Neuromodulation of cortical circuits in health and disease

描述（由申请人提供）：包括专门的神经元亚群及其选择性突触连接的皮质微电路形成到其他皮质和皮质下目标的功能隔离的输出通道。皮质微回路的活动受许多“调节性”神经递质（如5-羟色胺（5-HT））的调节，这些神经递质优化了特定认知任务的回路性能，并且与广泛的精神健康障碍有关。例如，中断的5-HT信号有助于精神分裂症，抑郁症和焦虑症，而多巴胺能药物被广泛用于治疗这些疾病。然而，尽管它们的功能和临床的重要性，很少有人知道如何调节递质选择性地调节皮质神经元亚群subserving特定的功能角色内皮层微电路的活动。 我们的长期目标是表征调节性神经递质对皮质微电路功能的功能影响。通过识别差异调节的皮层微回路的关键细胞和突触成分，这里提出的研究代表了朝着这一目标迈出的重要的第一步 5-HT。兴奋性皮质神经元中的5-羟色胺能信号主要依赖于两种G蛋白偶联受体5-HT 1A（1A）和5-HT 2A（2A），它们对神经元兴奋性具有相反的影响。基于最近的结果显示连合/胼胝体（COM）投射神经元选择性兴奋的5-HT，我们的中心假设是，内源性5-HT的行为，选择性地增强参与特定的执行功能的神经元的活动，同时抑制大量的皮质输出到皮质下结构。我们的首要目标是确定 皮质回路的细胞成分，在功能上被内源性5-HT兴奋或抑制。这将在其中通道视紫红质-2在5-HT神经元中选择性表达的小鼠模型中并且使用体内递送的荧光逆行示踪剂来实现。我们的第二个目标是表征5-HT兴奋的神经元群体之间的突触连接，以确定它们是否形成能够与执行功能相关的持续活动的网络。最后，我们的第三个目标将在行为动物中证实2A激动剂对COM或其他5-HT兴奋的神经元群体的优先激活、恐惧条件化和条件恐惧的消退。这些目标是创新的结合解剖学，生理学，光遗传学和行为的方法来表征选择性调制的细胞成分和突触连接功能定义的皮层输出通道。结果将是重要的，在提供一个框架，了解功能作用的5 HT在调节皮层回路输出中的作用。所获得的新知识将深入了解5-HT如何促进正常的认知和行为，以及为什么大脑皮层中多巴胺能信号的失调会导致精神分裂症，抑郁症和其他精神健康疾病中观察到的行为缺陷。

DESCRIPTION (provided by applicant): Cortical microcircuits, comprising specialized neuron subpopulations and their selective synaptic connections, form functionally segregated output channels to other cortical and subcortical targets. The activity of cortical microcircuits is regulated by a number of "modulatory" neurotransmitters, such as serotonin (5-HT), that optimize circuit performance for specific cognitive tasks, and which are implicated in a wide spectrum of mental health disorders. For instance, disrupted 5-HT signaling contributes to schizophrenia, depression, and anxiety, while serotonergic drugs are widely used to treat these disorders. However, despite their functional and clinical importance, little is known about how modulatory transmitters selectively regulate the activity of cortical neuron subpopulations subserving specific functional roles within cortical microcircuits. Our long-term goal is to characterize the functional impact of modulatory neurotransmitters on cortical microcircuit function. The research proposed here represents an important first step toward this goal by identifying key cellular and synaptic components of cortical microcircuits differentially regulated by 5-HT. Serotonergic signaling in excitatory cortical neurons relies primarily on two G-protein coupled receptors, 5-HT1A (1A) and 5-HT2A (2A), that have opposing influences on neuron excitability. Based on recent results showing commissural/callosal (COM) projection neurons are selectively excited by 5-HT, our central hypothesis is that endogenous 5-HT acts to selectively enhance the activity of neurons participating in specific executive functions, while suppressing the bulk of cortical output to subcortical structures. Our first aim is to identify the cellular components of cortical circuits that are functionally excited or inhibited by endogenous 5-HT. This will be accomplished in a mouse model in which channelrhodopsin-2 is selectively expressed in 5-HT neurons, and using fluorescent retrograde tracers delivered in vivo. Our second aim is to characterize synaptic connectivity among populations of 5-HT-excited neurons to determine whether they form networks capable of the sustained activity associated with executive functions. Finally, our third aim will confirm in behaving animals preferential activatio of COM or other 5-HT-excited neuron populations by 2A agonists, fear conditioning, and extinction of conditioned fear. These aims are innovative in combining anatomical, physiological, optogenetic, and behavioral approaches to characterize selective modulation of cellular components and synaptic connections underlying functionally defined cortical output channels. The results will be significant in providing a framework for understanding the functional role of 5 HT in regulating the output of cortical circuits. The new knowledge gained will provide insight into how 5-HT facilitates normal cognition and behavior, and why dysregulation of serotonergic signaling in the cerebral cortex leads to the behavioral deficits observed in schizophrenia, depression, and other mental health disorders.