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1
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Ye P, Zhang W, Liao Y, Hu T, Jiang CL. Unlocking the brain's code: The crucial role of post-translational modifications in neurodevelopment and neurological function. Phys Life Rev 2025; 53:187-214. [PMID: 40120399 DOI: 10.1016/j.plrev.2025.03.011] [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: 03/10/2025] [Accepted: 03/13/2025] [Indexed: 03/25/2025]
Abstract
Post-translational modifications (PTMs) represent a crucial regulatory mechanism in the brain, influencing various processes, including neurodevelopment and neurological function. This review discusses the effects of PTMs, such as phosphorylation, ubiquitination, acetylation, and glycosylation, on neurodevelopment and central nervous system functionality. Although neurodevelopmental processes linked to PTMs are complex, proteins frequently converge within shared pathways. These pathways encompass neurodevelopmental processes, signaling mechanisms, neuronal migration, and synaptic connection formation, where PTMs act as dynamic regulators, ensuring the precise execution of brain functions. A detailed investigation of the fundamental mechanisms governing these pathways will contribute to a deeper understanding of nervous system functions and facilitate the identification of potential therapeutic targets. A thorough examination of the PTM landscape holds significant potential, not only in advancing knowledge but also in developing treatments for various neurological disorders.
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Affiliation(s)
- Peng Ye
- Department of Ear-Nose-Throat, Eastern Theater Naval Hospital, No. 98, Wen Hua Road, ZheJiang 316000, China.
| | - Wangzheqi Zhang
- School of Anesthesiology, Changhai Hospital, Naval Medical University, No. 168, Changhai Road, Shanghai 200433, China; School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai 200433, China.
| | - Yan Liao
- School of Anesthesiology, Changhai Hospital, Naval Medical University, No. 168, Changhai Road, Shanghai 200433, China; School of Anesthesiology, Naval Medical University, 168 Changhai Road, Shanghai 200433, China.
| | - Ting Hu
- Department of Stress Medicine, Faculty of Psychology, Naval Medical University, No. 800, Xiangyin Road, Shanghai 200433, China.
| | - Chun-Lei Jiang
- Department of Stress Medicine, Faculty of Psychology, Naval Medical University, No. 800, Xiangyin Road, Shanghai 200433, China.
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2
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Jiang BC, Zhang J, Yang M, Yang HD, Zhang XB. Prevalence and risk factors of depressive and anxiety symptoms and functional constipation among university students in Eastern China. World J Psychiatry 2025; 15:106451. [DOI: 10.5498/wjp.v15.i6.106451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/04/2025] [Accepted: 04/24/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Depression and anxiety are prevalent among university students worldwide, often coexisting with functional constipation (FC). Family relationships have been identified as crucial factors affecting mental health, yet the gender-specific associations between these conditions remain underexplored.
AIM To assess prevalence of depressive symptoms, anxiety symptoms, and FC among Chinese university students and explore their associations.
METHODS Using a cross-sectional survey design, data were collected from 12721 students at two universities in Jiangsu Province and Shandong Province. Depressive symptoms were assessed using the Patient Health Questionnaire-9, anxiety symptoms using the Generalized Anxiety Disorder-7 scale, and FC using the ROME IV. Gender-stratified analyses and population attributable risk proportions were calculated to evaluate risk factor patterns and population impact.
RESULTS The prevalence of self-reported depressive, anxiety, and comorbid depressive and anxiety symptoms was 16.3%, 24.9%, and 13.3%, respectively, whereas that of FC was 22%. Students with depressive symptoms were 1.811 times more likely to have FC than those without. Female gender, parental relationships, and lower household income were significant risk factors for both mental health conditions. For depressive symptoms, females experienced stronger effects from both parental conflict [odds ratio (OR) = 8.006 vs OR = 7.661 in males] and FC (OR = 1.954 vs OR = 1.628 in males). For anxiety symptoms, conflicted parental relationships had stronger effects in males (OR = 5.946) than females (OR = 4.262). Overall, poor parental relationships contributed to 38.6% of depressive and 33.5% of anxiety symptoms.
CONCLUSION Family relationships significantly impact student mental health, with gender-specific patterns. Targeted interventions addressing family dynamics could reduce mental health burden in university settings.
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Affiliation(s)
- Bo-Chen Jiang
- Department of Clinical Medicine, Shandong University, Ji’nan 250012, Shandong Province, China
| | - Jing Zhang
- Department of Psychiatry, The Fourth People’s Hospital of Lianyungang, The Affiliated Kangda College of Nanjing Medical University, Lianyungang 222003, Jiangsu Province, China
- Department of Medicine, Yangzhou University, Yangzhou 225003, Jiangsu Province, China
| | - Man Yang
- Department of Psychiatry, The Fourth People’s Hospital of Lianyungang, The Affiliated Kangda College of Nanjing Medical University, Lianyungang 222003, Jiangsu Province, China
| | - Hai-Dong Yang
- Department of Psychiatry, The Fourth People’s Hospital of Lianyungang, The Affiliated Kangda College of Nanjing Medical University, Lianyungang 222003, Jiangsu Province, China
- Department of Psychiatry, Suzhou Psychiatric Hospital, Institute of Mental Health, The Affiliated Guangji Hospital of Soochow University, Suzhou 215137, Jiangsu Province, China
| | - Xiao-Bin Zhang
- Department of Psychiatry, Suzhou Psychiatric Hospital, Institute of Mental Health, The Affiliated Guangji Hospital of Soochow University, Suzhou 215137, Jiangsu Province, China
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3
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Liu Y, Gang X, Gao Y, Wang G. Causal associations between congenital adrenal hyperplasia and neuropsychiatric conditions- a Mendelian Randomization Study. Endocrine 2025:10.1007/s12020-025-04237-4. [PMID: 40307628 DOI: 10.1007/s12020-025-04237-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 04/10/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND Congenital adrenal hyperplasia (CAH), predominantly caused by 21-hydroxylase deficiency (21-OHD) due to CYP21A2 mutations, disrupts cortisol synthesis and adrenal androgen homeostasis. Observational studies suggest CAH patients exhibit elevated risks of neuropsychiatric disorders, but causal mechanisms remain unestablished. We hypothesized that reduced CYP21A2 expression, reflecting CAH, differentially influences psychiatric outcomes via tissue-specific pathways. METHODS Using two-sample Mendelian randomization (MR), we analyzed tissue-specific CYP21A2 expression quantitative trait loci (eQTLs) from adrenal (GTEx v8) and whole blood (GTEx v8 and eQTLGen meta-analysis). Genetic instruments were validated via positive control MR with classical CAH biomarkers. Associations with ten neuropsychiatric disorders were assessed using inverse-variance-weighted MR, supplemented by sensitivity analyses (LCV, SMR) and LD score regression. RESULTS Adrenal-derived CYP21A2 downregulation reduced Alzheimer's disease (AD) risk (discovery: OR = 1.245, replication: OR = 1.100) but increased autism spectrum disorder (ASD) susceptibility (discovery: OR = 0.766, replication: OR = 0.659). Conversely, blood-derived eQTLs showed opposing effects that decreased ASD risk (discovery: OR = 1.072, replication: OR = 1.071) and elevated AD risk (OR = 0.968 for both discovery and replication). Both tissues linked reduced CYP21A2 expression to elevated bioavailable testosterone (adrenal: OR = 0.972, p = 0.04; blood: OR = 0.983, p = 0.01), consistent with CAH pathophysiology. CONCLUSION Our research indicates that adrenal-driven pathways of CYP21A2 deficiency may reduce the risk of AD while increasing the ASD risk. These findings underscore the pivotal role of endocrine mechanisms in the pathogenesis of neuropsychiatric disorders and advocate for personalized CAH management integrating mental health monitoring.
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Affiliation(s)
- Yang Liu
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yuan Gao
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Guixia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin Province, China.
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Wang Y, Guo C, Zang B, Wang P, Yang C, Shi R, Kong Y, Sui A, Li S, Lin Y. Anxiolytic effects of accelerated continuous theta burst stimulation on mice exposed to chronic restraint stress and the underlying mechanism involving gut microbiota. J Affect Disord 2025; 375:49-63. [PMID: 39848468 DOI: 10.1016/j.jad.2025.01.104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 01/10/2025] [Accepted: 01/20/2025] [Indexed: 01/25/2025]
Abstract
BACKGROUND Accelerated continuous theta burst stimulation (acTBS) is a more intensive and rapid protocol than continuous theta burst stimulation (cTBS). However, it remains uncertain whether acTBS exhibits anxiolytic effects. The aim of this study was to investigate the impact of acTBS on anxiety model mice and elucidate the underlying mechanisms involved, in order to provide a more comprehensive understanding of its effects. METHODS Chronic restraint stress (CRS) model was employed to observe the anxiolytic effects of acTBS. The study focused on evaluating the impact of acTBS on behavior, neuroinflammation, gut and gut microbiota in mice with anxiety induced by CRS. RESULTS The application of acTBS ameliorated anxiety-like behaviors in CRS-induced mice. Notably, it effectively suppressed the activation of microglia and reduced the level pro-inflammatory cytokines in PFC, hippocampus, and amygdala of anxiety mice. Additionally, acTBS alleviated astrocyte activation specifically in hippocampus. The NF-κB signaling pathway involved in the anti-inflammatory effects of acTBS. Furthermore, acTBS ameliorated inflammation and histological damage in colon. 16S rRNA analysis revealed that acTBS significantly enhanced the relative abundance of Lactobacillus, while normalized the dysregulated levels of Coriobacterales, Bacteroides, and Parabacteroides caused by CRS. These changes facilitated chemoheterotrophic and fermentation functions within the microbiota. Importantly, changes in microbiota composition influenced by acTBS was found to be correlated with anxiety-like behaviors and neuroinflammation. CONCLUSIONS acTBS exerted anxiolytic effects on mice exposed to CRS, which was associated with the modulation of gut microbiota.
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Affiliation(s)
- Yihan Wang
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116021, China
| | - Cong Guo
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116021, China
| | - Bowen Zang
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116021, China
| | - Peng Wang
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116021, China
| | - Chuyan Yang
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116021, China
| | - Ruifeng Shi
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116021, China
| | - Yue Kong
- Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, Dalian Medical University, Dalian 116044, China
| | - Aoran Sui
- Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, Dalian Medical University, Dalian 116044, China
| | - Shao Li
- Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, Dalian Medical University, Dalian 116044, China.
| | - Yongzhong Lin
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116021, China.
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Balmer GL, Guha S, Poll S. Engrams across diseases: Different pathologies - unifying mechanisms? Neurobiol Learn Mem 2025; 219:108036. [PMID: 40023216 DOI: 10.1016/j.nlm.2025.108036] [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: 11/08/2024] [Revised: 02/21/2025] [Accepted: 02/25/2025] [Indexed: 03/04/2025]
Abstract
Memories are our reservoir of knowledge and thus, are crucial for guiding decisions and defining our self. The physical correlate of a memory in the brain is termed an engram and since decades helps researchers to elucidate the intricate nature of our imprinted experiences and knowledge. Given the importance that memories have for our lives, their impairment can present a tremendous burden. In this review we aim to discuss engram malfunctioning across diseases, covering dementia-associated pathologies, epilepsy, chronic pain and psychiatric disorders. Current neuroscientific tools allow to witness the emergence and fate of engram cells and enable their manipulation. We further suggest that specific mechanisms of mnemonic malfunction can be derived from engram cell readouts. While depicting the way diseases act on the mnemonic component - specifically, on the cellular engram - we emphasize a differentiation between forms of amnesia and hypermnesia. Finally, we highlight commonalities and distinctions of engram impairments on the cellular level across diseases independent of their pathogenic origins and discuss prospective therapeutic measures.
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Affiliation(s)
- Greta Leonore Balmer
- University of Bonn, Faculty of Medicine, Institute of Experimental Epileptology and Cognition Research (IEECR), Cellular Neuropathology and Cognition Group, Venusberg-Campus 1/C76, 53127 Bonn, Germany; University Hospital Bonn, Germany
| | - Shuvrangshu Guha
- University of Bonn, Faculty of Medicine, Institute of Experimental Epileptology and Cognition Research (IEECR), Cellular Neuropathology and Cognition Group, Venusberg-Campus 1/C76, 53127 Bonn, Germany; University Hospital Bonn, Germany
| | - Stefanie Poll
- University of Bonn, Faculty of Medicine, Institute of Experimental Epileptology and Cognition Research (IEECR), Cellular Neuropathology and Cognition Group, Venusberg-Campus 1/C76, 53127 Bonn, Germany; University Hospital Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE) Bonn, Germany.
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6
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Velloso LA, Donato J. Growth Hormone, Hypothalamic Inflammation, and Aging. J Obes Metab Syndr 2024; 33:302-313. [PMID: 39639711 PMCID: PMC11704225 DOI: 10.7570/jomes24032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 09/26/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024] Open
Abstract
While inflammation is a crucial response in injury repair and tissue regeneration, chronic inflammation is a prevalent feature in various chronic, non-communicable diseases such as obesity, diabetes, and cancer and in cardiovascular and neurodegenerative diseases. Long-term inflammation considerably affects disease prevalence, quality of life, and longevity. Our research indicates that the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is a pivotal regulator of inflammation in some tissues, including the hypothalamus, which is a key player in systemic metabolism regulation. Moreover, the GH/IGF-1 axis is strongly linked to longevity, as GH- or GH receptor-deficient mice live approximately twice as long as wild-type animals and exhibit protection against aging-induced inflammation. Conversely, GH excess leads to increased neuroinflammation and reduced longevity. Our review studies the associations between the GH/IGF-1 axis, inflammation, and aging, with a particular focus on evidence suggesting that GH receptor signaling directly induces hypothalamic inflammation. This finding underscores the significant impact of changes in the GH axis on metabolism and on the predisposition to chronic, non-communicable diseases.
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Affiliation(s)
- Licio A. Velloso
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation, Campinas, Brazil
| | - Jose Donato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
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Tavares MR, Dos Santos WO, Amaral AG, List EO, Kopchick JJ, Alves GA, Frazao R, Dos Santos JDM, Cruz AG, Camporez JP, Donato J. Growth hormone receptor in VGLUT2 or Sim1 cells regulates glycemia and insulin sensitivity. Proc Natl Acad Sci U S A 2024; 121:e2407225121. [PMID: 39700135 DOI: 10.1073/pnas.2407225121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 11/20/2024] [Indexed: 12/21/2024] Open
Abstract
Growth hormone (GH) has several metabolic effects, including a profound impact on glucose homeostasis. For example, GH oversecretion induces insulin resistance and increases the risk of developing diabetes mellitus. Here, we show that GH receptor (GHR) ablation in vesicular glutamate transporter 2 (VGLUT2)-expressing cells, which comprise a subgroup of glutamatergic neurons, led to a slight decrease in lean body mass without inducing changes in body adiposity. VGLUT2∆GHR mice exhibited reduced glycemia and improved glucose tolerance and insulin sensitivity. Among different glutamatergic neuronal populations, we found that GHR inactivation in Sim1-expressing cells recapitulated the phenotype observed in VGLUT2∆GHR mice. Furthermore, Sim1∆GHR mice exhibited reduced endogenous glucose production and improved hepatic insulin sensitivity without alterations in whole-body or muscle glucose uptake. Sim1∆GHR mice were protected against acute but not chronic diabetogenic effects of exogenous GH administration. Pharmacological activation of ATP-sensitive potassium channels in the brain normalized blood glucose levels in Sim1∆GHR mice. In conclusion, the absence of GHR signaling in VGLUT2/Sim1-expressing cells causes a persistent reduction in glycemia and improves hepatic insulin sensitivity. Central glucose-sensing mechanisms are likely involved in the reduced glycemia exhibited by Sim1∆GHR mice. The current findings uncover a mechanism involved in the effects of GHR signaling in regulating glucose homeostasis.
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Affiliation(s)
- Mariana R Tavares
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Willian O Dos Santos
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Andressa G Amaral
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Edward O List
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701
| | - John J Kopchick
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701
| | - Guilherme A Alves
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil
| | - Renata Frazao
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil
| | - Jessica D M Dos Santos
- Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil
| | - Alessandra G Cruz
- Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil
| | - João Paulo Camporez
- Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil
| | - Jose Donato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
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Recinella L, Libero ML, Brunetti L, Acquaviva A, Chiavaroli A, Orlando G, Granata R, Salvatori R, Leone S. Effects of growth hormone-releasing hormone deficiency in mice beyond growth. Rev Endocr Metab Disord 2024:10.1007/s11154-024-09936-3. [PMID: 39695049 DOI: 10.1007/s11154-024-09936-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/28/2024] [Indexed: 12/20/2024]
Abstract
This paper provides a critical overview on GHRH and its deficiency, discussing its multiple roles in both central and peripheral tissues. Genetically engineered mice have been instrumental in elucidating the multifaceted roles of GHRH and GH, each offering unique insights into the physiological and pathological roles of these hormones, although in many of these models dissecting the direct effect of GHRH from the effect of GH is not possible. Key findings highlight the effects of GHRH deficiency on emotional behavior, including anxiety and depression, its impact on memory and learning capabilities, as well as on adipose tissue, immune system, inflammation and pain.
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Affiliation(s)
- Lucia Recinella
- Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Maria Loreta Libero
- Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Luigi Brunetti
- Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy.
| | - Alessandra Acquaviva
- Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Annalisa Chiavaroli
- Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Giustino Orlando
- Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Riccarda Granata
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Roberto Salvatori
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sheila Leone
- Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
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Kim HJ, Kim JH, Lee S, Do PA, Lee JY, Cha SK, Lee J. PM2.5 Exposure Triggers Hypothalamic Oxidative and ER Stress Leading to Depressive-like Behaviors in Rats. Int J Mol Sci 2024; 25:13527. [PMID: 39769289 PMCID: PMC11677780 DOI: 10.3390/ijms252413527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/13/2024] [Accepted: 12/15/2024] [Indexed: 01/11/2025] Open
Abstract
Epidemiological studies have linked fine dust pollution to depression, yet the underlying mechanisms remain unclear. Oxidative stress and endoplasmic reticulum (ER) stress are known contributors to depression, but their induction by particulate matter (PM), particularly PM2.5, in animal models has been limited. This study aimed to establish a rat model of PM2.5-induced depression-like behaviors and elucidate the underlying molecular mechanisms. Adult male Sprague-Dawley rats received daily intranasal PM2.5 for four weeks. Behavioral assessments, including the open field test (OFT), forced swim test (FST), and light-dark box (LDB) test, were conducted weekly. PM2.5-exposed rats displayed depressive-like behaviors, particularly in the FST, reflecting decreased motivation and learned helplessness. Molecular analyses indicated a specific increase in ER stress markers (CHOP, eIF2α, GRP78, and P16) and NOX4 in the hypothalamus, while other brain regions (striatum, cortex, and hippocampus) were not as pronounced. Additionally, PM2.5 exposure reduced tyrosine hydroxylase (TH) levels in the hypothalamus, suggesting impaired dopamine synthesis. These findings indicate that PM2.5 induces depressive-like behaviors via hypothalamic ER stress and oxidative stress pathways, leading to dopaminergic dysfunction. Targeting oxidative and ER stress within the hypothalamus may offer new therapeutic strategies for treating depression associated with environmental pollutants.
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Affiliation(s)
- Hi-Ju Kim
- Department of Psychiatry, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Ji-Hee Kim
- Department of Occupational Therapy, Soonchunhyang University, Asan 31538, Republic of Korea;
| | - Subo Lee
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (S.L.); (P.A.D.)
- Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
- Organelle Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
| | - Phuong Anh Do
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (S.L.); (P.A.D.)
- Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
- Organelle Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
| | - Ji Yong Lee
- Research Institute of Hyperbaric Medicine and Science, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Seung-Kuy Cha
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea; (S.L.); (P.A.D.)
- Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
- Organelle Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
| | - Jinhee Lee
- Department of Psychiatry, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
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Jiang M, Kang L, Wang YL, Zhou B, Li HY, Yan Q, Liu ZG. Mechanisms of microbiota-gut-brain axis communication in anxiety disorders. Front Neurosci 2024; 18:1501134. [PMID: 39717701 PMCID: PMC11663871 DOI: 10.3389/fnins.2024.1501134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 11/26/2024] [Indexed: 12/25/2024] Open
Abstract
Anxiety disorders, prevalent mental health conditions, receive significant attention globally due to their intricate etiology and the suboptimal effectiveness of existing therapies. Research is increasingly recognizing that the genesis of anxiety involves not only neurochemical brain alterations but also changes in gut microbiota. The microbiota-gut-brain axis (MGBA), serving as a bidirectional communication pathway between the gut microbiota and the central nervous system (CNS), is at the forefront of novel approaches to deciphering the complex pathophysiology of anxiety disorders. This review scrutinizes the role and recent advancements in the MGBA concerning anxiety disorders through a review of the literature, emphasizing mechanisms via neural signals, endocrine pathways, and immune responses. The evidence robustly supports the critical influence of MGBA in both the development and progression of these disorders. Furthermore, this discussion explores potential therapeutic avenues stemming from these insights, alongside the challenges and issues present in this realm. Collectively, our findings aim to enhance understanding of the pathological mechanisms and foster improved preventative and therapeutic strategies for anxiety disorders.
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Affiliation(s)
- Min Jiang
- Department of Clinical Laboratory, Neijiang Central District People’s Hospital, Neijiang, Sichuan, China
| | - Li Kang
- Department of Anesthesiology, The First People’s Hospital of Neijiang, Neijiang, Sichuan, China
| | - Ya-Li Wang
- Department of Neurology, Neijiang Central District People’s Hospital, Neijiang, Sichuan, China
| | - Bin Zhou
- Department of Neurology, Neijiang Central District People’s Hospital, Neijiang, Sichuan, China
| | - Hong-Yi Li
- Department of Neurology, Neijiang Central District People’s Hospital, Neijiang, Sichuan, China
| | - Qiang Yan
- Department of Clinical Laboratory, Neijiang Central District People’s Hospital, Neijiang, Sichuan, China
| | - Zhi-Gang Liu
- Department of Clinical Laboratory, Neijiang Central District People’s Hospital, Neijiang, Sichuan, China
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11
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Tavares MR, Dos Santos WO, Furigo IC, List EO, Kopchick JJ, Donato J. Growth Hormone Receptor in Lateral Hypothalamic Neurons Is Required for Increased Food-Seeking Behavior during Food Restriction in Male Mice. J Neurosci 2024; 44:e1761232024. [PMID: 39358046 PMCID: PMC11580784 DOI: 10.1523/jneurosci.1761-23.2024] [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: 09/18/2023] [Revised: 09/20/2024] [Accepted: 09/26/2024] [Indexed: 10/04/2024] Open
Abstract
Growth hormone (GH) action in the brain regulates neuroendocrine axes, energy and glucose homeostasis, and several neurological functions. The lateral hypothalamic area (LHA) contains numerous neurons that respond to a systemic GH injection by expressing the phosphorylated STAT5, a GH receptor (GHR) signaling marker. However, the potential role of GHR signaling in the LHA is unknown. In this study, we demonstrated that ∼70% of orexin- and leptin receptor (LepR)-expressing neurons in the LHA are responsive to GH. Male mice carrying inactivation of the Ghr gene in the LHA were generated via bilateral injections of an adeno-associated virus. In ad libitum-fed mice, GHR ablation in LHA neurons did not significantly change energy and glucose homeostasis. Subsequently, mice were subjected to 5 d of 40% food restriction. Food restriction decreased body weight, energy expenditure, and carbohydrate oxidation. These effects were similarly observed in control and LHAΔGHR mice. While food-deprived control mice progressively increased ambulatory/exploratory activity and food-seeking behavior, LHAΔGHR mice did not show hyperactivity induced by food restriction. GHR ablation in the LHA reduced the percentage of orexin neurons expressing c-Fos during food restriction. Additionally, an acute GH injection increased the expression of c-Fos in LHAORX neurons. Inactivation of Ghr in LepR-expressing cells did not prevent hyperactivity in food-deprived mice, whereas whole-brain Ghr knock-out mice showed reduced ambulatory activity during food restriction. Our findings indicate that GHR signaling in the LHA regulates the activity of orexin neurons and is necessary to increase food-seeking behavior in food-deprived male mice.
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Affiliation(s)
- Mariana R Tavares
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Sao Paulo, Brazil
| | - Willian O Dos Santos
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Sao Paulo, Brazil
| | - Isadora C Furigo
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Sao Paulo, Brazil
- Centre for Health and Life Sciences, Coventry University, Coventry CV1 2DS, Warwickshire, United Kingdom
| | - Edward O List
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701
| | - John J Kopchick
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701
| | - Jose Donato
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Sao Paulo, Brazil
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Donato J, Kopchick JJ. New findings on brain actions of growth hormone and potential clinical implications. Rev Endocr Metab Disord 2024; 25:541-553. [PMID: 38060062 PMCID: PMC11156798 DOI: 10.1007/s11154-023-09861-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/29/2023] [Indexed: 12/08/2023]
Abstract
Growth hormone (GH) is secreted by somatotropic cells of the anterior pituitary gland. The classical effects of GH comprise the stimulation of cell proliferation, tissue and body growth, lipolysis, and insulin resistance. The GH receptor (GHR) is expressed in numerous brain regions. Notably, a growing body of evidence indicates that GH-induced GHR signaling in specific neuronal populations regulates multiple physiological functions, including energy balance, glucose homeostasis, stress response, behavior, and several neurological/cognitive aspects. The importance of central GHR signaling is particularly evident when the organism is under metabolic stress, such as pregnancy, chronic food deprivation, hypoglycemia, and prolonged exercise. These particular situations are associated with elevated GH secretion. Thus, central GH action represents an internal signal that coordinates metabolic, neurological, neuroendocrine, and behavioral adaptations that are evolutionarily advantageous to increase the chances of survival. This review summarizes and discusses recent findings indicating that the brain is an important target of GH, and GHR signaling in different neuronal populations regulates essential physiological functions.
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Affiliation(s)
- Jose Donato
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Lineu Prestes, 1524, Sao Paulo, SP, 05508-000, Brazil.
| | - John J Kopchick
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA
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Menezes F, Wasinski F, de Souza GO, Nunes AP, Bernardes ES, dos Santos SN, da Silva FFA, Peroni CN, Oliveira JE, Kopchick JJ, Brown RSE, Fernandez G, De Francesco PN, Perelló M, Soares CRJ, Donato J. The Pattern of GH Action in the Mouse Brain. Endocrinology 2024; 165:bqae057. [PMID: 38728240 PMCID: PMC11137758 DOI: 10.1210/endocr/bqae057] [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: 02/07/2024] [Revised: 04/12/2024] [Accepted: 05/10/2024] [Indexed: 05/12/2024]
Abstract
GH acts in numerous organs expressing the GH receptor (GHR), including the brain. However, the mechanisms behind the brain's permeability to GH and how this hormone accesses different brain regions remain unclear. It is well-known that an acute GH administration induces phosphorylation of the signal transducer and activator of transcription 5 (pSTAT5) in the mouse brain. Thus, the pattern of pSTAT5 immunoreactive cells was analyzed at different time points after IP or intracerebroventricular GH injections. After a systemic GH injection, the first cells expressing pSTAT5 were those near circumventricular organs, such as arcuate nucleus neurons adjacent to the median eminence. Both systemic and central GH injections induced a medial-to-lateral pattern of pSTAT5 immunoreactivity over time because GH-responsive cells were initially observed in periventricular areas and were progressively detected in lateral brain structures. Very few choroid plexus cells exhibited GH-induced pSTAT5. Additionally, Ghr mRNA was poorly expressed in the mouse choroid plexus. In contrast, some tanycytes lining the floor of the third ventricle expressed Ghr mRNA and exhibited GH-induced pSTAT5. The transport of radiolabeled GH into the hypothalamus did not differ between wild-type and dwarf Ghr knockout mice, indicating that GH transport into the mouse brain is GHR independent. Also, single-photon emission computed tomography confirmed that radiolabeled GH rapidly reaches the ventral part of the tuberal hypothalamus. In conclusion, our study provides novel and valuable information about the pattern and mechanisms behind GH transport into the mouse brain.
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Affiliation(s)
- Filipe Menezes
- Biotechnology Center, Instituto de Pesquisas Energéticas e Nucleares, IPEN-CNEN/SP, São Paulo 05508-000, Brazil
| | - Frederick Wasinski
- Departamento de Fisiologia e Biofísica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Brazil
- Department of Neurology and Neurosurgery, Federal University of Sao Paulo, Sao Paulo 04039-032, Brazil
| | - Gabriel O de Souza
- Departamento de Fisiologia e Biofísica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Amanda P Nunes
- Biotechnology Center, Instituto de Pesquisas Energéticas e Nucleares, IPEN-CNEN/SP, São Paulo 05508-000, Brazil
| | - Emerson S Bernardes
- Radiopharmacy Center, Instituto de Pesquisas Energéticas e Nucleares, IPEN-CNEN/SP, São Paulo 05508-000, Brazil
| | - Sofia N dos Santos
- Radiopharmacy Center, Instituto de Pesquisas Energéticas e Nucleares, IPEN-CNEN/SP, São Paulo 05508-000, Brazil
| | - Fábio F A da Silva
- Radiopharmacy Center, Instituto de Pesquisas Energéticas e Nucleares, IPEN-CNEN/SP, São Paulo 05508-000, Brazil
| | - Cibele N Peroni
- Biotechnology Center, Instituto de Pesquisas Energéticas e Nucleares, IPEN-CNEN/SP, São Paulo 05508-000, Brazil
| | - João E Oliveira
- Biotechnology Center, Instituto de Pesquisas Energéticas e Nucleares, IPEN-CNEN/SP, São Paulo 05508-000, Brazil
| | - John J Kopchick
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - Rosemary S E Brown
- Department of Physiology, Centre for Neuroendocrinology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Gimena Fernandez
- Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology, La Plata, BA 1900, Argentina
| | - Pablo N De Francesco
- Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology, La Plata, BA 1900, Argentina
| | - Mario Perelló
- Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology, La Plata, BA 1900, Argentina
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, University of Uppsala, Uppsala 75312, Sweden
| | - Carlos R J Soares
- Biotechnology Center, Instituto de Pesquisas Energéticas e Nucleares, IPEN-CNEN/SP, São Paulo 05508-000, Brazil
| | - Jose Donato
- Departamento de Fisiologia e Biofísica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, Brazil
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