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）：神经精神疾病会影响几个领域的功能：感知（情感，感觉），整合（信息，情感，感觉），认知（工作记忆，社交认知，注意力），动机（Hedonic Drive，执行功能）等。这些大脑功能的障碍提供了可能洞悉混乱，幻觉，妄想，缺乏相关性，参与性，分心和认知能力下降的症状，这些疾病表征了这些疾病。一个假设是，其中一些功能障碍似乎是由于各个大脑区域之间刺激的整合受损而导致的。确实，大脑如何将外部和内部刺激的多样性整合到连贯的体验中，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，例如精神分裂症，自闭症，躁郁症，强迫症和其他复杂的神经疾病，可能被视为大脑无法将各种功能适当地整合到无缝的整体中。大脑中刺激的整合可能是通过几种机制发生的。在这里，我们专注于claustrum（CL）作为有助于整合大脑功能的一种潜在结构。根据其连通性，CL已被理论化以在高阶认知处理和情感行为中发挥作用1,2。令人惊讶的是，对CL知之甚少，但是由于血清素能神经元的密集神经及其高清5-羟色胺2A受体（HTR2A）的高水平表达，我们的小组对这种神秘的结构产生了兴趣。我们假设CL的HTR2A受体是致幻药的作用部位，例如LSD（脂肪酸二乙基酰胺） - 如此有效破坏正常感觉感知和自我意识的药物。通过扩展，我们已经推测CL功能是否可能在整合功能似乎中断的神经精神疾病中受到损害。随着我们开发新的实验工具，我们对CL的兴趣变得更加具体，我们认为可以为CL功能如何改变行为提供新的见解。在这项探索性赠款中，我们建议表征起源于CL的神经元电路的解剖结构，并评估5-羟色胺如何调节这些电路以控制复杂的情绪和认知行为。在AIM 1中，我们建议研究由HTR2A表达定义的claustro-cortical电路的投影，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）启动子作为引导CL中基因表达的工具生成敲入CRE系。我们将测试这些工具是否可以用白喉毒素作为靶向CL功能的最简单方法来消除Clate CL神经元。最后，我们将回答另一个重要问题：CL中的HTR2A信号是致幻药的作用部位。这项研究的工具和结果将来可以直接操纵CL的神经元活动，并揭示血清素能作用对情绪和认知功能的新神经底物。