Lu
- Department of Pharmacy, Nantong Third Hospital Affiliated to Nantong University, #60 Middle Qingnian Road, Nantong 226006, Jiangsu, China
| | - Zhongxia Shen
- Department of Psychosomatic and Psychiatric Diseases, Huzhou Third Municipal Hospital, the Affiliated Hospital of Huzhou University, #2088 Tiaoxi East Road, Huzhou 313000, Zhejiang, China
| | - Xinhua Shen
- Department of Psychosomatic and Psychiatric Diseases, Huzhou Third Municipal Hospital, the Affiliated Hospital of Huzhou University, #2088 Tiaoxi East Road, Huzhou 313000, Zhejiang, China
| | - Chao Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China.
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26
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Musazzi L, Tornese P, Sala N, Lee FS, Popoli M, Ieraci A. Acute stress induces an aberrant increase of presynaptic release of glutamate and cellular activation in the hippocampus of BDNF Val/Met mice. J Cell Physiol 2022; 237:3834-3844. [PMID: 35908196 PMCID: PMC9796250 DOI: 10.1002/jcp.30833] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/15/2022] [Accepted: 07/11/2022] [Indexed: 01/01/2023]
Abstract
Stressful life events are considered major risk factors for the development of several psychiatric disorders, though people differentially cope with stress. The reasons for this are still largely unknown but could be accounted for by individual genetic variants, previous life events, or the kind of stressors. The human brain-derived neurotrophic factor (BDNF) Val66Met variant, which was found to impair intracellular trafficking and activity-dependent secretion of BDNF, has been associated with increased susceptibility to develop several neuropsychiatric disorders, although there is still some controversial evidence. On the other hand, acute stress has been consistently demonstrated to promote the release of glutamate in cortico-limbic regions and altered glutamatergic transmission has been reported in psychiatric disorders. However, it is not known if the BDNF Val66Met single-nucleotide polymorphism (SNP) affects the stress-induced presynaptic glutamate release. In this study, we exposed adult male BDNFVal/Val and BDNFVal/Met knock-in mice to 30 min of acute restraint stress. Plasma corticosterone levels, glutamate release, protein, and gene expression in the hippocampus were analyzed immediately after the end of the stress session. Acute restraint stress similarly increased plasma corticosterone levels and nuclear glucocorticoid receptor levels and phosphorylation in both BDNFVal/Val and BDNFVal/Met mice. However, acute restraint stress induced higher increases in hippocampal presynaptic release of glutamate, phosphorylation of cAMP-response element binding protein (CREB), and levels of the immediate early gene c-fos of BDNFVal/Met compared to BFNFVal/Val mice. Moreover, acute restraint stress selectively increased phosphorylation levels of synapsin I at Ser9 and at Ser603 in BDNFVal/Val and BDNFVal/Met mice, respectively. In conclusion, we report here that the BDNF Val66Met SNP knock-in mice display an altered response to acute restraint stress in terms of hippocampal glutamate release, CREB phosphorylation, and neuronal activation, compared to wild-type animals. Taken together, these results could partially explain the enhanced vulnerability to stressful events of Met carriers reported in both preclinical and clinical studies.
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Affiliation(s)
- Laura Musazzi
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMonzaItaly
| | - Paolo Tornese
- Dipartimento di Scienze FarmaceuticheUniversity of MilanMilanItaly
| | - Nathalie Sala
- Dipartimento di Scienze FarmaceuticheUniversity of MilanMilanItaly
| | - Francis S. Lee
- Department of PsychiatryWeill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Maurizio Popoli
- Dipartimento di Scienze FarmaceuticheUniversity of MilanMilanItaly
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27
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Ng H, Alfian SD, Abdulah R, Barliana MI. BDNF val66met genotype is not associated with psychological distress: A cross-sectional study in Indonesian Pharmacy young adults. Medicine (Baltimore) 2022; 101:e29481. [PMID: 35905264 PMCID: PMC9333470 DOI: 10.1097/md.0000000000029481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The number of mental disorders has been increasing but has yet to receive sufficient attention. In particular, healthcare students and professionals tend to have high stress burden. Finding the root cause of psychological distress is important to formulate a method for early detection and prevention. The association of brain-derived neurotrophic factor val66met polymorphism to neuropsychiatric disorders has been widely studied. To study the interplay between brain-derived neurotrophic factor val66met polymorphism and sociodemographic factors in the pathogenesis of psychological distress among Indonesian Pharmacy students. Level of psychological distress and sociodemographic profiling was collected by using the Kessler Psychological Distress Scale and sociodemographic questionnaires, respectively. Genotyping was performed using polymerase chain reaction-amplified refractory mutation system. Pearson's chi square and binomial logistic tests were used to evaluate the correlation. This study recruited 148 participants. The psychological distress levels of the participants were well (27.03%), mild (37.16%), moderate (25.00%), and severe (10.81%). Genotypic distributions were AA (25.67%), GA (50.68%), and GG (23.65%). No statistical significance between genotype and psychological distress was found in the study (P = .076). The sociodemographic factors also showed non significance, except for the source of tuition fee among women students (P = .049). Psychological distress is not affected by genotypic and sociodemographic factors. Further confirmatory research with larger and broader populations is required.
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Affiliation(s)
- Henry Ng
- Department of Biological Pharmacy, Biotechnology Laboratory, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Sofa Dewi Alfian
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Rizky Abdulah
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Melisa I. Barliana
- Department of Biological Pharmacy, Biotechnology Laboratory, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
- *Correspondence: Melisa I. Barliana, Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung Sumedang KM. 21, Jatinangor 45363, Indonesia (e-mail: )
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28
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Williams RA, Johnson KW, Lee FS, Hemmings HC, Platholi J. A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures. Front Mol Neurosci 2022; 15:927149. [PMID: 35813074 PMCID: PMC9260310 DOI: 10.3389/fnmol.2022.927149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 06/07/2022] [Indexed: 12/02/2022] Open
Abstract
Multiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more prolonged neurological dysfunction following anesthesia are less clear. Here, we show that brain-derived neurotrophic factor (BDNF), a growth factor implicated in synaptic plasticity and dysfunction, enhances glutamate synaptic vesicle exocytosis, and that attenuation of vesicular BDNF release by isoflurane contributes to transient depression of excitatory synaptic transmission in mice. This reduction in synaptic vesicle exocytosis by isoflurane was acutely irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met; rs6265) compared to neurons from wild-type mice. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism in persistent changes of synaptic function following isoflurane exposure. These short-term persistent alterations in excitatory synaptic transmission indicate a role for human genetic variation in anesthetic effects on synaptic plasticity and neurocognitive function.
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Affiliation(s)
- Riley A. Williams
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, United States
| | - Kenneth W. Johnson
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States
| | - Francis S. Lee
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States,Department of Psychiatry, Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY, United States,Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States
| | - Hugh C. Hemmings
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, United States,Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States
| | - Jimcy Platholi
- Department of Anesthesiology, Weill Cornell Medicine, New York, NY, United States,Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States,*Correspondence: Jimcy Platholi,
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29
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Touchant M, Labonté B. Sex-Specific Brain Transcriptional Signatures in Human MDD and Their Correlates in Mouse Models of Depression. Front Behav Neurosci 2022; 16:845491. [PMID: 35592639 PMCID: PMC9110970 DOI: 10.3389/fnbeh.2022.845491] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 04/05/2022] [Indexed: 01/13/2023] Open
Abstract
Major depressive disorder (MDD) is amongst the most devastating psychiatric conditions affecting several millions of people worldwide every year. Despite the importance of this disease and its impact on modern societies, still very little is known about the etiological mechanisms. Treatment strategies have stagnated over the last decades and very little progress has been made to improve the efficiency of current therapeutic approaches. In order to better understand the disease, it is necessary for researchers to use appropriate animal models that reproduce specific aspects of the complex clinical manifestations at the behavioral and molecular levels. Here, we review the current literature describing the use of mouse models to reproduce specific aspects of MDD and anxiety in males and females. We first describe some of the most commonly used mouse models and their capacity to display unique but also shared features relevant to MDD. We then transition toward an integral description, combined with genome-wide transcriptional strategies. The use of these models reveals crucial insights into the molecular programs underlying the expression of stress susceptibility and resilience in a sex-specific fashion. These studies performed on human and mouse tissues establish correlates into the mechanisms mediating the impact of stress and the extent to which different mouse models of chronic stress recapitulate the molecular changes observed in depressed humans. The focus of this review is specifically to highlight the sex differences revealed from different stress paradigms and transcriptional analyses both in human and animal models.
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Affiliation(s)
- Maureen Touchant
- CERVO Brain Research Centre, Québec, QC, Canada
- Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Benoit Labonté
- CERVO Brain Research Centre, Québec, QC, Canada
- Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec, QC, Canada
- *Correspondence: Benoit Labonté
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30
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Wolff BS, Allen HR, Feng LR, Saligan LN. BDNF Val66Met Polymorphism Reduces the Fatigue-Like Effects of 5-Fluorouracil on Voluntary Wheel-Running Activity in Mice. Front Behav Neurosci 2022; 16:880969. [PMID: 35558437 PMCID: PMC9087735 DOI: 10.3389/fnbeh.2022.880969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Fatigue is a persistent and debilitating symptom following cancer treatments such as chemotherapy. Recent clinical studies have suggested a common single-nucleotide polymorphism of brain-derived neurotrophic factor (BDNF), Val66Met (rs6265), may be related to the severity of fatigue following cancer treatment. In this study, we tested transgenic mice homozygous for the human Val66Met BDNF gene and wild-type controls. We injected three doses of 5-fluorouracil (5FU) as a model of chemotherapy treatment, and we used changes in voluntary wheel running activity (VWRA) as a measure of fatigue-like behavior. Prior to 5FU injection, we found that during the baseline wheel-running period, the Val66Met mice lost more weight than WT controls. We next administered 5FU and saw a robust fatigue-like phenotype that lasted about 2 weeks. During the first week, the fatigue-like phenotype was less severe in the Val66Met mice and unrelated to the age of the mice. In contrast, during the second week after 5FU treatment, the fatigue-like phenotype was unrelated to the BDNF genotype but was more severe in middle aged mice compared to young mice. We conclude that the BDNF polymorphism may play a direct, protective role against chemotherapy-induced fatigue.
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31
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Caradonna SG, Zhang TY, O’Toole N, Shen MJ, Khalil H, Einhorn NR, Wen X, Parent C, Lee FS, Akil H, Meaney MJ, McEwen BS, Marrocco J. Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress. Neuropsychopharmacology 2022; 47:987-999. [PMID: 34848858 PMCID: PMC8938529 DOI: 10.1038/s41386-021-01219-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/28/2021] [Accepted: 10/18/2021] [Indexed: 12/24/2022]
Abstract
The multifactorial etiology of stress-related disorders necessitates a constant interrogation of the molecular convergences in preclinical models of stress that use disparate paradigms as stressors spanning from environmental challenges to genetic predisposition to hormonal signaling. Using RNA-sequencing, we investigated the genomic signatures in the ventral hippocampus common to mouse models of stress. Chronic oral corticosterone (CORT) induced increased anxiety- and depression-like behavior in wild-type male mice and male mice heterozygous for the gene coding for brain-derived neurotrophic factor Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of male mice, chronic social defeat stress (CSDS) led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, namely standard housing or enriched environment. Rank-rank-hypergeometric overlap (RRHO), a threshold-free approach that ranks genes by their p value and effect size direction, was used to identify genes from a continuous gradient of significancy that were concordant across groups. In mice treated with CORT and in standard-housed susceptible mice, differentially expressed genes (DEGs) were concordant for gene networks involved in neurotransmission, cytoskeleton function, and vascularization. Weighted gene co-expression analysis generated 54 gene hub modules and revealed two modules in which both CORT and CSDS-induced enrichment in DEGs, whose function was concordant with the RRHO predictions, and correlated with behavioral resilience or susceptibility. These data showed transcriptional concordance across models in which the stress coping depends upon hormonal, environmental, or genetic factors revealing common genomic drivers that embody the multifaceted nature of stress-related disorders.
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Affiliation(s)
- Salvatore G. Caradonna
- grid.134907.80000 0001 2166 1519Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY USA
| | - Tie-Yuan Zhang
- grid.14709.3b0000 0004 1936 8649Douglas Mental Health University Institute, McGill University, Montreal, QC Canada
| | - Nicholas O’Toole
- grid.14709.3b0000 0004 1936 8649Douglas Mental Health University Institute, McGill University, Montreal, QC Canada
| | - Mo-Jun Shen
- grid.452264.30000 0004 0530 269XSingapore Institute for Clinical Sciences, Singapore, Singapore
| | - Huzefa Khalil
- grid.214458.e0000000086837370Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI USA
| | - Nathan R. Einhorn
- grid.134907.80000 0001 2166 1519Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY USA
| | - Xianglan Wen
- grid.14709.3b0000 0004 1936 8649Douglas Mental Health University Institute, McGill University, Montreal, QC Canada
| | - Carine Parent
- grid.14709.3b0000 0004 1936 8649Douglas Mental Health University Institute, McGill University, Montreal, QC Canada
| | - Francis S. Lee
- grid.5386.8000000041936877XDepartment of Psychiatry, Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, NY USA
| | - Huda Akil
- grid.214458.e0000000086837370Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI USA
| | - Michael J. Meaney
- grid.14709.3b0000 0004 1936 8649Douglas Mental Health University Institute, McGill University, Montreal, QC Canada ,grid.452264.30000 0004 0530 269XSingapore Institute for Clinical Sciences, Singapore, Singapore ,grid.4280.e0000 0001 2180 6431Yong Loo Lin School of Medicine, Singapore, Singapore ,grid.14709.3b0000 0004 1936 8649Sackler Program for Epigenetics & Psychobiology, McGill University, Montreal, QC Canada
| | - Bruce S. McEwen
- grid.134907.80000 0001 2166 1519Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY USA
| | - Jordan Marrocco
- Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.
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Tan P, Xue T, Wang Y, Hu Z, Su J, Yang R, Ji J, Ye M, Chen Z, Huang C, Lu X. Hippocampal NR6A1 impairs CREB-BDNF signaling and leads to the development of depression-like behaviors in mice. Neuropharmacology 2022; 209:108990. [PMID: 35183538 DOI: 10.1016/j.neuropharm.2022.108990] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 12/20/2022]
Abstract
Chronic stress exposure is a risk factor that can induce the development of depression-like behaviors by impairing the hippocampal cyclic adenosine monophosphate-response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling, but its underlying mechanisms remain largely unknown. We identified an orphan receptor that can suppress the activity of CREB, nuclear receptor sub-family 6, group A, member 1 (NR6A1), in mouse brain neurons. Given the critical role of the impaired CREB-BDNF signaling in depression, we speculate that the neuronal NR6A1 may mediate the pathogenesis of depression. Results showed that chronic unpredictable stress (CUS) markedly increased the expression levels of hippocampal NR6A1 protein, which reduced hippocampal CREB phosphorylation and BDNF protein expression. Overexpression of hippocampal NR6A1 in stress-naïve mice simulated chronic stress, inducing depression-like behaviors in the tail suspension test, forced swimming test, and sucrose preference test, and impairing the hippocampal CREB-BDNF signaling cascade. Genetic knockdown of hippocampal NR6A1 did not affect mouse behaviors but prevented the CUS-induced depression-like behaviors in mice and impairment in hippocampal CREB-BDNF signaling. Furthermore, genetic knockdown of hippocampal CREB or BDNF abrogated the preventive effect of hippocampal NR6A1 down-regulation on CUS-induced depression-like behaviors in mice. Collectively, these results for the first time identified a nuclear expression of NR6A1 in mouse brain neurons, and showed that the abnormally increased NR6A1 protein in the hippocampus in mice treated with or without chronic stress can impair the CREB-BDNF signaling cascade and lead to the development of depression-like behaviors. Hippocampal NR6A1 could be a novel target for the development of antidepressants.
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Affiliation(s)
- Pingping Tan
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Ting Xue
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Yue Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Zhichao Hu
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Jianbin Su
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University, First People's Hospital of Nantong City, #6 North Road Hai'er Xiang, Nantong, 226001, Jiangsu, China
| | - Rongrong Yang
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Jiangsu Province, #20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Jianlin Ji
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Minxiu Ye
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Zhuo Chen
- Invasive Technology Department, Affiliated Hospital 2 of Nantong University, First People's Hospital of Nantong City, #6 North Road Hai'er Xiang, Nantong, 226001, Jiangsu, China
| | - Chao Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu, China.
| | - Xu Lu
- Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu, China.
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Laine M, Shansky R. Rodent models of stress and dendritic plasticity – Implications for psychopathology. Neurobiol Stress 2022; 17:100438. [PMID: 35257016 PMCID: PMC8897597 DOI: 10.1016/j.ynstr.2022.100438] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/04/2022] [Accepted: 02/09/2022] [Indexed: 11/28/2022] Open
Abstract
Stress, as commonplace as it is, is a major environmental risk factor for psychopathology. While this association intuitively, anecdotally, and empirically makes sense, we are still very early in the process of understanding what the neurobiological manifestations of this risk truly are. Seminal work from the past few decades has established structural plasticity in the brain as a potential key mechanism. In this review we discuss evidence linking particularly chronic stress exposure in rodent models to plasticity at the dendrites, like remodeling of dendritic branches and spines, in a range of brain regions. A number of candidate mechanisms that seek to explain how stress influences neuroanatomy at this level have been proposed, utilizing in vivo, ex vivo and in vitro methods. However, a large gap still remains in our knowledge of how such dynamic structural changes ultimately relate to downstream effects such as altered affective and cognitive states relevant for psychopathology. We propose that future work expand our understanding of plasticity of specific stress-related brain circuits and cell-types. We also note that the vast majority of the work has been conducted solely on male rodents. The next big strides in our understanding of the neurobiology of psychopathology will require the inclusion of female subjects, as several studies have suggested both sex divergent and convergent features. By understanding plasticity, we can harness it. The growth of this body of knowledge will inform our efforts to improve the therapeutic options for stress-related psychopathology.
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Gomes MGS, Tractenberg SG, Orso R, Viola TW, Grassi-Oliveira R. Sex differences in risk behavior parameters in adolescent mice: Relationship with brain-derived neurotrophic factor in the medial prefrontal cortex. Neurosci Lett 2022; 766:136339. [PMID: 34762979 DOI: 10.1016/j.neulet.2021.136339] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 02/08/2023]
Abstract
Adolescence is as a period of development characterized by impulsive and risk-seeking behaviors. Risk behaviors (RB) involves exposure to dangerous or negative consequences to achieve goal-directed behaviors, such as reward-seeking. On the other hand, risk aversion/assessment behaviors allow the individual to gather information or avoid potentially threatening situations. Evidence has suggested that both behavioral processes, RB and risk assessment (RA), may have sex-differences. However, sex-specific behavioral patterns implicated in RB and RA are not fully understood. To address that, we investigated sex differences in risk-behavioral parameters in a decision-making task developed for rodents. In addition, we investigated the potential role of sex-dependent differences in gene expression of brain-derived neurotrophic factor (BDNF) exon IV in the medial prefrontal cortex (mPFC), which has been implicated to mediate PFC-related behavioral dysfunctions. Male and female C57BL/6J adolescent mice were evaluated in the elevated plus-maze (EPM) to assess anxiety-like behaviors and in the predator-odor risk taking (PORT) task. The PORT task is a decision-making paradigm in which a conflict between the motivation towards reward pursuit and the threat elicited by predatory olfactory cues (coyote urine) is explored. After behavioral testing, animals were euthanized and BDNF exon IV gene expression was measured by RT-qPCR. Comparative and correlational analyses for behavioral and molecular parameters were performed for both sexes. We observed that female mice spent more time exploring the middle chamber of the PORT apparatus in the aversive condition, which is an indicative of avoidance behavior. Female mice also had a higher latency to collect the reward than male mice and presented less time exploring the open arms of the EPM. BDNF exon IV gene expression was higher among females, and there was a positive correlation between the BDNF and PORT behavioral parameters. Our findings suggest sex-dependent effects in the PORT task. Females presented higher RA and avoidance behavior profile and expressed higher levels of BDNF exon IV in the mPFC. Moreover, higher BDNF expression was correlated with RA behaviors, which suggests that adolescent females tend to evaluate the risks more than adolescent males and that BDNF gene expression may be mediating decision-making processes.
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Affiliation(s)
- Marco G S Gomes
- Developmental Cognitive Neuroscience Lab (DCNL), Brain Institute of Rio Grande do Sul (BraIns), Pontifical University Catholic of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - Saulo G Tractenberg
- Developmental Cognitive Neuroscience Lab (DCNL), Brain Institute of Rio Grande do Sul (BraIns), Pontifical University Catholic of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - Rodrigo Orso
- Developmental Cognitive Neuroscience Lab (DCNL), Brain Institute of Rio Grande do Sul (BraIns), Pontifical University Catholic of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Denmark
| | - Thiago W Viola
- Developmental Cognitive Neuroscience Lab (DCNL), Brain Institute of Rio Grande do Sul (BraIns), Pontifical University Catholic of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil
| | - Rodrigo Grassi-Oliveira
- Developmental Cognitive Neuroscience Lab (DCNL), Brain Institute of Rio Grande do Sul (BraIns), Pontifical University Catholic of Rio Grande Do Sul (PUCRS), Porto Alegre, Brazil; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Denmark.
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Sandrini L, Amadio P, Ieraci A, Malara A, Werba JP, Soprano PM, Balduini A, Zarà M, Bonomi A, Veglia F, Colombo GI, Popoli M, Lee FS, Tremoli E, Barbieri SS. The α 2-adrenergic receptor pathway modulating depression influences the risk of arterial thrombosis associated with BDNFVal66Met polymorphism. Biomed Pharmacother 2021; 146:112557. [PMID: 34965503 DOI: 10.1016/j.biopha.2021.112557] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/09/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022] Open
Abstract
Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have previously shown that the Brain-Derived Neurotrophic Factor (BDNF)Val66Met polymorphism, related to depression, is associated with arterial thrombosis in mice, and with an increased risk of acute myocardial infarction in humans. Herein, expanding the previous findings on BDNFVal66Met polymorphism, we show that desipramine, a norepinephrine reuptake-inhibitor, rescues behavioral impairments, reduces the arterial thrombosis risk, abolishes pathological coagulation and platelet hyper-reactivity, normalizes leukocyte, platelet, and bone marrow megakaryocyte number and restores physiological norepinephrine levels in homozygous knock-in BDNF Val66Met (BDNFMet/Met) mice. The in vitro data confirm the enhanced procoagulant activity and the alpha2A-adrenergic receptor (α2A-ADR) overexpression found in BDNFMet/Met mice and we provide evidence that, in presence of Met variant, norepinephrine is crucial to up-regulate procoagulant activity and to enhance platelet generation. The α2-ADR antagonist rauwolscine rescues the prothrombotic phenotype in BDNFMet/Met mice and reduces procoagulant activity and platelet generation in cells transfected with BDNFMet plasmid or exposed to pro-BDNFMet peptide. Finally, we show that homozygous BDNFMet/Met CAD patients have hyper-reactive platelets overexpressing abundant α2A-ADR. The great proplatelet release from their megakaryocytes well reflects their higher circulating platelet number compared to BDNFVal/Val patients. These data reveal an unprecedented described role of Met allele in the dysregulation of norepinephrine/α2A-ADR pathway that may explain the predisposition to arterial thrombosis. Overall, the development of α2A-ADR inhibitors might represent a pharmacological treatment for depression-associated thrombotic conditions in this specific subgroup of CAD patients.
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Affiliation(s)
| | | | - Alessandro Ieraci
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Alessandro Malara
- Department of Molecular Medicine, University of Pavia, Pavia, Italy; IRCCS San Matteo Foundation, Pavia, Italy
| | - José P Werba
- Centro Cardiologico Monzino, IRCCS, Milan, Italy
| | - Paolo M Soprano
- Department of Molecular Medicine, University of Pavia, Pavia, Italy; IRCCS San Matteo Foundation, Pavia, Italy
| | - Alessandra Balduini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy; IRCCS San Matteo Foundation, Pavia, Italy
| | - Marta Zarà
- Centro Cardiologico Monzino, IRCCS, Milan, Italy
| | - Alice Bonomi
- Centro Cardiologico Monzino, IRCCS, Milan, Italy
| | | | | | - Maurizio Popoli
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Francis S Lee
- Department of Psychiatry, Weill Cornell Medical College, New York, USA
| | - Elena Tremoli
- Centro Cardiologico Monzino, IRCCS, Milan, Italy; Maria Cecilia Hospital, Cotignola, Italy
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Jia Y, Zhuang X, Zhang Y, Zhao M, Chen N, Li W, Zhu F, Guo C, Li Y, Wang Q, Li Y, Zhang L. The brain targeted delivery of programmed cell death 4 specific siRNA protects mice from CRS-induced depressive behavior. Cell Death Dis 2021; 12:1077. [PMID: 34772918 PMCID: PMC8590023 DOI: 10.1038/s41419-021-04361-9] [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: 05/07/2021] [Revised: 10/13/2021] [Accepted: 10/27/2021] [Indexed: 12/12/2022]
Abstract
Depression is one of the most common psychiatric disorders. Recently, studies demonstrate that antidepressants generating BDNF not only maintain synaptic signal transmission but also repress neuroinflammatory cytokines such as IL-6 and IL-1β. Therefore, promoting BDNF expression provides a strategy for the treatment of depression. Our recent research has indicated that programmed cell death 4 (Pdcd4) is a new target for antidepressant treatment by facilitating BDNF. Herein, we modified Pdcd4 specific small interfering RNA (siPdcd4) with the rabies virus glycoprotein peptide (RVG/siPdcd4) which enables it cross the blood-brain barrier (BBB). We found that RVG/siPdcd4 complex was selectively delivered to neurons and microglia and silenced the expression of Pdcd4, thereby up-regulating the level of BDNF and down-regulating IL-6 and IL-1β expression. More importantly, RVG/siPdcd4 injection attenuated synaptic plasticity impairment and protected mice from CRS-induced depressive behavior. These findings suggest that RVG/siPdcd4 complex is a potential therapeutic medicine for depression.
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Affiliation(s)
- Yufeng Jia
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Xiao Zhuang
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Yi Zhang
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Ming Zhao
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Nuo Chen
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Wen Li
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Faliang Zhu
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Chun Guo
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Yan Li
- Department of Pathogenic Biology, School of Basic Medical Science, Shandong University, 250012, Jinan, Shandong, China
| | - Qun Wang
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China
| | - Yuan Li
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China.
| | - Lining Zhang
- Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, 250012, Jinan, Shandong, China.
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A Role of BDNF in the Depression Pathogenesis and a Potential Target as Antidepressant: The Modulator of Stress Sensitivity "Shati/Nat8l-BDNF System" in the Dorsal Striatum. Pharmaceuticals (Basel) 2021; 14:ph14090889. [PMID: 34577589 PMCID: PMC8469819 DOI: 10.3390/ph14090889] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/27/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Depression is one of the most common mental diseases, with increasing numbers of patients globally each year. In addition, approximately 30% of patients with depression are resistant to any treatment and do not show an expected response to first-line antidepressant drugs. Therefore, novel antidepressant agents and strategies are required. Although depression is triggered by post-birth stress, while some individuals show the pathology of depression, others remain resilient. The molecular mechanisms underlying stress sensitivity remain unknown. Brain-derived neurotrophic factor (BDNF) has both pro- and anti-depressant effects, dependent on brain region. Considering the strong region-specific contribution of BDNF to depression pathogenesis, the regulation of BDNF in the whole brain is not a beneficial strategy for the treatment of depression. We reviewed a novel finding of BDNF function in the dorsal striatum, which induces vulnerability to social stress, in addition to recent research progress regarding the brain regional functions of BDNF, including the prefrontal cortex, hippocampus, and nucleus accumbens. Striatal BDNF is regulated by Shati/Nat8l, an N-acetyltransferase through epigenetic regulation. Targeting of Shati/Nat8l would allow BDNF to be striatum-specifically regulated, and the striatal Shati/Nat8l-BDNF pathway could be a promising novel therapeutic agent for the treatment of depression by modulating sensitivity to stress.
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Zhong CC, Gao YN, Huang XC, Zhu X, Miao HH, Xu XG, Qin YB. Cannabinoid receptor agonist WIN55212-2 reduces unpredictable mild stress-induced depressive behavior of rats. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1170. [PMID: 34430611 PMCID: PMC8350660 DOI: 10.21037/atm-21-3143] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 07/02/2021] [Indexed: 12/12/2022]
Abstract
Background Depression is a neurological disorder characterized by persistent low mood. A number of studies have suggested that the use of type 1 cannabinoid receptor (CB1R) agonists can reduce depressive behavior, but its effect on the depressive behavior and nerve damage of rats exposed to chronic unpredictable mild stress (CUMS) has not been reported. Methods Rats were exposed to CUMS for 4 weeks to induce depressive behavior. Male Sprague-Dawley (SD) rats aged 6–8 weeks were randomly divided into six groups: control group (control), depression group (CUMS), depression + fluoxetine group (Flu), depression + WIN55212-2 group (WIN), depression + NF-κB inhibitor group (PDTC), and depression + WIN + PDTC group (WIN + PDTC). We performed four behavioral experiments test to evaluate the depressive behaviors of rats. Hematoxylin and eosin (HE) and Nissl staining were performed to observe the neuron structures of the hippocampus. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2). Biochemical experiments were performed to evaluate the concentrations of nitric oxide (NO), malondialdehyde (MDA), reactive oxygen species (ROS), and superoxide dismutase (SOD). Fluorescence quantitative PCR was used to detect the mRNA expression of brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB), and inducible nitric oxide synthase (iNOS) in the hippocampus, and western blot was performed to detect protein expression levels related to the NF-κB signaling pathway in the hippocampus. Results Compared with the normal control group, CUMS significantly induced abnormal behaviors in stressed rats. The concentrations of pro-inflammatory factors and oxidative stress injury factors in the hippocampus of the CUMS group increased significantly. The interventions of Flu, WIN, and PDTC significantly reduced neuroinflammation and oxidative stress injury. Compared with the WIN group, the WIN + PDTC intervention group had better results. In addition, WIN could significantly inhibit the activation of the NF-κB signaling pathway. Conclusions This study showed that cannabinoid receptor agonists can reduce the CUMS-induced depressive behaviors of rats by blocking the NF-κB signaling pathway to alleviate neuroinflammation and oxidative stress injury.
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Affiliation(s)
- Chao-Chao Zhong
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| | - Ya-Nan Gao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xin-Chong Huang
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xiang Zhu
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| | - Hai-Hang Miao
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xing-Guo Xu
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yi-Bin Qin
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
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Li N, Teng SW, Zhao L, Li JR, Xu JL, Li N, Shuai JC, Chen ZY. Carboxypeptidase E Regulates Activity-Dependent TrkB Neuronal Surface Insertion and Hippocampal Memory. J Neurosci 2021; 41:6987-7002. [PMID: 34266900 PMCID: PMC8372023 DOI: 10.1523/jneurosci.0236-21.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/14/2021] [Accepted: 07/09/2021] [Indexed: 11/21/2022] Open
Abstract
Activity-dependent insertion of the tropomyosin-related kinase B (TrkB) receptor into the plasma membrane can explain, in part, the preferential effect of brain-derived neurotrophic factor (BDNF) on active neurons and synapses; however, the underlying molecular mechanisms remain obscure. Here, we report a novel function for carboxypeptidase E (CPE) in controlling chemical long-term potentiation stimuli-induced TrkB surface delivery in hippocampal neurons. Total internal reflection fluorescence assays and line plot assays showed that CPE facilitates TrkB transport from dendritic shafts to the plasma membrane. The Box2 domain in the juxtamembrane region of TrkB and the C terminus of CPE are critical for the activity-dependent plasma membrane insertion of TrkB. Moreover, the transactivator of transcription TAT-CPE452-466, which could block the association between CPE and TrkB, significantly inhibited neuronal activity-enhanced BDNF signaling and dendritic spine morphologic plasticity in cultured hippocampal neurons. Microinfusion of TAT-CPE452-466 into the dorsal hippocampus of male C57BL/6 mice inhibited the endogenous interaction between TrkB and CPE and diminished fear-conditioning-induced TrkB phosphorylation, which might lead to an impairment in hippocampal memory acquisition and consolidation but not retrieval. These results suggest that CPE modulates activity-induced TrkB surface insertion and hippocampal-dependent memory and sheds light on our understanding of the role of CPE in TrkB-dependent synaptic plasticity and memory modulation.SIGNIFICANCE STATEMENT It is well known that BDNF acts preferentially on active neurons; however, the underlying molecular mechanism is not fully understood. In this study, we found that the cytoplasmic tail of CPE could interact with TrkB and facilitate the neuronal activity-dependent movement of TrkB vesicles to the plasma membrane. Blocking the association between CPE and TrkB decreased fear-conditioning-induced TrkB phosphorylation and led to hippocampal memory deficits. These findings provide novel insights into the role of CPE in TrkB intracellular trafficking as well as in mediating BDNF/TrkB function in synaptic plasticity and hippocampal memory.
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Affiliation(s)
- Na Li
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | | | - Ling Zhao
- Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Jing-Rui Li
- College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Institute of Biomedical Sciences, Shandong Normal University, Jinan 250014, China
| | - Jia-Ling Xu
- Institution of Traditional Chinese Medicine Innovation Research, Shandong University of Traditional Chinese Medicine, Jinan, 250355 China
| | - Na Li
- Departments of Anatomy and Neurobiology and
| | | | - Zhe-Yu Chen
- Departments of Anatomy and Neurobiology and
- Institute of Brain Science, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Institution of Traditional Chinese Medicine Innovation Research, Shandong University of Traditional Chinese Medicine, Jinan, 250355 China
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40
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Greening DW, Notaras M, Chen M, Xu R, Smith JD, Cheng L, Simpson RJ, Hill AF, van den Buuse M. Chronic methamphetamine interacts with BDNF Val66Met to remodel psychosis pathways in the mesocorticolimbic proteome. Mol Psychiatry 2021; 26:4431-4447. [PMID: 31822818 DOI: 10.1038/s41380-019-0617-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 11/17/2019] [Accepted: 11/21/2019] [Indexed: 02/06/2023]
Abstract
Methamphetamine (Meth) abuse has reached epidemic proportions in many countries and can induce psychotic episodes mimicking the clinical profile of schizophrenia. Brain-derived neurotrophic factor (BDNF) is implicated in both Meth effects and schizophrenia. We therefore studied the long-term effects of chronic Meth exposure in transgenic mice engineered to harbor the human BDNFVal66Met polymorphism expressed via endogenous mouse promoters. These mice were chronically treated with an escalating Meth regime during late adolescence. At least 4 weeks later, all hBDNFVal66Met Meth-treated mice exhibited sensitization confirming persistent behavioral effects of Meth. We used high-resolution quantitative mass spectrometry-based proteomics to biochemically map the long-term effects of Meth within the brain, resulting in the unbiased detection of 4808 proteins across the mesocorticolimbic circuitry. Meth differentially altered dopamine signaling markers (e.g., Dat, Comt, and Th) between hBDNFVal/Val and hBDNFMet/Met mice, implicating involvement of BDNF in Meth-induced reprogramming of the mesolimbic proteome. Targeted analysis of 336 schizophrenia-risk genes, as well as 82 growth factor cascade markers, similarly revealed that hBDNFVal66Met genotype gated the recruitment of these factors by Meth in a region-specific manner. Cumulatively, these data represent the first comprehensive analysis of the long-term effects of chronic Meth exposure within the mesocorticolimbic circuitry. In addition, these data reveal that long-term Meth-induced brain changes are strongly dependent upon BDNF genetic variation, illustrating how drug-induced psychosis may be modulated at the molecular level by a single genetic locus.
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Affiliation(s)
- David W Greening
- Baker Heart and Diabetes Institute, Molecular Proteomics, Melbourne, VIC, Australia.,Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Michael Notaras
- Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Maoshan Chen
- Australian Centre for Blood Diseases (ACBD), Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Rong Xu
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Joel D Smith
- Biological Research Unit, Racing Analytical Services Ltd, Flemington, VIC, Australia
| | - Lesley Cheng
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Richard J Simpson
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Andrew F Hill
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Maarten van den Buuse
- School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia. .,Department of Pharmacology, University of Melbourne, Melbourne, VIC, Australia. .,College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia.
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41
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Koo JW, Wohleb ES. How Stress Shapes Neuroimmune Function: Implications for the Neurobiology of Psychiatric Disorders. Biol Psychiatry 2021; 90:74-84. [PMID: 33485589 PMCID: PMC8126571 DOI: 10.1016/j.biopsych.2020.11.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/09/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022]
Abstract
Chronic stress causes physiological and hormonal adaptations that lead to neurobiological consequences and behavioral and cognitive impairments. In particular, chronic stress has been shown to drive reduced neurogenesis and altered synaptic plasticity in brain regions that regulate mood and motivation. The neurobiological and behavioral effects of stress resemble the pathophysiology and symptoms observed in psychiatric disorders, suggesting that there are similar underlying mechanisms. Accumulating evidence indicates that neuroimmune systems, particularly microglia, have a critical role in regulating the neurobiology of stress. Preclinical models indicate that chronic stress provokes changes in microglia phenotype and increases inflammatory cytokine signaling, which affects neuronal function and leads to synaptic plasticity deficits and impaired neurogenesis. More recent work has shown that microglia can also phagocytose neuronal elements and contribute to structural remodeling of neurons in response to chronic stress. In this review we highlight work by the Duman research group (as well as others) that has revealed how chronic stress shapes neuroimmune function and, in turn, how inflammatory mediators and microglia contribute to the neurobiological effects of chronic stress. We also provide considerations to engage the therapeutic potential of neuroimmune systems, with the goal of improving treatment for psychiatric disorders.
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Affiliation(s)
- Ja Wook Koo
- Department of Neural Development and Disease, Korea Brain
Research Institute, Daegu, Korea,Department of Brain and Cognitive Sciences, Daegu Gyeongbuk
Institute of Science and Technology (DGIST), Daegu, Korea
| | - Eric S. Wohleb
- Department of Pharmacology & Systems Physiology,
University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of
America,Corresponding author: Eric S. Wohleb, Department
of Pharmacology & Systems Physiology, University of Cincinnati College of
Medicine, 2120 East Galbraith Road, Cincinnati, OH 45237 U.S.A.,
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42
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Girgenti MJ, Pothula S, Newton SS. Stress and Its Impact on the Transcriptome. Biol Psychiatry 2021; 90:102-108. [PMID: 33637305 PMCID: PMC8213869 DOI: 10.1016/j.biopsych.2020.12.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 12/01/2020] [Accepted: 12/14/2020] [Indexed: 01/30/2023]
Abstract
Exposure to stress during the course of a lifetime is inevitable in the animal kingdom. It is the response to stress, the valence of the exposure, and the developmental time point that largely determine the consequences to the initial and subsequent exposures. The versatility of transcriptomic methods to yield rich, high-resolution, information-laden datasets from entire brain regions to single cells makes it a powerful approach to investigate the effects of stress from several angles. Dysregulation of the transcriptome is now a phenotypic signature of many neuropsychiatric disorders. New insight has been gained from examining stress-induced changes in gene expression at a global scale. Human postmortem datasets from depression and posttraumatic stress disorder studies have identified major gene expression changes in the diseased brain, including sex-specific changes and marked differences in male and female molecular profiles for the same disorder. Extensions of this work into animal models have explored the impact of transcriptomic dysregulation on early-life stress, chronic stress, and transgenerational impact of stress. Here, we explore the findings of human postmortem genomic studies of neuropsychiatric disorders and comparable animal models through the lens of transcriptomic dysregulation and how these findings have contributed to our understanding of stress.
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Affiliation(s)
- Matthew J Girgenti
- Department of Psychiatry, Yale School of Medicine, New Haven, CT,Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT,National Center for PTSD, U.S. Department of Veterans Affairs
| | - Santosh Pothula
- Department of Psychiatry, Yale School of Medicine, New Haven, CT
| | - Samuel S Newton
- Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota; Sioux Falls VA Healthcare System, Sioux Falls, South Dakota.
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Casaril AM, Lourenço DDA, Domingues M, Smaniotto TÂ, Birmann PT, Vieira B, Sonego MS, Seixas FK, Collares T, Lenardão EJ, Savegnago L. Anhedonic- and anxiogenic-like behaviors and neurochemical alterations are abolished by a single administration of a selenium-containing compound in chronically stressed mice. COMPREHENSIVE PSYCHONEUROENDOCRINOLOGY 2021; 6:100054. [PMID: 35757368 PMCID: PMC9216694 DOI: 10.1016/j.cpnec.2021.100054] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/02/2021] [Accepted: 03/22/2021] [Indexed: 12/30/2022] Open
Affiliation(s)
- Angela Maria Casaril
- Technological Development Center, Division of Biotechnology, Nanobiotechnology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Darling de Andrade Lourenço
- Technological Development Center, Division of Biotechnology, Nanobiotechnology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Micaela Domingues
- Technological Development Center, Division of Biotechnology, Nanobiotechnology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Thiago Ângelo Smaniotto
- Technological Development Center, Division of Biotechnology, Nanobiotechnology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Paloma Taborda Birmann
- Technological Development Center, Division of Biotechnology, Nanobiotechnology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Beatriz Vieira
- Center of Chemical, Pharmaceutical and Food Sciences, Laboratory of Clean Organic Synthesis, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Mariana Souza Sonego
- Technological Development Center, Division of Biotechnology, Molecular and Cellular Oncology Research Group, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Fabiana Kömmling Seixas
- Technological Development Center, Division of Biotechnology, Molecular and Cellular Oncology Research Group, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Tiago Collares
- Technological Development Center, Division of Biotechnology, Molecular and Cellular Oncology Research Group, Laboratory of Cancer Biotechnology, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Eder João Lenardão
- Center of Chemical, Pharmaceutical and Food Sciences, Laboratory of Clean Organic Synthesis, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Lucielli Savegnago
- Technological Development Center, Division of Biotechnology, Nanobiotechnology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil
- Corresponding author. Neurobiotechnology Research Group, Biotechnology Unit Federal University of Pelotas, 96010-900, Pelotas, RS, Brazil.
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Pten is a key intrinsic factor regulating raphe 5-HT neuronal plasticity and depressive behaviors in mice. Transl Psychiatry 2021; 11:186. [PMID: 33771970 PMCID: PMC7998026 DOI: 10.1038/s41398-021-01303-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 02/20/2021] [Accepted: 03/03/2021] [Indexed: 12/14/2022] Open
Abstract
Serotonin (5-HT)-based antidepressants, selective serotonin reuptake inhibitors (SSRIs) aim to enhance serotonergic activity by blocking its reuptake. We propose PTEN as a target for an alternative approach for regulating 5-HT neuron activity in the brain and depressive behaviors. We show that PTEN is elevated in central 5-HT neurons in the raphe nucleus by chronic stress in mice, and selective deletion of Pten in the 5-HT neurons induces its structural plasticity shown by increases of dendritic branching and density of PSD95-positive puncta in the dendrites. 5-HT levels are elevated and electrical stimulation of raphe neurons evokes more 5-HT release in the brain of condition knockout (cKO) mice with Pten-deficient 5-HT neurons. In addition, the 5-HT neurons remain normal electrophysiological properties but have increased excitatory synaptic inputs. Single-cell RNA sequencing revealed gene transcript alterations that may underlay morphological and functional changes in Pten-deficient 5-HT neurons. Finally, Pten cKO mice and wild-type mice treated with systemic application of PTEN inhibitor display reduced depression-like behaviors. Thus, PTEN is an intrinsic regulator of 5-HT neuron activity, representing a novel therapeutic strategy for producing antidepressant action.
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Woodburn SC, Bollinger JL, Wohleb ES. Synaptic and behavioral effects of chronic stress are linked to dynamic and sex-specific changes in microglia function and astrocyte dystrophy. Neurobiol Stress 2021; 14:100312. [PMID: 33748354 PMCID: PMC7970222 DOI: 10.1016/j.ynstr.2021.100312] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 01/28/2021] [Accepted: 02/26/2021] [Indexed: 01/13/2023] Open
Abstract
Emerging evidence indicates that males and females display different neurobiological responses to chronic stress which contribute to varied behavioral adaptations. In particular, pyramidal neurons undergo dendritic atrophy and synapse loss in the prefrontal cortex (PFC) of male, but not female, mice. Our recent work shows that chronic stress also provokes microglia-mediated neuronal remodeling, which contributes to synaptic deficits in the PFC and associated behavioral consequences in males. Separate studies indicate that chronic stress promotes astrocyte dystrophy in the PFC which is associated with behavioral despair. Notably, these prior reports focused primarily on stress effects in males. In the present studies, male and female mice were exposed to 14 or 28 days of chronic unpredictable stress (CUS) to assess molecular and cellular adaptations of microglia, astrocytes, and neurons in the medial PFC. Consistent with our recent work, male, but not female, mice displayed behavioral and cognitive deficits with corresponding perturbations of neuroimmune factors in the PFC after 14 days of CUS. Fluorescence-activated cell sorting and gene expression analyses revealed that CUS increased expression of select markers of phagocytosis in male PFC microglia. Confocal imaging in Thy1-GFP(M) mice showed that CUS reduced dendritic spine density, decreased GFAP immunolabeling, and increased microglia-mediated neuronal remodeling only in male mice. After 28 days of CUS, both male and female mice displayed behavioral and cognitive impairments. Interestingly, there were limited stress effects on neuroimmune factors and measures of microglial phagocytosis in the PFC of both sexes. Despite limited changes in neuroimmune function, reduced GFAP immunolabeling and dendritic spine deficits persisted in male mice. Further, GFAP immunolabeling and dendritic spine density remained unaltered in the PFC of females. These findings indicate that chronic stress causes sex-specific and temporally dynamic changes in microglial function which are associated with different neurobiological and behavioral adaptations. In all, these results suggest that microglia-mediated neuronal remodeling, astrocyte dystrophy, and synapse loss contribute to stress-induced PFC dysfunction and associated behavioral consequences in male mice.
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Affiliation(s)
- Samuel C. Woodburn
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Justin L. Bollinger
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Eric S. Wohleb
- Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Corresponding author. Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, 2120 East Galbraith Road, Cincinnati, OH, 45237, USA.
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Jeong JE, Jeon S, Han JS, Cho EY, Hong KS, Park SN, Kim JJ. The Mediating Effect of Psychological Distress on the Association between BDNF, 5-HTTLPR, and Tinnitus Severity. Psychiatry Investig 2021; 18:187-195. [PMID: 33685039 PMCID: PMC8016684 DOI: 10.30773/pi.2020.0295] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/13/2020] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To investigate the association between genetic polymorphisms of brain-derived neurotrophic factor (BDNF) or serotonin transporter gene-linked polymorphic region (5-HTTLPR) and tinnitus, and the mediating effects of psychological distress on this association. METHODS Eighty-six patients experiencing tinnitus and 252 controls were recruited. The Tinnitus Handicap Inventory was used to assess the severity of tinnitus and the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory-II (BAI-II), and the Korean version of the Brief Encounter Psychosocial Instrument (BEPSI-K) were used to assess psychological distress. We compared the association of BDNF rs6265 (Val66Met) and 5-HTTLPR variants in the two groups. The mediating effects of BDI-II, BAI-II, and BEPSI-K were examined using multiple regression analysis and validated by the Sobel test and bootstrapping. RESULTS No significant differences were found between the groups regarding BDNF Val66Met and 5-HTTLPR, but the 5-HTTLPR variants trended toward association. Depressive symptoms appeared to act as a mediator on the relationship within the 5-HTTLPR s/s genotype and the severity of tinnitus. CONCLUSION Our findings provide a speculative idea on the association between the serotonergic system and tinnitus and suggest that depressive symptoms act as a mediator in tinnitus. Therefore, screening for depressive symptoms in patients with tinnitus is essential and intervention for depressive symptoms may help alleviate the severity of tinnitus.
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Affiliation(s)
- Jo-Eun Jeong
- Department of Psychiatry, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sekye Jeon
- Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jae Sang Han
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Young Cho
- Center of Clinical Research, Samsung Biomedical Research Institute, Seoul, Republic of Korea
| | - Kyung Sue Hong
- Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Seoul Hospital, Seoul, Republic of Korea
| | - Shi Nae Park
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Jin Kim
- Department of Psychiatry, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Li A, Jing D, Dellarco DV, Hall BS, Yang R, Heilberg RT, Huang C, Liston C, Casey BJ, Lee FS. Role of BDNF in the development of an OFC-amygdala circuit regulating sociability in mouse and human. Mol Psychiatry 2021; 26:955-973. [PMID: 30992540 PMCID: PMC6883137 DOI: 10.1038/s41380-019-0422-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 03/17/2019] [Accepted: 04/03/2019] [Indexed: 01/29/2023]
Abstract
Social deficits are common in many psychiatric disorders. However, due to inadequate tools for manipulating circuit activity in humans and unspecific paradigms for modeling social behaviors in rodents, our understanding of the molecular and circuit mechanisms mediating social behaviors remains relatively limited. Using human functional neuroimaging and rodent fiber photometry, we identified a mOFC-BLA projection that modulates social approach behavior and influences susceptibility to social anxiety. In humans and knock-in mice with a loss of function BDNF SNP (Val66Met), the functionality of this circuit was altered, resulting in social behavioral changes in human and mice. We further showed that the development of this circuit is disrupted in BDNF Met carriers due to insufficient BDNF bioavailability, specifically during a peri-adolescent timeframe. These findings define one mechanism by which social anxiety may stem from altered maturation of orbitofronto-amygdala projections and identify a developmental window in which BDNF-based interventions may have therapeutic potential.
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Affiliation(s)
- Anfei Li
- Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY, USA
| | - Deqiang Jing
- Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA
| | - Danielle V Dellarco
- Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY, USA
| | - Baila S Hall
- Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Ruirong Yang
- Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA
| | - Ross T Heilberg
- Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA
| | - Chienchun Huang
- Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA
| | - Conor Liston
- Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY, USA
- Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA
- Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - B J Casey
- Department of Psychology, Yale University, New Haven, CT, USA.
| | - Francis S Lee
- Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY, USA.
- Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA.
- Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
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HUZARD D, RAPPENEAU V, MEIJER OC, TOUMA C, ARANGO-LIEVANO M, GARABEDIAN MJ, JEANNETEAU F. Experience and activity-dependent control of glucocorticoid receptors during the stress response in large-scale brain networks. Stress 2021; 24:130-153. [PMID: 32755268 PMCID: PMC7907260 DOI: 10.1080/10253890.2020.1806226] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The diversity of actions of the glucocorticoid stress hormones among individuals and within organs, tissues and cells is shaped by age, gender, genetics, metabolism, and the quantity of exposure. However, such factors cannot explain the heterogeneity of responses in the brain within cells of the same lineage, or similar tissue environment, or in the same individual. Here, we argue that the stress response is continuously updated by synchronized neural activity on large-scale brain networks. This occurs at the molecular, cellular and behavioral levels by crosstalk communication between activity-dependent and glucocorticoid signaling pathways, which updates the diversity of responses based on prior experience. Such a Bayesian process determines adaptation to the demands of the body and external world. We propose a framework for understanding how the diversity of glucocorticoid actions throughout brain networks is essential for supporting optimal health, while its disruption may contribute to the pathophysiology of stress-related disorders, such as major depression, and resistance to therapeutic treatments.
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Affiliation(s)
- Damien HUZARD
- Department of Neuroscience and Physiology, University of Montpellier, CNRS, INSERM, Institut de Génomique Fonctionnelle, Montpellier, France
| | - Virginie RAPPENEAU
- Department of Behavioural Biology, University of Osnabrück, Osnabrück, Germany
| | - Onno C. MEIJER
- Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden University, Leiden, the Netherlands
| | - Chadi TOUMA
- Department of Behavioural Biology, University of Osnabrück, Osnabrück, Germany
| | - Margarita ARANGO-LIEVANO
- Department of Neuroscience and Physiology, University of Montpellier, CNRS, INSERM, Institut de Génomique Fonctionnelle, Montpellier, France
| | | | - Freddy JEANNETEAU
- Department of Neuroscience and Physiology, University of Montpellier, CNRS, INSERM, Institut de Génomique Fonctionnelle, Montpellier, France
- Corresponding author:
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Vanneste S, Mohan A, De Ridder D, To WT. The BDNF Val 66Met polymorphism regulates vulnerability to chronic stress and phantom perception. PROGRESS IN BRAIN RESEARCH 2021; 260:301-326. [PMID: 33637225 DOI: 10.1016/bs.pbr.2020.08.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Auditory phantom percepts, such as tinnitus, are a heterogeneous condition with great interindividual variations regarding both the percept itself and its concomitants. Tinnitus causes a considerable amount of distress, with as many as 25% of affected people reporting that it interferes with their daily lives. Although previous research gives an idea about the neural correlates of tinnitus-related distress, it cannot explain why some tinnitus patients develop distress and while others are not bothered by their tinnitus. BDNF Val66Met polymorphism (rs6265) is a known risk factor for affective disorders due to its common frequency and established functionality. To elucidate, we explore the neural activation pattern of tinnitus associated with the BDNF Val66Met polymorphism using electrophysiological data to assess activity and connectivity changes. A total of 110 participants (55 tinnitus and 55 matched control subjects) were included. In this study, we validate that the BDNF Val66Met polymorphism plays an important role in the susceptibility to the clinical manifestation of tinnitus-related distress. We demonstrate that Val/Met carriers have increased alpha power in the subgenual anterior cingulate cortex that correlates with distress levels. Furthermore, distress mediates the relationship between BDNF Val66Met polymorphism and tinnitus loudness. In other words, for Val/Met carriers, the subgenual anterior cingulate cortex sends distress-related information to the parahippocampus, which likely integrates the loudness and distress of the tinnitus percept.
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Affiliation(s)
- Sven Vanneste
- Lab for Clinical and Integrative Neuroscience, Global Brain Health Institute, Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland; Lab for Clinical and Integrative Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, United States.
| | - Anusha Mohan
- Lab for Clinical and Integrative Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, United States
| | - Dirk De Ridder
- Department of Surgical Sciences, Section of Neurosurgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Wing Ting To
- Lab for Clinical and Integrative Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, United States
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Chen JJ, Shen JX, Yu ZH, Pan C, Han F, Zhu XL, Xu H, Xu RT, Wei TY, Lu YP. The Antidepressant Effects of Resveratrol are Accompanied by the Attenuation of Dendrite/Dendritic Spine Loss and the Upregulation of BDNF/p-cofilin1 Levels in Chronic Restraint Mice. Neurochem Res 2021; 46:660-674. [PMID: 33392910 DOI: 10.1007/s11064-020-03200-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 12/04/2020] [Accepted: 12/09/2020] [Indexed: 11/27/2022]
Abstract
Depression afflicts more than 300 million people worldwide, but there is currently no universally effective drug in clinical practice. In this study, chronic restraint stress (CRS)-induced mice depression model was used to study the antidepressant effects of resveratrol and its mechanism. Our results showed that resveratrol significantly attenuated depression-like behavior in mice. Consistent with behavioral changes, resveratrol significantly attenuated CRS-induced reduction in the density of dendrites and dendritic spines in both hippocampus and medial prefrontal cortex (mPFC). Meanwhile, in hippocampus and mPFC, resveratrol consistently alleviated CRS-induced cofilin1 activation by increasing its ser3 phosphorylation. In addition, cofilin1 immunofluorescence distribution in neuronal inner peri-membrane in controls, and cofilin1 diffusely distribution in the cytoplasm in CRS group were common in hippocampus. However, the distribution of cofilin1 in mPFC was reversed. Pearson's correlation analysis revealed that there was a significant positive correlation found between the sucrose consumption in sucrose preference test and the dendrite density in multiple sub-regions of hippocampus and mPFC, and a significant negative correlation between the immobility time in tail suspension test and the dendrite/dendritic spine density in several different areas of hippocampus and mPFC. P-cofilin1 was significantly positively correlated with the overall dendritic spine density in mPFC as well as with the overall dendrite density or BDNF in the hippocampus. Our results suggest that the BDNF/cofilin1 pathway, in which cofilin1 may be activated in a brain-specific manner, was involved in resveratrol's attenuating the dendrite and dendritic spine loss and behavioral abnormality.
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Affiliation(s)
- Jing-Jing Chen
- College of Life Science, Anhui Normal University, No. 1 Beijing East Road, Wuhu, 241000, China
| | - Jun-Xian Shen
- College of Life Science, Anhui Normal University, No. 1 Beijing East Road, Wuhu, 241000, China
| | - Zong-Hao Yu
- College of Life Science, Anhui Normal University, No. 1 Beijing East Road, Wuhu, 241000, China
| | - Chuan Pan
- College of Life Science, Anhui Normal University, No. 1 Beijing East Road, Wuhu, 241000, China
| | - Fei Han
- College of Life Science, Anhui Normal University, No. 1 Beijing East Road, Wuhu, 241000, China
| | - Xiu-Ling Zhu
- College of Life Science, Anhui Normal University, No. 1 Beijing East Road, Wuhu, 241000, China
- Department of Anatomy, Wannan Medical College, No. 22 Wenchang West Road, Wuhu, 241002, China
| | - Hui Xu
- College of Life Science, Anhui Normal University, No. 1 Beijing East Road, Wuhu, 241000, China
- Anhui College of Traditional Chinese Medicine, No. 18 Wuxiashan West Road, Wuhu, 241002, China
| | - Rui-Ting Xu
- College of Life Science, Anhui Normal University, No. 1 Beijing East Road, Wuhu, 241000, China
| | - Tong-Yao Wei
- College of Life Science, Anhui Normal University, No. 1 Beijing East Road, Wuhu, 241000, China
| | - Ya-Ping Lu
- College of Life Science, Anhui Normal University, No. 1 Beijing East Road, Wuhu, 241000, China.
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