Specification of sleep-wake control neurons in the basal forebrain

基底前脑睡眠-觉醒控制神经元的规范

• 批准号: 10558029
• 负责人: Ritchie Edward Brown
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558029
• 关键词: Affect; Amygdaloid structure; Anatomy; Anhedonia; Antidepressive Agents; Attention; Award; Basal Cell; Behavior; Behavioral; Behavioral Research; Bilateral; Biological Psychiatry; Boston; Brain region; Cells; Cerebrum; Chronic; Chronic stress; Clozapine; Corticotropin-Releasing Hormone; Data; Dementia; Depressive disorder; Development; Diagnosis; Disease; Doctor of Philosophy; Electrodes; Electroencephalography; Electrophysiology (science); Equilibrium; Experimental Designs; Future; Generations; Goals; Grant; Health; Health Care Costs; Health Sciences; Healthcare; Healthcare Systems; Hormones; In Vitro; Incidence; Individual; Infusion procedures; Injections; K-Series Research Career Programs; Ligands; Literature; Maryland; Mediating; Mental Depression; Mental disorders; Mentors; Mentorship; Methods; Microscopy; Modeling; Molecular Medicine; Mood Disorders; Moods; Motivation; Mus; Neuroanatomy; Neurobiology; Neurologic; Neurons; Neurosciences; Outcome; Oxides; Paper; Parvalbumins; Patch-Clamp Techniques; Pathogenesis; Phenotype; Physiological; Population; Pre-Clinical Model; Predisposition; Productivity; Psychiatry; Publications; Publishing; Recording of previous events; Research; Research Personnel; Research Project Grants; Rewards; Risk; Risk Factors; Rodent; Rodent Model; Role; Saline; Schizophrenia; Scientist; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Sleeplessness; Source; Specialist; Stress; Structure; Suicide; Synapses; Techniques; Testing; Training; Underrepresented Minority; United States Department of Veterans Affairs; United States National Academy of Sciences; Universities; Veterans; Viral; Wakefulness; Work; active duty; adeno-associated viral vector; basal forebrain; brain circuitry; career development; cell type; cholinergic; combat; disability; electrical property; experimental study; improved; in vivo; interest; medical schools; member; mid-career faculty; multimodality; neuropsychiatry; neurotransmission; new therapeutic target; novel; novel therapeutics; parent grant; patch clamp; pre-clinical; programs; receptor; red fluorescent protein; risk variant; service member; sleep abnormalities; sleep behavior; stress disorder; stressor; suicidal risk; tool; training opportunity; transcription factor

Chronic stress is a risk factor for the onset of psychiatric and somatic disease. Deployment and combat exposure are routinely cited as stressors for Service members, and stress-related psychiatric conditions are a leading cause of permanent disability and illness within VA Healthcare. On a neurological level, stress disrupts the physiological balance between excitatory and inhibitory neurotransmission. This dysregulation of synaptic network activity is routinely cited as a cause for numerous intractable psychiatric conditions, including depression, schizophrenia, and insomnia. Veterans Affairs has faced a steep rise in the incidence and diagnosis of sleep disorders like insomnia in recent years, representing an increasing healthcare cost for the VA and, critically, an enhanced risk factor for suicide among Veterans. An overarching goal of the parent grant is to advance understanding of the neurobiology of sleep, facilitating development of next-generation therapeutics. It will identify novel populations of GABAergic neurons in the basal forebrain (BF), an integratory brain region that regulates sleep and attention. Of these cell types, our preliminary data indicate chemogenetic activation of BF neuronal PAS domain 1-expressing (NPAS1+) cells strongly promotes wakefulness. Recent preclinical literature has identified a role of BF NPAS1+ cell activation in stress susceptibility and affect (Morais-Silva et al., 2021), potentially mediated by dense projections of stress-activated corticotropin-releasing factor (CRF) neurons from the central amygdala (Hunt et al., 2018). These findings support a hypothesis that stress upregulates the activity of BF NPAS1+ cells, contributing to the onset of insomnia and related psychiatric conditions. This hypothesis will be investigated in 2 aims, exploring the effects of stress on in vitro electrical properties of NPAS1+ neurons (aim 1) and resultant in vivo effects on sleep behavior (aim 2). This research supplement provides an ideal training opportunity for Dr. Timothy Troppoli, the mentee. Dr. Troppoli received a Ph.D. from the University of Maryland’s Molecular Medicine program in September 2021 and has recently joined the Department of Psychiatry at Harvard Medical School (HMS) and VA BHS as a Health Science Specialist. The mentee’s primary research interest concerns stress-induced disruption of synaptic neurotransmission and the onset of depressive disorders and psychiatric disease. Dr. Troppoli has a history of productive, high-impact research in this field, publishing 4 papers (two as first author) investigating the mechanisms and target engagement of novel antidepressant-like compounds. The mentee’s research background and expertise compliment the goals of this research supplement, while the proposed experiments will significantly enhance Dr. Troppoli’s independence and productivity as a neuroscientist at VA BHS using state-of-the-art whole-cell patch-clamp techniques, advanced microscopy, chemogenetics, and sleep/EEG analysis. Training in these approaches will be provided by mentor Dr. Ritchie Brown and co-mentor Dr. James McKenna, members of VA BHS/HMS and experts in the field of sleep research. Dr. Brown has successfully mentored 8 junior researchers, including VA CDA2 recipients. He will train the mentee in electrophysiology and chemogenetics and guide his career development. Dr. McKenna’s background in BF neuroanatomy and preclinical models of stress-induced insomnia will bolster the analytical rigor of this work, aid in interpretation of results and assist in experimental design for future BF work. Successful completion of the proposed aims will characterize stress-induced functional deficits of NPAS1+ cells of the BF, providing the first evidence of their role in stress-induced insomnia and psychiatric disease. The proposed experiments expand the scope of the parent grant, will guide the development of novel therapeutics for Veterans, and provide preliminary data for a future VA Career Development Award with a distinct focus on convergent mechanisms of stress, sleep, and depression.

长期压力是精神和躯体疾病发病的一个危险因素。部署和作战 暴露通常被认为是服务人员的压力源，与压力相关的精神疾病是一种 VA Healthcare内永久性残疾和疾病的主要原因。在神经层面上，压力会扰乱神经系统 兴奋性和抑制性神经传递之间的生理平衡这种突触的失调 网络活动通常被认为是许多棘手的精神疾病的原因，包括 抑郁症精神分裂症和失眠症退伍军人事务部面临着发病率的急剧上升， 近年来，睡眠障碍如失眠的诊断，代表了医疗保健费用的增加 对于退伍军人事务部来说，更重要的是，这是退伍军人自杀的风险因素。 家长补助金的首要目标是促进对睡眠神经生物学的理解， 促进下一代疗法的发展。它将识别新的GABA能神经元群体， 在基底前脑（BF），一个整合的大脑区域，调节睡眠和注意力。在这些细胞类型中， 我们的初步数据表明BF神经元PAS结构域1表达（NPAS 1+）的化学发生激活 细胞强烈促进清醒。最近的临床前文献已经确定了BF NPAS 1+细胞的作用， 应激敏感性和情感的激活（Morais-Silva等人，2021年），可能由密集介导 应激激活的促肾上腺皮质激素释放因子（CRF）神经元从中央杏仁核的投射（Hunt et 例如，2018年）。这些发现支持了应激上调BF NPAS 1+细胞活性的假设， 导致失眠和相关精神疾病的发作。这一假设将是 研究了2个目的，探讨应激对体外培养的NPAS 1+神经元电特性的影响（目的 1)以及由此产生的对睡眠行为的体内影响（目的2）。 本研究补充为学员Timothy Troppoli博士提供了理想的培训机会。 博士Troppoli获得了博士学位。来自马里兰州大学的分子医学项目， 2021年，最近加入了哈佛医学院（HMS）和VA BHS的精神病学系， 健康科学专家学员的主要研究兴趣涉及压力引起的破坏， 突触神经传递与抑郁症和精神疾病的发病。特罗波利博士有一个 在这一领域的生产力，高影响力的研究历史，发表4篇论文（两个作为第一作者） 研究新型抗抑郁药样化合物的机制和靶点作用。 学员的研究背景和专业知识补充了本研究补充的目标， 虽然拟议中的实验将大大提高特罗波利博士的独立性和生产力， VA BHS的神经科学家使用最先进的全细胞膜片钳技术，先进的显微镜， 化学遗传学和睡眠/脑电图分析导师里奇博士将提供这些方法的培训 布朗和共同导师詹姆斯麦肯纳博士，VA BHS/HMS的成员和睡眠领域的专家 research.布朗博士成功指导了8名初级研究人员，包括VA CDA 2接受者。他将 对学员进行电生理学和化学遗传学方面的培训，并指导其职业发展。麦肯纳医生 BF神经解剖学的背景和压力诱导失眠的临床前模型将支持分析 这项工作的严谨性，帮助解释结果，并协助未来高炉工作的实验设计。 成功完成拟议的目标将表征压力引起的功能缺陷， BF的NPAS 1+细胞，为它们在应激诱导的失眠和精神疾病中的作用提供了第一个证据。 疾病本次实验拟扩大家长资助的范围，将引导小说的发展 退伍军人治疗，并为未来的退伍军人管理局职业发展奖提供初步数据 专注于压力、睡眠和抑郁的收敛机制。