Serotonergic modulation of claustro-cortical circuits

描述（由申请人提供）：神经精神疾病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，社会认知，注意力），动机（享乐驱动，执行功能）等。这些脑功能的损害可能有助于了解这些疾病的症状，如紊乱、幻觉、妄想、缺乏相关性、内乱、注意力不集中和认知能力下降。一种假设是，这些功能障碍中的一些似乎是由于不同大脑区域之间的刺激整合受损。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，有争议的是，许多复杂的神经精神疾病，如精神分裂症、自闭症、双相情感障碍、强迫症和其他疾病，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。刺激在大脑中的整合可能通过几种机制发生。在这里，我们重点关注屏状体（CL）作为一个潜在的结构，帮助整合不同的大脑功能的作用。基于其连通性，CL在高阶认知加工和情绪行为中起着理论作用1,2。令人惊讶的是，我们对CL知之甚少，但我们的研究小组对这种神秘的结构产生了兴趣，因为它被5 -羟色胺能神经元密集支配，并且5 -羟色胺2A受体（Htr2A）的表达水平很高。我们假设CL的Htr2A受体是致幻药物的作用部位，如LSD（麦角酸二乙胺）——这种药物能有效地破坏正常的感觉知觉和自我意识。由此，我们推测在综合功能出现紊乱的神经精神疾病中，CL功能是否可能受损。我们对CL的兴趣变得更加具体，因为我们开发了新的实验工具，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。在这项探索性研究中，我们建议对起源于CL的神经元回路的解剖结构进行表征，并评估血清素如何调节这些回路来控制复杂的情绪和认知行为。在Aim 1中，我们拟研究由Htr2A表达定义的幽闭-皮质回路的投射、位置和神经元类型。接下来，我们将使用Htr2A和Gng2（一种CL特异性基因）启动子作为指导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使用白喉毒素作为靶向CL功能的最简单方法来消融CL神经元。最后，我们将回答另一个重要的问题：致幻药物的作用部位是CL中的Htr2A信号传导吗？本研究的工具和结果可用于未来直接操纵CL的神经元活动，并揭示血清素能作用于情绪和认知功能的新神经基质。

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.