Serotonergic modulation of claustro-cortical circuits

描述(申请人提供)：神经精神障碍影响几个领域的功能：知觉(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)，以及其他。这些大脑功能的损害提供了对这些障碍的特征的混乱、幻觉、妄想、缺乏关联性、内隐、注意力分散和认知能力下降等症状的可能洞察。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造成的。事实上，大脑如何将各种外部和内部刺激整合到一个连贯的体验中，是人类体验的特征之一。然而，可以说，许多复杂的神经精神障碍，如精神分裂症、自闭症、躁郁症、强迫症和其他疾病，可能被视为大脑未能适当地将各种功能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，我们重点介绍屏状核(CL)作为一种帮助整合不同大脑功能的潜在结构的作用。基于其连通性，CL被认为在更高级的认知加工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，但我们的团队对这种神秘的结构感兴趣，因为它由5-羟色胺能神经元进行密集的神经支配，并高水平表达5-羟色胺2A受体(Htr2A)。我们假设CL的Htr2A受体是致幻药物如LSD(麦角酸二乙胺)的作用部位，这些药物可以如此有效地扰乱正常的感官知觉和自我感觉。推而广之，我们推测CL功能是否可能在神经精神障碍中受损，其中整合功能似乎被破坏。随着我们开发了新的实验工具，我们对化学发光的兴趣变得更加具体，我们相信这些工具可以为化学发光功能如何改变行为提供新的见解。在这项探索性授权中，我们建议描述起源于CL的神经元回路的解剖学特征，并评估5-羟色胺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的表达所定义的屏状皮质环路的投射、位置和神经元类型。接下来，我们将使用Htr2A和Gng2(CL特异基因)启动子作为工具来指导CL中的基因表达，从而产生敲入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融CL神经元。最后，我们将回答另一个重要的问题：Htr2A在CL中是否为致幻药物的作用部位。这项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5-羟色胺能作用于情绪和认知功能的新的神经底物。

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.