Serotonergic modulation of claustro-cortical circuits

幽闭皮质回路的血清素调节

• 批准号: 8726489
• 负责人: JAY A GINGRICH
• 金额: $ 19.98万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726489
• 关键词: Ablation; Adult; Affect; Anatomy; Anxiety Disorders; Area; Attention; Autistic Disorder; Behavior; Behavior Control; Behavioral; Bipolar Disorder; Brain; Brain Diseases; Brain region; Cell Death; Chemosensitization; Claustral structure; Cognition; Cognitive; Complex; Conscious; Delusions; Development; Diphtheria Toxin; Disease; Emotional; Emotions; Esthesia; Exhibits; Failure; Functional disorder; Future; Gene Expression; Generations; Genes; Genetic; Goals; Grant; Hallucinations; Hallucinogens; Human; Impaired cognition; Impairment; Internal Ribosome Entry Site; Knock-in Mouse; Knock-out; Location; Lysergic Acid Diethylamide; Mediating; Mental disorders; Mood Disorders; Motivation; Mus; Nature; Neurons; Obsessive-Compulsive Disorder; Perception; Pharmaceutical Preparations; Pharmacogenetics; Play; Population; Process; Regulation; Research; Role; Rosa; Schizophrenia; Sensory; Serotonin; Serotonin Receptor 5-HT2A; Short-Term Memory; Signal Transduction; Site; Stimulus; Structure; Symptoms; Syndrome; Testing; Therapeutic Intervention; Time Perception; Validation; Viral; Virus; autism spectrum disorder; base; cognitive function; design; executive function; experience; hedonic; insight; interest; mature animal; nerve supply; neural circuit; neuronal circuitry; neuropsychiatry; novel; prevent; promoter; public health relevance; receptor; relating to nervous system; response; sensory integration; social cognition; tool

DESCRIPTION (provided by applicant): Neuropsychiatric disorders affect function in several domains: perception (emotional, sensory), integration (information, emotion, sensations), cognition (working memory, social cognition, attention), motivation (hedonic drive, executive function), and others. The impairment in these brain functions offers possible insight into the symptoms of disorganization, hallucinations, delusions, lack of relatedness, involution, distractedness, and cognitive decline that characterize these disorders. One hypothesis is that some of these dysfunctions appear to result from impaired integration of stimuli among various brain regions. Indeed, how the brain integrates the diversity of external and internal stimuli intoa coherent experience is one of the features that characterize the human experience. Yet, arguably, many of the complex neuropsychiatric disorders such as schizophrenia, autism, bipolar disorder, obsessive-compulsive disorder, and others may be viewed as failure of the brain to appropriately integrate various functions into the seamless whole that many of us take for granted. The integration of stimuli in the brain likely occurs through several mechanisms. Here, we focus on the role of the claustrum (CL) as one potential structure that helps integrate diverse brain functions. Based on its connectivity the CL has been theorized to function in higher order cognitive processing and emotional behaviors1,2. Surprisingly little is known about the CL, but our group became interested in this enigmatic structure due to its dense innervation by serotonergic neurons and its high level of expression of serotonin 2A receptors (Htr2A). We have hypothesized that the Htr2A receptors of the CL is the site of action of hallucinogenic drugs such as LSD (lysergic acid diethylamide) - agents that so potently disrupt normal sensory perception and sense of self. By extension, we have speculated whether CL function may be impaired in neuropsychiatric disorders where integrative functions appear disrupted. Our interest in the CL became more concrete as we developed new experimental tools that we believe can provide new insights into how CL function may be altering behavior. In this exploratory grant, we propose to characterize the anatomy of neuronal circuits originating in the CL and assess how serotonin may be modulating these circuits to control complex emotional and cognitive behaviors. In Aim 1, we propose to investigate the projections, the location and neuronal types of claustro-cortical circuits defined by the expression of Htr2A. Next we will generate knock-in Cre lines using the Htr2A and Gng2 (a CL-specific gene) promoters as tools to direct gene expression in the CL. We will test whether these tools can be used to ablate CL neurons with diphtheria toxin as the simplest way to target CL function. Lastly, we will answer another important question: is Htr2A signaling in the CL the site of action of hallucinogenic drugs. The tools and results from this study can be used in the future to directly manipulate neuronal activity of the CL and reveal new neural substrates of serotonergic action on emotional and cognitive function.

描述（由申请人提供）：神经精神疾病影响多个领域的功能：感知（情绪、感觉）、整合（信息、情绪、感觉）、认知（工作记忆、社会认知、注意力）、动机（享乐驱动、执行功能）等。这些大脑功能的损伤为了解这些疾病所特有的紊乱、幻觉、妄想、缺乏关联性、退化、注意力分散和认知能力下降等症状提供了可能。一种假设是，其中一些功能障碍似乎是由于不同大脑区域之间的刺激整合受损所致。事实上，大脑如何将外部和内部刺激的多样性整合成连贯的体验是人类体验的特征之一。然而，可以说，许多复杂的神经精神疾病，如精神分裂症、自闭症、双向情感障碍、强迫症等，可能被视为大脑未能将各种功能适当地整合到我们许多人认为理所当然的无缝整体中。大脑中的刺激整合可能通过多种机制发生。在这里，我们重点关注屏状核 (CL) 作为一种有助于整合不同大脑功能的潜在结构的作用。基于其连通性，CL 被理论化为在高阶认知处理和情绪行为中发挥作用 1,2。令人惊讶的是，人们对 CL 知之甚少，但我们的小组对这种神秘的结构产生了兴趣，因为它受到血清素能神经元的密集神经支配，并且血清素 2A 受体 (Htr2A) 的高水平表达。我们假设 CL 的 Htr2A 受体是致幻药物（如 LSD（麦角酸二乙酰胺））的作用位点，这种药物会严重破坏正常的感官知觉和自我意识。通过扩展，我们推测 CL 功能是否可能在整合功能受到破坏的神经精神疾病中受损。随着我们开发出新的实验工具，我们对 CL 的兴趣变得更加具体，我们相信这些工具可以为 CL 功能如何改变行为提供新的见解。在这项探索性资助中，我们建议描述起源于 CL 的神经元回路的解剖结构，并评估血清素如何调节这些回路以控制复杂的情绪和认知行为。在目标 1 中，我们建议研究由 Htr2A 表达定义的幽闭皮质回路的投影、位置和神经元类型。接下来，我们将使用 Htr2A 和 Gng2（CL 特异性基因）启动子作为工具来生成敲入 Cre 系，以指导 CL 中的基因表达。我们将测试这些工具是否可用于用白喉毒素消融 CL 神经元，作为靶向 CL 功能的最简单方法。最后，我们将回答另一个重要问题：CL 中的 Htr2A 信号传导是否是致幻药物的作用位点。这项研究的工具和结果将来可用于直接操纵 CL 的神经元活动，并揭示血清素作用对情绪和认知功能的新神经基质。