125 results on '"Ai-Min Bao"'
Search Results
2. Distinct proteomic profiles in prefrontal subareas of elderly major depressive disorder and bipolar disorder patients
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Yang-Jian Qi, Yun-Rong Lu, Li-Gen Shi, Jeroen A. A. Demmers, Karel Bezstarosti, Erikjan Rijkers, Rawien Balesar, Dick Swaab, and Ai-Min Bao
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract We investigated for the first time the proteomic profiles both in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) of major depressive disorder (MDD) and bipolar disorder (BD) patients. Cryostat sections of DLPFC and ACC of MDD and BD patients with their respective well-matched controls were used for study. Proteins were quantified by tandem mass tag and high-performance liquid chromatography-mass spectrometry system. Gene Ontology terms and functional cluster alteration were analyzed through bioinformatic analysis. Over 3000 proteins were accurately quantified, with more than 100 protein expressions identified as significantly changed in these two brain areas of MDD and BD patients as compared to their respective controls. These include OGDH, SDHA and COX5B in the DLPFC in MDD patients; PFN1, HSP90AA1 and PDCD6IP in the ACC of MDD patients; DBN1, DBNL and MYH9 in the DLPFC in BD patients. Impressively, depending on brain area and distinct diseases, the most notable change we found in the DLPFC of MDD was ‘suppressed energy metabolism’; in the ACC of MDD it was ‘suppressed tissue remodeling and suppressed immune response’; and in the DLPFC of BD it was differentiated ‘suppressed tissue remodeling and suppressed neuronal projection’. In summary, there are distinct proteomic changes in different brain areas of the same mood disorder, and in the same brain area between MDD and BD patients, which strengthens the distinct pathogeneses and thus treatment targets.
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- 2022
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3. Sex differences in hippocampal β-amyloid accumulation in the triple-transgenic mouse model of Alzheimer’s disease and the potential role of local estrogens
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Yu-Ting Hu, Xin-Lu Chen, Ya-Nan Zhang, Hugo McGurran, Jochem Stormmesand, Nicole Breeuwsma, Arja Sluiter, Juan Zhao, Dick Swaab, and Ai-Min Bao
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Alzheimer’s disease ,triple-transgenic AD mouse ,β-amyloid ,17β-estradiol ,sex differences ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
IntroductionEpidemiological studies show that women have a higher prevalence of Alzheimer’s disease (AD) than men. Peripheral estrogen reduction during aging in women is proposed to play a key role in this sex-associated prevalence, however, the underlying mechanism remains elusive. We previously found that transcription factor early growth response-1 (EGR1) significantly regulates cholinergic function. EGR1 stimulates acetylcholinesterase (AChE) gene expression and is involved in AD pathogenesis. We aimed to investigate whether the triple-transgenic AD (3xTg-AD) mice harboring PS1M146V, APPSwe, and TauP301L show sex differences in β-amyloid (Aβ) and hyperphosphorylated tau (p-Tau), the two primary AD hallmarks, and how local 17β-estradiol (E2) may regulate the expression of EGR1 and AChE.MethodsWe first sacrificed male and female 3xTg-AD mice at 3–4, 7–8, and 11–12 months and measured the levels of Aβ, p-Tau, EGR1, and AChE in the hippocampal complex. Second, we infected SH-SY5Y cells with lentivirus containing the amyloid precursor protein construct C99, cultured with or without E2 administration we measured the levels of extracellular Aβ and intracellular EGR1 and AChE.ResultsFemale 3xTg-AD mice had higher levels of Aβ compared to males, while no p-Tau was found in either group. In SH-SY5Y cells infected with lentivirus containing the amyloid precursor protein construct C99, we observed significantly increased extracellular Aβ and decreased expression of intracellular EGR1 and AChE. By adding E2 to the culture medium, extracellular Aβ(1–42) was significantly decreased while intracellular EGR1 and AChE expression were elevated.DiscussionThis data shows that the 3xTg-AD mouse model can be useful for studying the human sex differences of AD, but only in regards to Aβ. Furthermore, in vitro data shows local E2 may be protective for EGR1 and cholinergic functions in AD while suppressing soluble Aβ(1–42) levels. Altogether, this study provides further in vivo and in vitro data supporting the human epidemiological data indicating a higher prevalence of AD in women is related to changes in brain estrogen levels.
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- 2023
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4. Different oxytocin and corticotropin-releasing hormone system changes in bipolar disorder and major depressive disorder patients
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Lei Guo, Yang-Jian Qi, Hong Tan, Dan Dai, Rawien Balesar, Arja Sluiter, Joop van Heerikhuize, Shao-Hua Hu, Dick F. Swaab, and Ai-Min Bao
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Oxytocin ,Corticotropin-releasing hormone ,Bipolar disorder ,Major depressive disorder ,Hypothalamus ,Prefrontal cortex ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Oxytocin (OXT) and corticotropin-releasing hormone (CRH) are both produced in hypothalamic paraventricular nucleus (PVN). Central CRH may cause depression-like symptoms, while peripheral higher OXT plasma levels were proposed to be a trait marker for bipolar disorder (BD). We aimed to investigate differential OXT and CRH expression in the PVN and their receptors in prefrontal cortex of major depressive disorder (MDD) and BD patients. In addition, we investigated mood-related changes by stimulating PVN-OXT in mice. Methods: Quantitative immunocytochemistry and in situ hybridization were performed in the PVN for OXT and CRH on 6 BD and 6 BD-controls, 9 MDD and 9 MDD-controls. mRNA expressions of their receptors (OXTR, CRHR1 and CRHR2) were determined in anterior cingulate cortex and dorsolateral prefrontal cortex (DLPFC) of 30 BD and 34 BD-controls, and 24 MDD and 12 MDD-controls. PVN of 41 OXT-cre mice was short- or long-term activated by chemogenetics, and mood-related behavior was compared with 26 controls. Findings: Significantly increased OXT-immunoreactivity (ir), OXT-mRNA in PVN and increased OXTR-mRNA in DLPFC, together with increased ratios of OXT-ir/CRH-ir and OXTR-mRNA/CRHR-mRNA were observed in BD, at least in male BD patients, but not in MDD patients. PVN-OXT stimulation induced depression-like behaviors in male mice, and mixed depression/mania-like behaviors in female mice in a time-dependent way. Interpretation: Increased PVN-OXT and DLPFC-OXTR expression are characteristic for BD, at least for male BD patients. Stimulation of PVN-OXT neurons induced mood changes in mice, in a pattern different from BD. Funding: National Natural Science Foundation of China (81971268, 82101592).
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- 2022
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5. The human hypothalamus in mood disorders: The HPA axis in the center
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Ai-Min Bao and Dick F. Swaab
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
There are no specific structural neuropathological hallmarks found in the brain of mood disorders. Instead, there are molecular, functional and structural alterations reported in many brain areas. The neurodevelopmental underpinning indicated the presence of various genetic and developmental risk factors. The effect of genetic polymorphisms and developmental sequalae, some of which may start in the womb, result in functional changes in a network mediated by neurotransmitters and neuropeptides, which make the emotion- and stress-related brain systems more vulnerable to stressful events. This network of stress-related neurocircuits consists of, for instance, brainstem nuclei, the amygdala, habenula, prefrontal cortex and hypothalamus. Various nuclei of the hypothalamus form indeed one of the crucial hubs in this network. This structure concerns not only the hypothalamo-pituitary-adrenal (HPA) axis that integrate the neuro-endocrine-immune responses to stress, but also other hypothalamic nuclei and systems that play a key role in the symptoms of depression, such as disordered day-night rhythm, lack of reward feelings, disturbed eating, sex, and disturbed cognitive functions. The present review will focus on the changes in the human hypothalamus in depression, with the HPA axis in the center. We will discuss the inordinate network of neurotransmitters and neuropeptides involved, with the hope to find the most vulnerable neurobiological systems and the possible development of tailor-made treatments for mood disorders in the future. Keywords: The hypothalamo-pituitary-adrenal axis, Glutamate, GABA, Neuropeptide, Sex differences
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- 2019
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6. Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression
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Jing Lu, Juan Zhao, Rawien Balesar, Rolf Fronczek, Qiong-Bin Zhu, Xue-Yan Wu, Shao-Hua Hu, Ai-Min Bao, and Dick F. Swaab
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Depression ,Hypocretin ,Hypocretin receptors ,Hypothalamus ,Sex difference ,Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Neurophysiological and behavioral processes regulated by hypocretin (orexin) are severely affected in depression. However, alterations in hypocretin have so far not been studied in the human brain. We explored the hypocretin system changes in the hypothalamus and cortex in depression from male and female subjects. Methods: We quantified the differences between depression patients and well-matched controls, in terms of hypothalamic hypocretin-1 immunoreactivity (ir) and hypocretin receptors (Hcrtr-receptors)-mRNA in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex. In addition, we determined the alterations in the hypocretin system in a frequently used model for depression, the chronic unpredictable mild stress (CUMS) rat. Results: i) Compared to control subjects, the amount of hypocretin-immunoreactivity (ir) was significantly increased in female but not in male depression patients; ii) hypothalamic hypocretin-ir showed a clear diurnal fluctuation, which was absent in depression; iii) male depressive patients who had committed suicide showed significantly increased ACC Hcrt-receptor-2-mRNA expression compared to male controls; and iv) female but not male CUMS rats showed a highly significant positive correlation between the mRNA levels of corticotropin-releasing hormone and prepro-hypocretin in the hypothalamus, and a significantly increased Hcrt-receptor-1-mRNA expression in the frontal cortex compared to female control rats. Conclusions: The clear sex-related change found in the hypothalamic hypocretin-1-ir in depression should be taken into account in the development of hypocretin-targeted therapeutic strategies.
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- 2017
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7. Correction: ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines
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Shu-Xia Cao, Ying Zhang, Xing-Yue Hu, Bin Hong, Peng Sun, Hai-Yang He, Hong-Yan Geng, Ai-Min Bao, Shu-Min Duan, Jian-Ming Yang, Tian-Ming Gao, Hong Lian, and Xiao-Ming Li
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Medicine ,Science ,Biology (General) ,QH301-705.5 - Published
- 2019
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8. ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines
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Shu-Xia Cao, Ying Zhang, Xing-Yue Hu, Bin Hong, Peng Sun, Hai-Yang He, Hong-Yan Geng, Ai-Min Bao, Shu-Min Duan, Jian-Ming Yang, Tian-Ming Gao, Hong Lian, and Xiao-Ming Li
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ErbB4 ,noradrenergic neuron ,Locus coeruleus ,mania ,bipolar disorder ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of bipolar disorder (BPD). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to BPD; however, how ErbB4 regulates NE neuronal function and contributes to BPD pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, Erbb4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.
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- 2018
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9. The stress systems in depression: a postmortem study
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Ai-Min Bao and Dick F. Swaab
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molecular mechanisms ,brain ,neurotransmitters ,neuromodulators ,genetics ,HPA axis ,sex steroids ,oxytocin ,orexin ,Psychiatry ,RC435-571 - Abstract
After trauma, depressive disorders are among the most frequent emerging diagnoses. However, although the symptoms of depression are well characterized, the molecular mechanisms underlying this disorder are largely unknown. Factors involved in the heterogeneous pathogenesis of depression include polymorphisms in stress-related genes, gender, age, developmental history, and environmental (traumatic) stressors such as epigenetic factors. These factors may make different parts of the stress-related brain systems more vulnerable to different stressful or traumatic life events or psychological stresses, causing alterations in a network of neurotransmitters and neuromodulators including amines, amino acids, nitric oxide (NO), and neuropeptides, and finally make individuals at risk for depression. The hypothalamo–pituitary–adrenal (HPA) axis has a prominent position in this network. With the postmortem brain material obtained from the Netherlands Brain Bank, we have carried on a series of studies with the aim to elucidate the specific changes in these systems in relation to special subtypes of depression. Our final destination is to set up tailor-made treatment for depressive patients on the basis of his/her developmental history, genetic and epigenetic background, and the vulnerability in particular neurobiological systems. This presentation is a review of our findings of changes in systems of sex steroids, receptors in the hypothalamic paraventricular nucleus, corticotrophin-releasing hormone, orexin, γ-aminobutyric acid, and NO in the etiology of depression, in relation to HPA activity, sex differences, and suicide.
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- 2014
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10. Sexually dimorphic age-related molecular differences in the entorhinal cortex of cognitively intact elderly: Relation to early Alzheimer's changes
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Xin‐Lu Chen, Jennifer Monteiro Fortes, Yu‐Ting Hu, Juliet van Iersel, Kang‐Ning He, Joop van Heerikhuize, Rawien Balesar, Dick Swaab, Ai‐Min Bao, and Netherlands Institute for Neuroscience (NIN)
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Abstract
INTRODUCTION: Women are more vulnerable to Alzheimer's disease (AD) than men. The entorhinal cortex (EC) is one of the earliest structures affected in AD. We identified in cognitively intact elderly different molecular changes in the EC in relation to age. METHODS: Changes in 12 characteristic molecules in relation to age were determined by quantitative immunohistochemistry or in situ hybridization in the EC. They were arbitrarily grouped into sex steroid-related molecules, markers of neuronal activity, neurotransmitter-related molecules, and cholinergic activity-related molecules. RESULTS: The changes in molecules indicated increasing local estrogenic and neuronal activity accompanied by a higher and faster hyperphosphorylated tau accumulation in women's EC in relation to age, versus a mainly stable local estrogenic/androgenic and neuronal activity in men's EC. DISCUSSION: EC employs a different neurobiological strategy in women and men to maintain cognitive function, which seems to be accompanied by an earlier start of AD in women. HIGHLIGHTS: Local estrogen system is activated with age only in women's entorhinal cortex (EC). EC neuronal activity increased with age only in elderly women with intact cognition. Men and women have different molecular strategies to retain cognition with aging. P-tau accumulation in the EC was higher and faster in cognitively intact elderly women.
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- 2023
11. Sex differences in the neuropathological hallmarks of Alzheimer’s disease: focus on cognitively intact elderly individuals
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Hugo McGurran, Jackson Boonstra, Ai-Min Bao, Dick F. Swaab, Rawien Balesar, Arja A. Sluiter, Jochem Stormmesand, Yu-Ting Hu, Ronald W.H. Verwer, and Netherlands Institute for Neuroscience (NIN)
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Male ,0301 basic medicine ,Aging ,Histology ,Amyloid ,Physiology ,tau Proteins ,Disease ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,β amyloid ,Physiology (medical) ,mental disorders ,Entorhinal Cortex ,Humans ,Medicine ,Aged ,Aged, 80 and over ,Sex Characteristics ,Amyloid beta-Peptides ,business.industry ,Brain ,Neurofibrillary Tangles ,Entorhinal cortex ,030104 developmental biology ,Neurology ,Female ,Brain bank ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
AIMS Women are more vulnerable to Alzheimer's disease (AD) than men. We investigated (i) whether and at what age the AD hallmarks, that is, β-amyloid (Aβ) and hyperphosphorylated Tau (p-Tau) show sex differences; and (ii) whether such sex differences may occur in cognitively intact elderly individuals. METHODS We first analysed the entire post-mortem brain collection of all non-demented 'controls' and AD donors from our Brain Bank (245 men and 403 women), for the presence of sex differences in AD hallmarks. Second, we quantitatively studied possible sex differences in Aβ, Aβ42 and p-Tau in the entorhinal cortex of well-matched female (n = 31) and male (n = 21) clinically cognitively intact elderly individuals. RESULTS Women had significantly higher Braak stages for tangles and amyloid scores than men, after 80 years. In the cognitively intact elderly, women showed higher levels of p-Tau, but not Aβ or Aβ42, in the entorhinal cortex than men, and a significant interaction of sex with age was found only for p-Tau but not Aβ or Aβ42. CONCLUSIONS Enhanced p-Tau in the entorhinal cortex may play a major role in the vulnerability to AD in women.
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- 2021
12. Sex differences in hippocampal b-amyloid accumulation in the triple-transgenic mouse model of Alzheimer's disease and the potential role of local estrogens.
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Yu-Ting Hu, Xin-Lu Chen, Ya-Nan Zhang, McGurran, Hugo, Stormmesand, Jochem, Breeuwsma, Nicole, Sluiter, Arja, Juan Zhao, Swaab, Dick, and Ai-Min Bao
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ALZHEIMER'S disease ,AMYLOID beta-protein precursor ,LABORATORY mice ,ANIMAL disease models ,HIPPOCAMPUS (Brain) - Abstract
Introduction: Epidemiological studies show that women have a higher prevalence of Alzheimer's disease (AD) than men. Peripheral estrogen reduction during aging in women is proposed to play a key role in this sex-associated prevalence, however, the underlying mechanism remains elusive. We previously found that transcription factor early growth response-1 (EGR1) significantly regulates cholinergic function. EGR1 stimulates acetylcholinesterase (AChE) gene expression and is involved in AD pathogenesis. We aimed to investigate whether the triple-transgenic AD (3xTg-AD) mice harboring PS1M146V, APPSwe, and TauP301L show sex differences in b-amyloid (Ab) and hyperphosphorylated tau (p-Tau), the two primary AD hallmarks, and how local 17b-estradiol (E2) may regulate the expression of EGR1 and AChE. Methods: We first sacrificed male and female 3xTg-AD mice at 3-4, 7-8, and 11-12 months and measured the levels of Ab, p-Tau, EGR1, and AChE in the hippocampal complex. Second, we infected SH-SY5Y cells with lentivirus containing the amyloid precursor protein construct C99, cultured with or without E2 administration we measured the levels of extracellular Ab and intracellular EGR1 and AChE. Results: Female 3xTg-AD mice had higher levels of Ab compared to males, while no p-Tau was found in either group. In SH-SY5Y cells infected with lentivirus containing the amyloid precursor protein construct C99, we observed significantly increased extracellular Ab and decreased expression of intracellular EGR1 and AChE. By adding E2 to the culture medium, extracellular Ab(1-42) was significantly decreased while intracellular EGR1 and AChE expression were elevated. Discussion: This data shows that the 3xTg-AD mouse model can be useful for studying the human sex differences of AD, but only in regards to Ab. Furthermore, in vitro data shows local E2 may be protective for EGR1 and cholinergic functions in AD while suppressing soluble Ab(1-42) levels. Altogether, this study provides further in vivo and in vitro data supporting the human epidemiological data indicating a higher prevalence of AD in women is related to changes in brain estrogen levels. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Corrigendum to 'Identifying Plasma Biomarkers with high specificity for major depressive disorder: A multi-level proteomics study'. Journal of Affective disorders 277 (2020) 620-630
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Ruize Song, Qiongqiong Zhan, Jianli Zhu, Yang Zhao, Liping Wang, Yachen Shi, Dick F. Swaab, Hongxing Zhang, Xiaowei Tang, Ai-Min Bao, Xiaobin Zhang, Zhijun Zhang, and Yang-Jian Qi
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Psychiatry and Mental health ,Clinical Psychology ,business.industry ,medicine ,MEDLINE ,Major depressive disorder ,Plasma biomarkers ,medicine.disease ,Bioinformatics ,Proteomics ,business - Published
- 2021
14. Alterations of melatonin receptors MT1 and MT2 in the hypothalamic suprachiasmatic nucleus during depression
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Wu, Ying-Hui, Ursinus, Jeanine, Zhou, Jiang-Ning, Scheer, Frank A.J.L., Ai-Min, Bao, Jockers, Ralf, van Heerikhuize, Joop, and Swaab, Dick F.
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- 2013
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15. Examining how our brain determines gender identity
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Ai-Min, Bao
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Male ,Brain ,Gender Identity ,Humans ,Female - Published
- 2022
16. Sexual Differentiation of the Human Brain in Relation to Gender-Identity, Sexual Orientation, and Neuropsychiatric Disorders
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Dick Swaab, Samantha E. C. Wolff, and Ai-Min Bao
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- 2022
17. Changes of hypocretin (orexin) system in schizophrenia
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Tingting Mou, Rolf Fronczek, Dick F. Swaab, Kangyu Jin, Jinfeng Duan, Haimei Li, Weijuan Xu, Ai-Min Bao, Jing Lu, Jin-Hui Li, Manli Huang, and Netherlands Institute for Neuroscience (NIN)
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Adult ,Male ,medicine.medical_specialty ,Prefrontal Cortex ,superior frontal gyrus ,Neurotransmission ,cerebrospinal fluid ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Sex Factors ,Orexin Receptors ,Internal medicine ,mental disorders ,medicine ,Humans ,hypothalamus ,Receptor ,orexin, hypocretin receptor ,plasma ,Orexins ,hypocretin receptor ,business.industry ,Middle Aged ,medicine.disease ,030227 psychiatry ,Orexin ,schizophrenia ,Psychiatry and Mental health ,Endocrinology ,Superior frontal gyrus ,orexin ,nervous system ,Schizophrenia ,Hypothalamus ,Female ,Autopsy ,hypocretin ,business ,030217 neurology & neurosurgery ,psychological phenomena and processes ,Hypocretin orexin ,Regular Articles - Abstract
Hypocretin (also called orexin) regulates various functions, such as sleep-wake rhythms, attention, cognition, and energy balance, which show significant changes in schizophrenia (SCZ). We aimed to identify alterations in the hypocretin system in SCZ patients. We measured plasma hypocretin-1 levels in SCZ patients and healthy controls and found significantly decreased plasma hypocretin-1 levels in SCZ patients, which was mainly due to a significant decrease in female SCZ patients compared with female controls. In addition, we measured postmortem hypothalamic hypocretin-1-immunoreactivity (ir), ventricular cerebrospinal fluid (CSF) hypocretin-1 levels, and hypocretin receptor (Hcrt-R) mRNA expression in the superior frontal gyrus (SFG) in SCZ patients and controls We observed a significant decrease in the amount of hypothalamic hypocretin-1 ir in SCZ patients, which was due to decreased amounts in female but not male patients. Moreover, Hcrt-R2 mRNA in the SFG was decreased in female SCZ patients compared with female controls, while male SCZ patients showed a trend of increased Hcrt-R1 mRNA and Hcrt-R2 mRNA expression compared with male controls. We conclude that central hypocretin neurotransmission is decreased in SCZ patients, especially female patients, and this is reflected in the plasma.
- Published
- 2021
18. Sexual differentiation of the human hypothalamus: Relationship to gender identity and sexual orientation
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Dick F, Swaab, Samantha E C, Wolff, and Ai-Min, Bao
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Male ,Sex Differentiation ,Pregnancy ,Sexual Behavior ,Hypothalamus ,Gender Identity ,Humans ,Female ,Transsexualism - Abstract
Gender identity (an individual's perception of being male or female) and sexual orientation (heterosexuality, homosexuality, or bisexuality) are programmed into our brain during early development. During the intrauterine period in the second half of pregnancy, a testosterone surge masculinizes the fetal male brain. If such a testosterone surge does not occur, this will result in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other and can result in gender dysphoria. Nature produces a great variability for all aspects of sexual differentiation of the brain. Mechanisms involved in sexual differentiation of the brain include hormones, genetics, epigenetics, endocrine disruptors, immune response, and self-organization. Furthermore, structural and functional differences in the hypothalamus relating to gender dysphoria and sexual orientation are described in this review. All the genetic, postmortem, and in vivo scanning observations support the neurobiological theory about the origin of gender dysphoria, i.e., it is the sizes of brain structures, the neuron numbers, the molecular composition, functions, and connectivity of brain structures that determine our gender identity or sexual orientation. There is no evidence that one's postnatal social environment plays a crucial role in the development of gender identity or sexual orientation.
- Published
- 2021
19. Matching of the postmortem hypothalamus from patients and controls
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Dick F, Swaab and Ai-Min, Bao
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Male ,Postmortem Changes ,Hypothalamus ,Brain ,Gender Identity ,Humans ,Female ,Neuropathology ,Aged ,Netherlands - Abstract
The quality of postmortem hypothalamus research depends strongly on a thorough clinical investigation and documentation of the patient's disorder and therapies. In addition, a systematic and professional neuropathological investigation of the entire brain of both the cases and the controls is absolutely crucial. In the experience of the Netherlands Brain Bank (NBB), about 20% of the clinical neurological diagnoses, despite being made in first rate clinics, have to be revised or require extra diagnoses after a complete and thorough neuropathologic review by the NBB. The neuropathology examination may reveal for instance that the elderly "controls" already have preclinical neurodegenerative alterations. In postmortem studies, the patient and control groups must be matched for as many as possible of the known confounding factors. This is necessary to make the groups as similar as possible, except for the topic being investigated. Confounding factors are present (i) before, (ii) during, and (iii) after death. They are, respectively: (i) genetic background, systemic diseases, duration and gravity of illness, medicines and addictive compounds used, age, sex, gender identity, sexual orientation, clock- and seasonal time of death, and lateralization; (ii) agonal state, stress of dying; and (iii) postmortem delay, freezing procedures, fixation, and storage time. Agonal state is generally estimated by measuring the pH of the brain. However, there are disorders in which pH is lower as a part of the disease process. Because of the large number of potentially confounding factors that differ according to, for instance, brain area and disease, a brain bank should have a large number of controls at its disposal for appropriate matching. If matching fails for some confounders, the influence of the confounders may be determined by statistical methods, such as analysis of variance or the regression models.
- Published
- 2021
20. The human hypothalamus in mood disorders: The HPA axis in the center
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Dick F. Swaab, Ai-Min Bao, and Netherlands Institute for Neuroscience (NIN)
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0301 basic medicine ,Neuropeptide ,Amygdala ,lcsh:RC321-571 ,GABA ,03 medical and health sciences ,0302 clinical medicine ,Sex differences ,medicine ,Prefrontal cortex ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Depression (differential diagnoses) ,Articles from the Special Issue on Emotion and mood disorders: from molecular mechanisms to neuronal circuits ,Edited by Jiang-Ning Zhou ,General Neuroscience ,Cognition ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Habenula ,Mood disorders ,Hypothalamus ,Glutamate ,Psychology ,Neuroscience ,The hypothalamo-pituitary-adrenal axis ,030217 neurology & neurosurgery - Abstract
There are no specific structural neuropathological hallmarks found in the brain of mood disorders. Instead, there are molecular, functional and structural alterations reported in many brain areas. The neurodevelopmental underpinning indicated the presence of various genetic and developmental risk factors. The effect of genetic polymorphisms and developmental sequalae, some of which may start in the womb, result in functional changes in a network mediated by neurotransmitters and neuropeptides, which make the emotion- and stress-related brain systems more vulnerable to stressful events. This network of stress-related neurocircuits consists of, for instance, brainstem nuclei, the amygdala, habenula, prefrontal cortex and hypothalamus. Various nuclei of the hypothalamus form indeed one of the crucial hubs in this network. This structure concerns not only the hypothalamo-pituitary-adrenal (HPA) axis that integrate the neuro-endocrine-immune responses to stress, but also other hypothalamic nuclei and systems that play a key role in the symptoms of depression, such as disordered day-night rhythm, lack of reward feelings, disturbed eating, sex, and disturbed cognitive functions. The present review will focus on the changes in the human hypothalamus in depression, with the HPA axis in the center. We will discuss the inordinate network of neurotransmitters and neuropeptides involved, with the hope to find the most vulnerable neurobiological systems and the possible development of tailor-made treatments for mood disorders in the future. Keywords: The hypothalamo-pituitary-adrenal axis, Glutamate, GABA, Neuropeptide, Sex differences
- Published
- 2019
21. Activation of the Brain to Postpone Dementia: A Concept Originating from Postmortem Human Brain Studies
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Dick F. Swaab, Ai-Min Bao, Qiong-Bin Zhu, and Netherlands Institute for Neuroscience (NIN)
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0301 basic medicine ,medicine.medical_specialty ,Neurology ,Physiology ,Models, Neurological ,Physical exercise ,Review ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Animals ,Humans ,Medicine ,Dementia ,Cognitive decline ,Cognitive reserve ,business.industry ,General Neuroscience ,Neurodegeneration ,Brain ,General Medicine ,Human brain ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Alzheimer’s disease (AD) is characterized by decreased neuronal activity and atrophy, while hyperactivity of neurons seems to make them resistant to aging and neurodegeneration, a phenomenon which we have paraphrased as ‘use it or lose it’. Our hypothesis proposes that (1) during their functioning, neurons are damaged; (2) accumulation of damage that is not repaired is the basis of aging; (3) the vulnerability to AD is determined by the genetic background and the balance between the amount of damage and the efficiency of repair, and (4) by stimulating the brain, repair mechanisms are stimulated and cognitive reserve is increased, resulting in a decreased rate of aging and risk for AD. Environmental stimulating factors such as bilingualism/multilingualism, education, occupation, musical experience, physical exercise, and leisure activities have been reported to reduce the risk of dementia and decrease the rate of cognitive decline, although methodological problems are present.
- Published
- 2019
22. Human Brain Slice Culture
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Ronald W.H. Verwer, Sabina Luchetti, Rawien Balesar, Dick F. Swaab, Ai-Min Bao, Jiang-Ning Zhou, Xin-Rui Qi, and Netherlands Institute for Neuroscience (NIN)
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Neurology ,Physiology ,Review ,Tissue Culture Techniques ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,medicine ,Humans ,Depression (differential diagnoses) ,Brain-derived neurotrophic factor ,Brain Diseases ,business.industry ,General Neuroscience ,Brain ,General Medicine ,Human brain ,030104 developmental biology ,medicine.anatomical_structure ,Neuropsychiatric disorder ,Cell culture ,Brain bank ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Investigating the pathophysiological mechanisms underlying brain disorders is a priority if novel therapeutic strategies are to be developed. In vivo studies of animal models and in vitro studies of cell lines/primary cell cultures may provide useful tools to study certain aspects of brain disorders. However, discrepancies among these studies or unsuccessful translation from animal/cell studies to human/clinical studies often occur, because these models generally represent only some symptoms of a neuropsychiatric disorder rather than the complete disorder. Human brain slice cultures from postmortem tissue or resected tissue from operations have shown that, in vitro, neurons and glia can stay alive for long periods of time, while their morphological and physiological characteristics, and their ability to respond to experimental manipulations are maintained. Human brain slices can thus provide a close representation of neuronal networks in vivo, be a valuable tool for investigation of the basis of neuropsychiatric disorders, and provide a platform for the evaluation of novel pharmacological treatments of human brain diseases. A brain bank needs to provide the necessary infrastructure to bring together donors, hospitals, and researchers who want to investigate human brain slices in cultures of clinically and neuropathologically well-documented material.
- Published
- 2019
23. Author response for 'Sex differences in the neuropathological hallmarks of Alzheimer's disease: focus on cognitively intact elderly individuals'
- Author
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Hugo McGurran, Jackson Boonstra, Ai-Min Bao, Jochem Stormmesand, Dick F. Swaab, Arja A. Sluiter, Yu-Ting Hu, Ronald W.H. Verwer, and Rawien Balesar
- Subjects
Focus (computing) ,Disease ,Psychology ,Clinical psychology - Published
- 2021
24. Brain transcriptional regulatory architecture and schizophrenia etiology converge between East Asian and European ancestral populations
- Author
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Richard F. Kopp, Yi Jiang, Duan F, Yan Xia, Faming Wang, Jufang Huang, Zhilin Ning, Maoyu Li, Wenying Qiu, Jiapei Dai, Xuhua Yan, Chunxia Ma, Shuhua Xu, Beisha Tang, Chao Chen, Sihan Liu, Liz Kuney, Ai-Min Bao, Chunyu Liu, and Yu Chen
- Subjects
Transcriptome ,Linkage disequilibrium ,Evolutionary biology ,Expression quantitative trait loci ,Quantitative trait locus ,Biology ,Gene ,Allele frequency ,Genetic architecture ,Genetic association - Abstract
Understanding the genetic architecture of gene expression and splicing in human brain is critical to unlocking the mechanisms of complex neuropsychiatric disorders like schizophrenia (SCZ). Large-scale brain transcriptomic studies are based primarily on populations of European (EUR) ancestry. The uniformity of mono-racial resources may limit important insights into the disease etiology. Here, we characterized brain transcriptional regulatory architecture of East Asians (EAS; n=151), identifying 3,278 expression quantitative trait loci (eQTL) and 4,726 spliceQTL (sQTL). Comparing these to PsychENCODE/BrainGVEX confirmed our hypothesis that the transcriptional regulatory architecture in EAS and EUR brains align. Furthermore, distinctive allelic frequency and linkage disequilibrium impede QTL translation and gene-expression prediction accuracy. Integration of eQTL/sQTL with genome-wide association studies reveals common and novel SCZ risk genes. Pathway-based analyses showing shared SCZ biology point to synaptic and GTPase dysfunction as a prospective pathogenesis. This study elucidates the transcriptional landscape of the EAS brain and emphasizes an essential convergence between EAS and EUR populations.
- Published
- 2021
25. Distinct Proteomic Profiles in Prefrontal Subareas of Major Depressive Disorder and Bipolar Disorder Patients
- Author
-
Yang-Jian Qi, Yun-Rong Lu, Li-Gen Shi, Jeroen A.A. Demmers, Karel Bezstarosti, Erikjan Rijkers, Rawien Balesar, Dick Swaab, and Ai-Min Bao
- Subjects
History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2021
26. Histamine H1 receptor deletion in cholinergic neurons induces sensorimotor gating ability deficit and social impairments in mice
- Author
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Lu Wang, Kuo Zhang, Xiangnan Zhang, Jingyu Yang, Weiwei Hu, Xiao-Dong Wang, Dick F. Swaab, Yi Wang, Li Cheng, Yanrong Zheng, Yujing Wang, Cenglin Xu, Zhong Chen, Dadao An, Ai-Min Bao, Lei Jiang, Yi-xin Xu, Yu-Dong Zhou, Shumin Duan, and Netherlands Institute for Neuroscience (NIN)
- Subjects
0301 basic medicine ,Science ,General Physics and Astronomy ,Histamine H1 receptor ,behavioral disciplines and activities ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Cholinergic neuron ,Receptor ,Prefrontal cortex ,Basal forebrain ,Multidisciplinary ,Sensory gating ,business.industry ,General Chemistry ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Schizophrenia ,behavior and behavior mechanisms ,Cholinergic ,business ,Neuroscience ,psychological phenomena and processes ,030217 neurology & neurosurgery - Abstract
Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H1 receptor (H1R) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H1R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H1R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H1R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.
- Published
- 2021
27. Matching of the postmortem hypothalamus from patients and controls
- Author
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Dick F. Swaab and Ai-Min Bao
- Subjects
Pediatrics ,medicine.medical_specialty ,Matching (statistics) ,Postmortem studies ,business.industry ,Addiction ,media_common.quotation_subject ,Confounding ,Neuropathology ,Disease ,Lateralization of brain function ,medicine ,Analysis of variance ,business ,media_common - Abstract
The quality of postmortem hypothalamus research depends strongly on a thorough clinical investigation and documentation of the patient's disorder and therapies. In addition, a systematic and professional neuropathological investigation of the entire brain of both the cases and the controls is absolutely crucial. In the experience of the Netherlands Brain Bank (NBB), about 20% of the clinical neurological diagnoses, despite being made in first rate clinics, have to be revised or require extra diagnoses after a complete and thorough neuropathologic review by the NBB. The neuropathology examination may reveal for instance that the elderly "controls" already have preclinical neurodegenerative alterations. In postmortem studies, the patient and control groups must be matched for as many as possible of the known confounding factors. This is necessary to make the groups as similar as possible, except for the topic being investigated. Confounding factors are present (i) before, (ii) during, and (iii) after death. They are, respectively: (i) genetic background, systemic diseases, duration and gravity of illness, medicines and addictive compounds used, age, sex, gender identity, sexual orientation, clock- and seasonal time of death, and lateralization; (ii) agonal state, stress of dying; and (iii) postmortem delay, freezing procedures, fixation, and storage time. Agonal state is generally estimated by measuring the pH of the brain. However, there are disorders in which pH is lower as a part of the disease process. Because of the large number of potentially confounding factors that differ according to, for instance, brain area and disease, a brain bank should have a large number of controls at its disposal for appropriate matching. If matching fails for some confounders, the influence of the confounders may be determined by statistical methods, such as analysis of variance or the regression models.
- Published
- 2021
28. Sexual differentiation of the human hypothalamus: Relationship to gender identity and sexual orientation
- Author
-
Ai-Min Bao, Samantha E C Wolff, and Dick F. Swaab
- Subjects
Gender dysphoria ,Sexual differentiation ,media_common.quotation_subject ,Social environment ,Testosterone (patch) ,medicine.disease ,Developmental psychology ,Perception ,Heterosexuality ,Sexual orientation ,medicine ,Homosexuality ,Psychology ,media_common - Abstract
Gender identity (an individual's perception of being male or female) and sexual orientation (heterosexuality, homosexuality, or bisexuality) are programmed into our brain during early development. During the intrauterine period in the second half of pregnancy, a testosterone surge masculinizes the fetal male brain. If such a testosterone surge does not occur, this will result in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other and can result in gender dysphoria. Nature produces a great variability for all aspects of sexual differentiation of the brain. Mechanisms involved in sexual differentiation of the brain include hormones, genetics, epigenetics, endocrine disruptors, immune response, and self-organization. Furthermore, structural and functional differences in the hypothalamus relating to gender dysphoria and sexual orientation are described in this review. All the genetic, postmortem, and in vivo scanning observations support the neurobiological theory about the origin of gender dysphoria, i.e., it is the sizes of brain structures, the neuron numbers, the molecular composition, functions, and connectivity of brain structures that determine our gender identity or sexual orientation. There is no evidence that one's postnatal social environment plays a crucial role in the development of gender identity or sexual orientation.
- Published
- 2021
29. Sex differences in stress-related disorders: Major depressive disorder, bipolar disorder, and posttraumatic stress disorder
- Author
-
Dick F, Swaab and Ai-Min, Bao
- Subjects
Adult ,Male ,Stress Disorders, Post-Traumatic ,Depressive Disorder, Major ,Sex Characteristics ,Bipolar Disorder ,Humans ,Pituitary-Adrenal System ,Female - Abstract
Stress-related disorders, such as mood disorders and posttraumatic stress disorder (PTSD), are more common in women than in men. This sex difference is at least partly due to the organizing effect of sex steroids during intrauterine development, while activating or inhibiting effects of circulating sex hormones in the postnatal period and adulthood also play a role. Such effects result in structural and functional changes in neuronal networks, neurotransmitters, and neuropeptides, which make the arousal- and stress-related brain systems more vulnerable to environmental stressful events in women. Certain brainstem nuclei, the amygdala, habenula, prefrontal cortex, and hypothalamus are important hubs in the stress-related neuronal network. Various hypothalamic nuclei play a central role in this sexually dimorphic network. This concerns not only the hypothalamus-pituitary-adrenal axis (HPA-axis), which integrates the neuro-endocrine-immune responses to stress, but also other hypothalamic nuclei and systems that play a key role in the symptoms of mood disorders, such as disordered day-night rhythm, lack of reward feelings, disturbed eating and sex, and disturbed cognitive functions. The present chapter focuses on the structural and functional sex differences that are present in the stress-related brain systems in mood disorders and PTSD, placing the HPA-axis in the center. The individual differences in the vulnerability of the discussed systems, caused by genetic and epigenetic developmental factors warrant further research to develop tailor-made therapeutic strategies.
- Published
- 2020
30. Identifying Plasma Biomarkers with high specificity for major depressive disorder: A multi-level proteomics study
- Author
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Ruize Song, Xiaowei Tang, Yachen Shi, Jianli Zhu, Yang Zhao, Hongxing Zhang, Ai-Min Bao, Liping Wang, Xiaobin Zhang, Yang-Jian Qi, Dick F. Swaab, Qiongqiong Zhan, Zhijun Zhang, and Netherlands Institute for Neuroscience (NIN)
- Subjects
Oncology ,Proteomics ,medicine.medical_specialty ,Bipolar I disorder ,Vitamin D-binding protein ,behavioral disciplines and activities ,03 medical and health sciences ,Plasma ,0302 clinical medicine ,Internal medicine ,mental disorders ,medicine ,Humans ,Depressive Disorder, Major ,business.industry ,Reproducibility of Results ,medicine.disease ,Blood proteins ,030227 psychiatry ,Dorsolateral prefrontal cortex ,Psychiatry and Mental health ,Clinical Psychology ,medicine.anatomical_structure ,Pharmaceutical Preparations ,Schizophrenia ,Cohort ,Major depressive disorder ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Background There are currently no objective diagnostic biomarkers for major depressive disorder (MDD) due to the biological complexity of the disorder. The existence of blood-based biomarkers with high specificity would be convenient for the clinical diagnosis of MDD. Methods A comprehensive plasma proteomic analysis was conducted in a highly homogeneous cohort [7 drug-naive MDD patients and 7 healthy controls (HCs)], with bioinformatics analysis combined with machine learning used to screen candidate proteins. Verification of reproducibility and specificity was conducted in independent cohorts [60 HCs and 74 MDD, 42 schizophrenia (SZ) and 39 bipolar I disorder (BD-I) drug-naive patients]. Furthermore, verification of consistency was accomplished by proteomic analysis of postmortem brain tissue from 16 MDD patients and 16 HCs. Results: Levels of C-reactive protein (CRP), antithrombin III (ATIII), inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) and vitamin D-binding protein (VDB) were significantly higher in MDD patients, both in the discovery cohort and independent replication cohort. In comparison with SZ or BD-I patients, two proteins (VDB and ITIH4) were significantly elevated only in MDD patients. In addition, increased VDB and ITIH4 were observed consistently in both plasma and postmortem dorsolateral prefrontal cortex tissues of MDD patients. Furthermore, a panel consisting of all four plasma proteins was able to distinguish MDD patients from HCs or SZ or BD-I patients with the highest accuracy. Conclusion Plasma ITIH4 and VDB may be potential plasma biomarkers of MDD with high specificity. The four-protein panel is more suitable as a potential clinical diagnostic marker for MDD.
- Published
- 2020
31. Sex differences in stress-related disorders: Major depressive disorder, bipolar disorder, and posttraumatic stress disorder
- Author
-
Ai-Min Bao and Dick F. Swaab
- Subjects
business.industry ,Stress-related disorders ,medicine.disease ,Amygdala ,030227 psychiatry ,Arousal ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Mood disorders ,Medicine ,Locus coeruleus ,Major depressive disorder ,Bipolar disorder ,business ,Prefrontal cortex ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Stress-related disorders, such as mood disorders and posttraumatic stress disorder (PTSD), are more common in women than in men. This sex difference is at least partly due to the organizing effect of sex steroids during intrauterine development, while activating or inhibiting effects of circulating sex hormones in the postnatal period and adulthood also play a role. Such effects result in structural and functional changes in neuronal networks, neurotransmitters, and neuropeptides, which make the arousal- and stress-related brain systems more vulnerable to environmental stressful events in women. Certain brainstem nuclei, the amygdala, habenula, prefrontal cortex, and hypothalamus are important hubs in the stress-related neuronal network. Various hypothalamic nuclei play a central role in this sexually dimorphic network. This concerns not only the hypothalamus-pituitary-adrenal axis (HPA-axis), which integrates the neuro-endocrine-immune responses to stress, but also other hypothalamic nuclei and systems that play a key role in the symptoms of mood disorders, such as disordered day-night rhythm, lack of reward feelings, disturbed eating and sex, and disturbed cognitive functions. The present chapter focuses on the structural and functional sex differences that are present in the stress-related brain systems in mood disorders and PTSD, placing the HPA-axis in the center. The individual differences in the vulnerability of the discussed systems, caused by genetic and epigenetic developmental factors warrant further research to develop tailor-made therapeutic strategies.
- Published
- 2020
32. Direct Involvement of Androgen Receptor in Oxytocin Gene Expression
- Author
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Dan Dai, Dick F. Swaab, Ai-Min Bao, Rawien Balesar, Qiao-Chu Li, Shaohua Hu, Qiong-Bin Zhu, and Netherlands Institute for Neuroscience (NIN)
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cytoplasm ,Immunocytochemistry ,Hypothalamus ,Gene Expression ,Oxytocin ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Cell Line, Tumor ,Gene expression ,medicine ,Journal Article ,Humans ,Testosterone ,RNA, Messenger ,Receptor ,Promoter Regions, Genetic ,Pharmacology ,Cell Nucleus ,Neurons ,Mood Disorders ,medicine.disease ,Immunohistochemistry ,Androgen receptor ,Psychiatry and Mental health ,030104 developmental biology ,Endocrinology ,Mood disorders ,Receptors, Androgen ,Original Article ,Psychopharmacology ,Psychology ,030217 neurology & neurosurgery ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Oxytocin (OXT), synthesized in the hypothalamic paraventricular nucleus (PVN) and then released into different brain areas, may play a crucial role in various behaviors and neuropsychiatric disorders, including depression. Testosterone has been proposed by clinical studies to have the opposite effect of oxytocin in these disorders. We began by studying, in the postmortem hypothalamus of fifteen patients with mood disorders and fifteen matched controls, the expression of OXT in the PVN by means of immunocytochemistry (ICC) and the co-localization of OXT and androgen receptor (AR) by means of double labeling ICC. Subsequently, the regulatory effect of AR on OXT gene expression was studied in vitro. We found a higher expression of PVN OXT in the mood disorder patients than in the control subjects, and observed a clear co-localization of AR in OXT-expressing neurons, both in the cytoplasm and in the nucleus. In addition, a significant decrease in OXT-mRNA levels was observed after pre-incubation of the SK-N-SH cells with testosterone. A further potential androgen-responsive element in the human OXT gene promotor was revealed by electrophoretic mobility shift assays and co-transfections in neuroblastoma cells. Finally, in vitro studies demonstrated that AR mediated the down-regulation of OXT gene expression. These results suggest that the fact that OXT and testosterone appear to have opposite effects in neuropsychiatric disorders might be based upon a direct inhibition of AR on OXT transcription, which may provide a novel target for therapeutic strategies in depression.Neuropsychopharmacology accepted article preview online, 27 April 2017. doi:10.1038/npp.2017.76.
- Published
- 2017
33. Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression
- Author
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Rolf Fronczek, Jing Lu, Xue-Yan Wu, Rawien Balesar, Qiong-Bin Zhu, Shaohua Hu, Juan Zhao, Ai-Min Bao, Dick F. Swaab, and Netherlands Institute for Neuroscience (NIN)
- Subjects
Male ,Bipolar Disorder ,Corticotropin-Releasing Hormone ,lcsh:Medicine ,Rats, Sprague-Dawley ,Corticotropin-releasing hormone ,0302 clinical medicine ,Orexin Receptors ,Cortex (anatomy) ,Prefrontal cortex ,Aged, 80 and over ,Sex Characteristics ,lcsh:R5-920 ,Depression ,General Medicine ,Middle Aged ,Immunohistochemistry ,Orexin receptor ,medicine.anatomical_structure ,Hypothalamus ,Female ,lcsh:Medicine (General) ,psychological phenomena and processes ,Research Paper ,medicine.medical_specialty ,Hypocretin ,Prefrontal Cortex ,Gyrus Cinguli ,General Biochemistry, Genetics and Molecular Biology ,Hypocretin receptors ,03 medical and health sciences ,Internal medicine ,mental disorders ,medicine ,Animals ,Humans ,RNA, Messenger ,Protein Precursors ,Anterior cingulate cortex ,Aged ,Depressive Disorder, Major ,Orexins ,business.industry ,lcsh:R ,Sex difference ,Rats ,030227 psychiatry ,Orexin ,Dorsolateral prefrontal cortex ,Disease Models, Animal ,Endocrinology ,nervous system ,Corticosterone ,business ,030217 neurology & neurosurgery - Abstract
Background Neurophysiological and behavioral processes regulated by hypocretin (orexin) are severely affected in depression. However, alterations in hypocretin have so far not been studied in the human brain. We explored the hypocretin system changes in the hypothalamus and cortex in depression from male and female subjects. Methods We quantified the differences between depression patients and well-matched controls, in terms of hypothalamic hypocretin-1 immunoreactivity (ir) and hypocretin receptors (Hcrtr-receptors)-mRNA in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex. In addition, we determined the alterations in the hypocretin system in a frequently used model for depression, the chronic unpredictable mild stress (CUMS) rat. Results i) Compared to control subjects, the amount of hypocretin-immunoreactivity (ir) was significantly increased in female but not in male depression patients; ii) hypothalamic hypocretin-ir showed a clear diurnal fluctuation, which was absent in depression; iii) male depressive patients who had committed suicide showed significantly increased ACC Hcrt-receptor-2-mRNA expression compared to male controls; and iv) female but not male CUMS rats showed a highly significant positive correlation between the mRNA levels of corticotropin-releasing hormone and prepro-hypocretin in the hypothalamus, and a significantly increased Hcrt-receptor-1-mRNA expression in the frontal cortex compared to female control rats. Conclusions The clear sex-related change found in the hypothalamic hypocretin-1-ir in depression should be taken into account in the development of hypocretin-targeted therapeutic strategies., Highlights • Hypocretin (orexin) changes were studied in human postmortem brain in depression. • A clear sex-related change was found in the hypothalamic hypocretin-1-immunoreactivity in depression. • A rat depression model did not reflect the changes in the hypocretin system in the human brain in depression. The stress systems of depressed patients are put into a higher gear by genetic and developmental factors. Over-reaction of these systems to stressful environmental situations makes people vulnerable to depression and suicide. This is the first postmortem study on changes in a relatively novel stress system in depression, consisting of the hypothalamic hypocretin neurons and hypocretin receptors in the prefrontal cortex. A clear sex-related change was found in the hypothalamic hypocretin-1-immunoreactivity in depression. Evaluation of the hypocretin system in a frequently used depression animal model, i.e. chronic unpredictable mild stress rats, did not replicate changes found in the hypocretin systems in the human brain in depression.
- Published
- 2017
34. Increased glutamic acid decarboxylase expression in the hypothalamic suprachiasmatic nucleus in depression
- Author
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Qiong-Bin Zhu, Manli Huang, Dick F. Swaab, Rawien Balesar, Ai-Min Bao, Safar Farajnia, Jing Lu, Xue-Yan Wu, and Netherlands Institute for Neuroscience (NIN)
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Vasopressin ,endocrine system ,Histology ,animal structures ,Glutamate decarboxylase ,In situ hybridization ,Biology ,Statistics, Nonparametric ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Internal medicine ,medicine ,Journal Article ,Humans ,RNA, Messenger ,Circadian rhythm ,gamma-Aminobutyric Acid ,Depression (differential diagnoses) ,Aged ,Aged, 80 and over ,Depression ,Glutamate Decarboxylase ,Suprachiasmatic nucleus ,General Neuroscience ,Arginine Vasopressin ,030104 developmental biology ,Endocrinology ,nervous system ,Hypothalamus ,GABAergic ,Female ,Suprachiasmatic Nucleus ,sense organs ,Erratum ,Anatomy ,030217 neurology & neurosurgery ,hormones, hormone substitutes, and hormone antagonists - Abstract
In depression, disrupted circadian rhythms reflect abnormalities in the central circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Although many SCN neurons are said to be GABAergic, it was not yet known whether and how SCN GABA changes occur in the SCN in depression. We, therefore, studied GABA in the SCN in relation to the changes in arginine vasopressin (AVP), which is one of the major SCN output systems. Postmortem hypothalamus specimens of 13 subjects suffering from depression and of 13 well-matched controls were collected. Quantitative immunocytochemistry was used to analyze the protein levels of glutamic acid decarboxylase (GAD)65/67 and AVP, and quantitative in situ hybridization was used to measure transcript levels of GAD67 in the SCN. There were a significant 58% increase of SCN GAD65/67-ir and a significant 169% increase of SCN GAD67-mRNA in the depression group. In addition, there were a significant 253% increase of AVP-ir in female depression subjects but not in male depression patients. This sex difference was supported by a re-analysis of SCN AVP-ir data of a previous study of our group. Moreover, SCN-AVP-ir showed a significant negative correlation with age in the control group and in the male, but not in the female depression group. Given the crucial role of GABA in mediating SCN function, our finding of increased SCN GABA expression may significantly contribute to the disordered circadian rhythms in depression. The increased SCN AVP-ir in female-but not in male-depression patients-may reflect the higher vulnerability for depression in women.
- Published
- 2017
35. Gehirn und Geschlecht
- Author
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Ai-Min Bao, Dick F. Swaab, and Laura Castellanos-Cruz
- Published
- 2019
36. Progress in Human Brain Banking in China
- Author
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Chao Ma, Xiao-Xin Yan, Dick F. Swaab, Ai-Min Bao, and Netherlands Institute for Neuroscience (NIN)
- Subjects
medicine.medical_specialty ,China ,Neurology ,Physiology ,business.industry ,General Neuroscience ,Pain medicine ,MEDLINE ,Brain ,General Medicine ,Human physiology ,Human brain ,Tissue Banks ,medicine.anatomical_structure ,Editorial ,Anesthesiology ,Medicine ,Humans ,business ,Intensive care medicine - Published
- 2019
37. Early growth response-1 regulates acetylcholinesterase and its relation with the course of Alzheimer's disease
- Author
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Ai-Min Bao, Shu-Han Huang, Arja A. Sluiter, Si-Yang Yu, Yi Shen, Juan Zhao, Dick F. Swaab, Qiong-Bin Zhu, Yu-Ting Hu, Joost Verhaagen, Xin-Lu Chen, and Netherlands Institute for Neuroscience (NIN)
- Subjects
0301 basic medicine ,medicine.medical_specialty ,endocrine system ,EGR1 ,Mice, Transgenic ,Biology ,Pathology and Forensic Medicine ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Alzheimer Disease ,Internal medicine ,medicine ,Animals ,Humans ,Electrophoretic mobility shift assay ,RNA, Messenger ,Promoter Regions, Genetic ,Prefrontal cortex ,Transcription factor ,Research Articles ,Early Growth Response Protein 1 ,Messenger RNA ,General Neuroscience ,Brain ,Promoter ,Acetylcholinesterase ,Frontal Lobe ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,chemistry ,Disease Progression ,Cholinergic ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Our previous studies showed that the transcription factor early growth response-1 (EGR1) may play a role in keeping the brain cholinergic function intact in the preclinical stages of Alzheimer's disease (AD). In order to elucidate the mechanisms involved, we first performed data mining on our previous microarray study on postmortem human prefrontal cortex (PFC) for the changes in the expression of EGR1 and acetylcholinesterase (AChE) and the relationship between them during the course of AD. The study contained 49 patients, ranging from non-demented controls (Braak stage 0) to late AD patients (Braak stage VI). We found EGR1-mRNA was high in early AD and decreased in late AD stages, while AChE-mRNA was stable in preclinical AD and slightly decreased in late AD stages. A significant positive correlation was found between the mRNA levels of these two molecules. In addition, we studied the relationship between EGR1 and AChE mRNA levels in the frontal cortex of 3-12-months old triple-transgenic AD (3xTg-AD) mice. EGR1- and AChE-mRNA were lower in 3xTg-AD mice compared with wild type (WT) mice. A significant positive correlation between these two molecules was present in the entire group and in each age group of either WT or 3xTg-AD mice. Subsequently, AChE expression was determined following up- or down-regulating EGR1 in cell lines and the EGR1 levels were found to regulate AChE at both the mRNA and protein levels. Dual-luciferase assay and electrophoretic mobility shift assay in the EGR1-overexpressing cells were performed to determine the functionally effective binding sites of the EGR1 on the AChE gene promoter. We conclude that the EGR1 can upregulate AChE expression by a direct effect on its gene promoter, which may contribute significantly to the changes in cholinergic function in the course of AD. The 3xTg-AD mouse model only reflects later stage AD. This article is protected by copyright. All rights reserved.
- Published
- 2019
38. MicroRNA-132 and early growth response-1 in nucleus basalis of Meynert during the course of Alzheimer's disease
- Author
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Yu-Ting Hu, Rawien Balesar, Koen Bossers, Ronald W.H. Verwer, Dick F. Swaab, Juan Zhao, Qiong-Bin Zhu, Unga A. Unmehopa, Ai-Min Bao, and Netherlands Institute for Neuroscience (NIN)
- Subjects
Male ,0301 basic medicine ,Apolipoprotein E ,Pathology ,medicine.medical_specialty ,Biology ,Nucleus basalis ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,medicine ,Humans ,Single-Blind Method ,Prefrontal cortex ,Aged ,Early Growth Response Protein 1 ,Aged, 80 and over ,Neurons ,Neurodegeneration ,Middle Aged ,medicine.disease ,Choline acetyltransferase ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Basal Nucleus of Meynert ,Disease Progression ,Cholinergic ,Female ,Neurology (clinical) ,Alzheimer's disease ,Nucleus ,030217 neurology & neurosurgery - Abstract
The cholinergic nucleus basalis of Meynert, which is important for memory functions, shows neuronal activation ('up-phase') during the early stages of Alzheimer's disease and neurodegeneration ('down-phase') in later stages of Alzheimer's disease. MicroRNA-132 (miR-132) and the transcription factor early growth response-1 (EGR1) were proposed as possible candidate molecules regulating such an up-down activity pattern of the nucleus basalis of Meynert during the course of Alzheimer's disease, as they both show this up-down pattern of expression in the prefrontal cortex during the course of Alzheimer's disease. Not only do these two molecules stimulate synaptic activity and plasticity, they are also involved in Alzheimer's disease pathology and might, in addition, affect cholinergic function. In the nucleus basalis of Meynert, we investigated the expression of miR-132 and EGR1 along the entire course of Alzheimer's disease. Forty-nine post-mortem nucleus basalis of Meynert samples were studied, ranging from non-demented controls (Braak stage = 0) to late Alzheimer's disease patients (Braak stage = VI), and from clinical Reisberg scale 1 to 7. Each Braak stage contained seven samples, that were all well matched for confounding factors, i.e. age (range 58-91), sex, post-mortem delay, cerebrospinal fluid pH (as a measure for agonal state), APOE genotype, clock time of death, tissue fixation time, and tissue storage time. The alterations of these two molecules were studied over the course of Alzheimer's disease in relation to the expression of 4G8-stained amyloid-β, hyperphosphorylated tau stained by antibody AT8, neuronal fibrillary tangles and neuropil threads stained by silver, and in relation to alterations in choline acetyltransferase. We found that the expression of miR-132 and EGR1 in the nucleus basalis of Meynert was quite stable during the early stages of Alzheimer's disease and decreased significantly only during late Alzheimer's disease stages. In addition, miR-132 and EGR1 showed a significant positive correlation with choline acetyltransferase expression (r = 0.49, P < 0.001 and r = 0.61, P < 0.001), while choline acetyltransferase expression showed a significantly negative correlation with hyperphosphorylated tau (r = -0.33, P = 0.021) but no correlation with 4G8-stained amyloid-β. From the functional changes of miR-132 and EGR1 along the course of Alzheimer's disease we conclude: (i) that these two molecules may play a role in keeping the cholinergic function intact in early Alzheimer's disease stages; and (ii) that these molecules may contribute to the late neurodegeneration of this cholinergic nucleus.
- Published
- 2016
39. A sensitive and practical RP-HPLC-FLD for determination of the low neuroactive amino acid levels in body fluids and its application in depression
- Author
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Juan-Li Wu, Shihua Wu, Si-Yang Yu, and Ai-Min Bao
- Subjects
Male ,0301 basic medicine ,Aging ,medicine.medical_specialty ,Bipolar Disorder ,Glutamic Acid ,Free amino ,Biochemistry ,01 natural sciences ,High-performance liquid chromatography ,gamma-Aminobutyric acid ,03 medical and health sciences ,Endocrinology ,Cerebrospinal fluid ,Internal medicine ,Genetics ,medicine ,Humans ,Sample preparation ,Bipolar disorder ,Amino Acids ,Molecular Biology ,Chromatography, High Pressure Liquid ,gamma-Aminobutyric Acid ,Aged ,Aged, 80 and over ,chemistry.chemical_classification ,Depressive Disorder ,Chromatography ,Depression ,Mood Disorders ,Chemistry ,General Neuroscience ,010401 analytical chemistry ,Cell Biology ,Glutamic acid ,Hydrogen-Ion Concentration ,Middle Aged ,medicine.disease ,Body Fluids ,0104 chemical sciences ,Amino acid ,030104 developmental biology ,Case-Control Studies ,Major depressive disorder ,Female ,medicine.drug - Abstract
Ion-exchange high performance liquid chromatography (HPLC) generally fails as a method to determine low levels of free amino acids (AAs) in body fluids. Here we present a modified reversed-phase HPLC (RP-HPLC) protocol for the determination of AAs in body fluids and its application in mood disorder patients. We improved a previous research protocol by modifying i) sample preparation, including deproteination, ii) derivitization, including derivating agent and condition, and iii) sample separation, which is mainly determined by the pH value, the components and the additives of the mobile phases. The combination of these modifications, together with fluorescence detection (FLD), allows sensitive and practical determination of free AA levels in body fluids of depressive patients. This protocol was validated by determining the postmortem cerebrospinal fluid (CSF) glutamic acid (Glu) and γ-aminobutyric acid (GABA) levels of 8 major depressive disorder (MDD) patients, 9 bipolar disorder (BD) patients, and 19 well-matched controls, while also testing the plasma and CSF AA levels of living MDD patients. CSF Glu and GABA levels were both significantly decreased in MDD but not in BD patients. The data indicate that this RP-HPLC-FLD protocol is applicable for detection of low levels of neuroactive AAs in body fluids, as well as for routine clinical applications.
- Published
- 2016
40. Rapid membrane effect of estrogens on stimulation of corticotropin-releasing hormone
- Author
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Zhong Ren, Zheng Fang, Ai-Min Bao, Yang-Jian Qi, Hong Tan, Yi Shen, Juan-Li Wu, Lei Guo, and Manli Huang
- Subjects
MAPK/ERK pathway ,endocrine system ,Membrane estrogen receptor ,Corticotropin-Releasing Hormone ,Endocrinology, Diabetes and Metabolism ,Nitric Oxide ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,Corticotropin-releasing hormone ,0302 clinical medicine ,Endocrinology ,Humans ,Protein kinase A ,Cells, Cultured ,Protein Kinase C ,Biological Psychiatry ,PI3K/AKT/mTOR pathway ,Protein kinase C ,Estradiol ,Endocrine and Autonomic Systems ,Chemistry ,Activator (genetics) ,Kinase ,Estrogens ,Serum Albumin, Bovine ,030227 psychiatry ,Cell biology ,Psychiatry and Mental health ,Gene Expression Regulation ,Receptors, Estrogen ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Background Classic nuclear-initiated estrogen signaling stimulates corticotropin-releasing hormone (CRH) gene expression as a transcription factor. However, the possible mechanism by which membrane-initiated estrogen signaling (MIES) influences CRH expression remains unclear. There are indications that MIES may upregulate nitric oxide (NO) production through the phosphatidylinositol 3-hydroxy kinase (PI3K) and potentially through the mitogen-activated protein kinase (MAPK) pathway. Objectives We investigated the effect of MIES-mediated kinase pathways on CRH expression with or without NO synthesis. Method In SK-N-SH cell culture, estradiol-bovine serum albumin (E2-BSA) was used as the specific membrane estrogen receptor activator, with a specific NO donor, and/or inhibitors for NO synthase (NOS), PI3K, MAPK, protein kinase A (PKA), and protein kinase C (PKC). Results E2-BSA significantly increased NO and CRH levels in the medium and NOS1-mRNA levels in the cells. In addition, NO donor up-regulated CRH expression, while NOS-inhibitor down-regulated it. When the inhibitor of MAPK and/or the inhibitor of PI3K was added to the medium, only the latter appeared to significantly block the stimulating effect of E2-BSA on NO synthesis, and this was accompanied by an increased CRH expression in the medium. We further studied the effect of the MIES-PKC-mediated pathway on CRH expression, with or without NOS-inhibitor, while the MIES-PKA(-PI3K) pathway served as a control. We found that MIES-PKC upregulated CRH expression independent of NO synthesis. Conclusion MIES can efficiently upregulate CRH expression via various intracellular kinase pathways and may thus be a crucial component in the stress response.
- Published
- 2020
41. Author response: ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines
- Author
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Shu-Xia Cao, Ying Zhang, Xing-Yue Hu, Bin Hong, Peng Sun, Hai-Yang He, Hong-Yan Geng, Ai-Min Bao, Shu-Min Duan, Jian-Ming Yang, Tian-Ming Gao, Hong Lian, and Xiao-Ming Li
- Published
- 2018
42. Quantification of Tyrosine Hydroxylase and ErbB4 in the Locus Coeruleus of Mood Disorder Patients Using a Multispectral Method to Prevent Interference with Immunocytochemical Signals by Neuromelanin
- Author
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Arja A. Sluiter, Rawien Balesar, Zheng Fang, Qingbin Zhu, Dick F. Swaab, Jochem Stormmesand, Joop Van Heerikhuize, Ai-Min Bao, Lei Guo, and Netherlands Institute for Neuroscience (NIN)
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Bipolar Disorder ,Receptor, ErbB-4 ,Tyrosine 3-Monooxygenase ,Physiology ,Method ,Biology ,Sensitivity and Specificity ,03 medical and health sciences ,0302 clinical medicine ,Neuromelanin ,Internal medicine ,mental disorders ,medicine ,Image Processing, Computer-Assisted ,Humans ,Bipolar disorder ,Receptor ,ERBB4 ,Aged ,Aged, 80 and over ,Melanins ,Neurons ,Depressive Disorder, Major ,Microscopy ,Tyrosine hydroxylase ,General Neuroscience ,Spectrum Analysis ,General Medicine ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Staining ,030104 developmental biology ,Endocrinology ,Major depressive disorder ,Locus coeruleus ,Female ,Locus Coeruleus ,030217 neurology & neurosurgery - Abstract
The locus coeruleus (LC) has been studied in major depressive disorder (MDD) and bipolar disorder (BD). A major problem of immunocytochemical studies in the human LC is interference with the staining of the immunocytochemical end-product by the omnipresent natural brown pigment neuromelanin. Here, we used a multispectral method to untangle the two colors: blue immunocytochemical staining and brown neuromelanin. We found significantly increased tyrosine hydroxylase (TH) in the LC of MDD patients-thus validating the method-but not in BD patients, and we did not find significant changes in the receptor tyrosine-protein kinase ErbB4 in the LC in MDD or BD patients. We observed clear co-localization of ErbB4, TH, and neuromelanin in the LC neurons. The different stress-related molecular changes in the LC may contribute to the different clinical symptoms in MDD and BD.
- Published
- 2018
43. ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines
- Author
-
Xing-Yue Hu, Peng Sun, Xiao-Ming Li, Bin Hong, Shu-Xia Cao, Tian-Ming Gao, Jian-Ming Yang, Hong-Yan Geng, Shumin Duan, Ai-Min Bao, Ying Zhang, Hai-Yang He, and Hong Lian
- Subjects
0301 basic medicine ,Adrenergic Neurons ,Bipolar Disorder ,Receptor, ErbB-4 ,Mouse ,Lithium (medication) ,Dopamine ,Action Potentials ,Pathogenesis ,ErbB4 ,Mice ,Norepinephrine ,0302 clinical medicine ,Catecholamines ,Biology (General) ,Phosphorylation ,Receptor ,ERBB4 ,Catecholaminergic ,Behavior, Animal ,General Neuroscience ,General Medicine ,NMDA receptor ,Medicine ,Locus Coeruleus ,medicine.symptom ,Mania ,Research Article ,medicine.drug ,Psychosis ,medicine.medical_specialty ,Tyrosine 3-Monooxygenase ,QH301-705.5 ,Science ,Green Fluorescent Proteins ,Biology ,Lithium ,Catechol O-Methyltransferase ,behavioral disciplines and activities ,Receptors, N-Methyl-D-Aspartate ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,mania ,Delusion ,Internal medicine ,mental disorders ,medicine ,Animals ,Bipolar disorder ,General Immunology and Microbiology ,Integrases ,Body Weight ,Excitatory Postsynaptic Potentials ,Correction ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,nervous system ,noradrenergic neuron ,Locus coeruleus ,Neuroscience ,030217 neurology & neurosurgery ,Gene Deletion - Abstract
Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of bipolar disorder (BPD). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to BPD; however, how ErbB4 regulates NE neuronal function and contributes to BPD pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, Erbb4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder., eLife digest Bipolar disorder is a mental illness that affects roughly 1 in 100 people worldwide. It features periods of depression interspersed with episodes of mania – a state of delusion, heightened excitation and increased activity. Evidence suggests that changes in a brain region called the locus coeruleus contribute to bipolar disorder. Cells within this area produce a chemical called norepinephrine, whose levels increase during mania and decrease during depression. But it is unclear exactly how norepinephrine-producing cells, also known as noradrenergic cells, contribute to bipolar disorder. The answer may lie in a protein called ErbB4, which is found within the outer membrane of many noradrenergic neurons. ErbB4 is active in both the developing and adult brain, and certain people with bipolar disorder have mutations in the gene that codes for the protein. Might changes in ErbB4 disrupt the activity of noradrenergic neurons? And could these changes increase the risk of bipolar disorder? To find out, Cao, Zhang et al. deleted the gene for ErbB4 from noradrenergic neurons in the locus coeruleus of mice. The mutant mice showed mania-like behaviors: compared to normal animals, they were hyperactive, less anxious, and consumed more of a sugary solution. Treating the mice with lithium, a medication used in bipolar disorder, reversed these changes and made the rodents behave more like non-mutant animals. Further experiments revealed that noradrenergic neurons in the mutant mice showed increased spontaneous activity. These animals also had more of the chemicals noradrenaline and dopamine in the fluid circulating around their brains and spinal cords. The results thus suggest that losing ErbB4 enhances the spontaneous firing of noradrenergic neurons in the locus coeruleus. This increases release of noradrenaline and dopamine, which in turn leads to mania-like behaviors. Future research should examine whether drugs that target ErbB4 could treat mania and improve the lives of people with bipolar disorder and related conditions.
- Published
- 2018
44. The art of matching brain tissue from patients and controls for postmortem research
- Author
-
Ai-Min, Bao and Dick F, Swaab
- Subjects
Mental Disorders ,Diagnosis ,Brain ,Humans ,Tissue Banks ,Nervous System Diseases ,Neuropathology ,Netherlands - Abstract
The quality of postmortem research depends strongly on a thorough clinical investigation and documentation of the patient's disorder and therapies. In addition, a systematic and professional neuropathologic investigation of both cases and controls is absolutely crucial. In the experience of the Netherlands Brain Bank (NBB), about 20% of clinical neurologic diagnoses, despite being made in first-rate clinics, have to be revised or require an extra diagnosis after a complete and thorough review by the NBB. The neuropathology examination may reveal for instance that the "controls" already have preclinical neurodegenerative alterations. In postmortem studies the patient and control groups must be matched for as many of the known confounding factors as possible. This is necessary to make the groups as similar as possible, except for the topic being investigated. Confounding factors are present before, during, and after death. They are respectively: (1) genetic background, systemic diseases, duration and gravity of illness, medicines and addictive compounds used, age, sex, gender identity, sexual orientation, circadian and seasonal fluctuations, lateralization; (2) agonal state, stress of dying; and (3) postmortem delay, freezing procedures, fixation and storage time. Consequently, a brain bank should have a large number of controls at its disposal for appropriate matching. If matching fails for some confounders, then their influence may be determined by statistical methods such as analysis of variance or regression models.
- Published
- 2018
45. Sex hormones affect acute and chronic stress responses in sexually dimorphic patterns: Consequences for depression models
- Author
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Yang He, Manli Huang, Ai-Min Bao, Juan-Li Wu, Lei Guo, Yu-Ting Hu, Matthew R. J. Mason, Xue-Yan Wu, Yi-Xi Chen, and Netherlands Institute for Neuroscience (NIN)
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Vasopressin ,Receptors, Steroid ,Corticotropin-Releasing Hormone ,Vasopressins ,Endocrinology, Diabetes and Metabolism ,Ovariectomy ,Hypothalamus ,Oxytocin ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Sex hormone-binding globulin ,Aromatase ,Sex Factors ,Stress, Physiological ,Internal medicine ,Journal Article ,medicine ,Animals ,Chronic stress ,Testosterone ,Gonadal Steroid Hormones ,Biological Psychiatry ,Depressive Disorder ,Sex Characteristics ,biology ,Estradiol ,Endocrine and Autonomic Systems ,business.industry ,Depression ,Brain ,Rats ,Sexual dimorphism ,Psychiatry and Mental health ,030104 developmental biology ,Sex steroid ,biology.protein ,Female ,business ,Orchiectomy ,030217 neurology & neurosurgery ,Hormone - Abstract
Background Alterations in peripheral sex hormones may play an important role in sex differences in terms of stress responses and mood disorders. It is not yet known whether and how stress-related brain systems and brain sex steroid levels fluctuate in relation to changes in peripheral sex hormone levels, or whether the different sexes show different patterns. We aimed to investigate systematically, in male and female rats, the effect of decreased circulating sex hormone levels following gonadectomy on acute and chronic stress responses, manifested as changes in plasma and hypothalamic sex steroids and hypothalamic stress-related molecules. Method Experiment (Exp)-1: Rats (14 males, 14 females) were gonadectomized or sham-operated (intact); Exp-2: gonadectomized and intact rats (28 males, 28 females) were exposed to acute foot shock or no stressor; and Exp-3: gonadectomized and intact rats (32 males, 32 females) were exposed to chronic unpredictable mild stress (CUMS) or no stressor. For all rats, plasma and hypothalamic testosterone (T), estradiol (E2), and the expression of stress-related molecules were determined, including corticotropin-releasing hormone, vasopressin, oxytocin, aromatase, and the receptors for estrogens, androgens, glucocorticoids, and mineralocorticoids. Results Surprisingly, no significant correlation was observed in terms of plasma sex hormones, brain sex steroids, and hypothalamic stress-related molecule mRNAs (p > 0.113) in intact or gonadectomized, male or female, rats. Male and female rats, either intact or gonadectomized and exposed to acute or chronic stress, showed different patterns of stress-related molecule changes. Conclusion Diminished peripheral sex hormone levels lead to different peripheral and central patterns of change in the stress response systems in male and female rats. This has implications for the choice of models for the study of the different types of mood disorders which also show sex differences.
- Published
- 2018
46. Early growth response-1 stimulates acetylcholinesterase during the course of Alzheimer's disease
- Author
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Yu-Ting Hu, Xin-Lu Chen, Dick F. Swaab, Ai-Min Bao, Shu-Han Huang, Hugo McGurran, and Jackson Boonstra
- Subjects
medicine.medical_specialty ,chemistry.chemical_compound ,Endocrinology ,chemistry ,business.industry ,General Neuroscience ,Internal medicine ,Early growth response 1 ,medicine ,Disease ,business ,Acetylcholinesterase - Published
- 2019
47. Sex differences in the stress response in SD rats
- Author
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Juan-Li Wu, Ai-Min Bao, Jia Li, Li-Gen Shi, Xue-Yan Wu, Manli Huang, Qi-Jun Zhang, Jing Lu, and Qiong-Bin Zhu
- Subjects
Male ,medicine.medical_specialty ,Vasopressin ,Hypothalamus ,Estrogen receptor ,Estrous Cycle ,Rats, Sprague-Dawley ,Random Allocation ,Behavioral Neuroscience ,chemistry.chemical_compound ,Glucocorticoid receptor ,Mineralocorticoid receptor ,Corticosterone ,Internal medicine ,medicine ,Animals ,Testosterone ,RNA, Messenger ,Electroshock ,Sex Characteristics ,Estradiol ,Foot ,Body Weight ,Endocrinology ,chemistry ,Oxytocin ,Acute Disease ,Chronic Disease ,Female ,Psychology ,Stress, Psychological ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Sex differences play an important role in depression, the basis of which is an excessive stress response. We aimed at revealing the neurobiological sex differences in the same study in acute- and chronically-stressed rats. Female Sprague-Dawley (SD) rats were randomly divided into 6 groups: chronic unpredictable mild stress (CUMS), acute foot shock (FS) and controls, animals in all 3 groups were sacrificed in proestrus or diestrus. Male SD rats were randomly divided into 3 groups: CUMS, FS and controls. Comparisons were made of behavioral changes in CUMS and control rats, plasma levels of corticosterone (CORT), testosterone (T) and estradiol (E2), and of the hypothalamic mRNA-expression of stress-related molecules, i.e. estrogen receptor α and β, androgen receptor, aromatase, mineralocorticoid receptor, glucocorticoid receptor, corticotropin-releasing hormone, arginine vasopressin and oxytocin. CUMS resulted in disordered estrus cycles, more behavioral and hypothalamic stress-related molecules changes and a stronger CORT response in female rats compared with male rats. Female rats also showed decreased E2 and T levels after FS and CUMS, while male FS rats showed increased E2 and male CUMS rats showed decreased T levels. Stress affects the behavioral, endocrine and the molecular response of the stress systems in the hypothalamus of SD rats in a clear sexual dimorphic way, which has parallels in human data on stress and depression.
- Published
- 2015
48. Changes in Histidine Decarboxylase, Histamine N-Methyltransferase and Histamine Receptors in Neuropsychiatric Disorders
- Author
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Ling, Shan, Ai-Min, Bao, and Dick F, Swaab
- Subjects
Histamine N-Methyltransferase ,Mental Disorders ,Animals ,Brain ,Humans ,Receptors, Histamine ,Histidine Decarboxylase ,Neuropsychiatry ,Histamine - Abstract
Compared to other monoamine neurotransmitters, information on the association between the histaminergic system and neuropsychiatric disorders is scarce, resulting in a lack of histamine-related treatment for these disorders. The current chapter tries to combine information obtained from genetic studies, neuroimaging, post-mortem human brain studies and cerebrospinal fluid measurements with data from recent clinical trials on histamine receptor agonists and antagonists, with a view to determining the possible role of the histaminergic system in neuropsychiatric disorders and to pave the way for novel histamine-related therapeutic strategies.
- Published
- 2017
49. Sexual Identity and Sexual Orientation
- Author
-
Dick F. Swaab, Laura Castellanos-Cruz, and Ai-Min Bao
- Subjects
0301 basic medicine ,Sexual identity ,Sexual differentiation ,media_common.quotation_subject ,Human sexuality ,Y chromosome ,Developmental psychology ,03 medical and health sciences ,Pedophilia ,030104 developmental biology ,0302 clinical medicine ,Heterosexuality ,Sexual orientation ,Homosexuality ,Psychology ,Social psychology ,030217 neurology & neurosurgery ,media_common - Abstract
Sexual differentiation of the brain, gender identity (an individual's perception of being male or female), and sexual orientation (heterosexuality, homosexuality, bisexuality, and pedophilia) is orchestrated and determined in our brain during early development. Sexual differentiation of the brain is determined by a series of events, starting with the influence from the SRY gene on the Y chromosome, followed by the influence of sex hormones regulated by different mechanisms, through different paths and with different endpoints, including epigenetic modifications. These complex mechanisms ensure the variability, necessary from an evolutionary perspective; however, it also provides multiple points where it may be disrupted or modified, and therefore influence sexual behaviors. This chapter will review the literature regarding the genetic, postmortem, and in vivo scanning observations that support the neurobiological theory about the origin of our gender identity and sexual orientation. In humans, there is no evidence that one's postnatal social environment plays a crucial role in the development of gender identity and sexual orientation.
- Published
- 2017
50. Changes in Histidine Decarboxylase, Histamine N-Methyltransferase and Histamine Receptors in Neuropsychiatric Disorders
- Author
-
Dick F. Swaab, Ai-Min Bao, and Ling Shan
- Subjects
0301 basic medicine ,Histamine N-methyltransferase ,Histaminergic ,Human brain ,Pharmacology ,Biology ,medicine.disease ,Histidine decarboxylase ,03 medical and health sciences ,Histamine receptor ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Monoamine neurotransmitter ,medicine.anatomical_structure ,Mood disorders ,chemistry ,medicine ,Neuroscience ,030217 neurology & neurosurgery ,Histamine - Abstract
Compared to other monoamine neurotransmitters, information on the association between the histaminergic system and neuropsychiatric disorders is scarce, resulting in a lack of histamine-related treatment for these disorders. The current chapter tries to combine information obtained from genetic studies, neuroimaging, post-mortem human brain studies and cerebrospinal fluid measurements with data from recent clinical trials on histamine receptor agonists and antagonists, with a view to determining the possible role of the histaminergic system in neuropsychiatric disorders and to pave the way for novel histamine-related therapeutic strategies.
- Published
- 2017
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