Neuromodulation of cortical circuits in health and disease

描述(申请人提供)：皮质微电路，包括专门的神经元亚群及其选择性突触连接，形成到其他皮质和皮质下靶点的功能隔离的输出通道。大脑皮层微回路的活动受许多“调节性”神经递质的调节，如5-羟色胺(5-羟色胺)，这些递质可优化特定认知任务的回路性能，并与广泛的精神健康障碍有关。例如，5-羟色胺信号中断会导致精神分裂症、抑郁和焦虑，而5-羟色胺能药物被广泛用于治疗这些疾病。然而，尽管它们在功能和临床上具有重要的意义，但人们对调制递质如何选择性地调节在皮质微回路中扮演特定功能的皮质神经元亚群的活动知之甚少。我们的长期目标是确定调节性神经递质对皮质微电路功能的功能影响。这里提出的研究是迈向这一目标的重要的第一步，通过识别不同调控的皮质微电路的关键细胞和突触成分 通过5-羟色胺。兴奋性皮质神经元中的5-羟色胺能信号主要依赖于两个G蛋白偶联受体，5-HT1A(1A)和5-HT2A(2A)，它们对神经元的兴奋性具有相反的影响。根据最近的研究结果表明，5-羟色胺选择性地兴奋了连合/痂(COM)投射神经元，我们的中心假设是，内源性5-羟色胺选择性地增强了参与特定执行功能的神经元的活性，同时抑制了大部分皮质输出到皮质下结构。我们的首要目标是确定 由内源性5-羟色胺兴奋或抑制的皮质环路的细胞成分。这将在小鼠模型中完成，在该模型中，通道视紫红质-2在5-羟色胺神经元中选择性表达，并使用体内传递的荧光逆行示踪剂。我们的第二个目标是表征5-羟色胺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证实，在动物行为中，2A激动剂优先激活COM或其他5-羟色胺兴奋的神经元群体，恐惧条件作用，以及条件性恐惧的消退。这些目标在结合解剖学、生理学、光遗传学和行为学方法来表征细胞成分和突触连接的选择性调节方面具有创新性，这些突触连接是在功能定义的皮质输出通道下进行的。这些结果将为理解5的功能作用提供一个框架，具有重要意义 羟色胺在调节皮层回路的输出中起重要作用。所获得的新知识将有助于深入了解5-羟色胺如何促进正常认知和行为，以及为什么大脑皮层5-羟色胺能信号调节失调会导致精神分裂症、抑郁症和其他精神健康障碍的行为缺陷。

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.