Cholinergic modulation of cortical circuits.

描述(申请人提供)：乙酰胆碱是大脑中一种重要的神经调节剂，对正常认知是必不可少的。行为学研究表明，皮质乙酰胆碱 从基底前脑释放的胆碱能轴突在调节注意的认知任务中起着重要作用。此外，胆碱能功能障碍与阿尔茨海默病和精神分裂症的认知障碍有关。尽管大脑皮层胆碱能系统很重要，但对皮层环路胆碱能调节的突触机制仍知之甚少。基底前脑胆碱能神经元投射到整个皮质，在那里它们提供皮质乙酰胆碱的主要来源。然而，对内源性释放的乙酰胆碱如何影响皮质神经元和突触的了解是有限的，因为使用传统方法还不可能选择性地刺激胆碱能轴突。通过用光遗传结构转导基底前脑中的胆碱能神经元，我已经证明了我可以克服这些技术挑战，选择性地激活皮质中的胆碱能轴突。乙酰胆碱受体以一种细胞类型特异性的方式表达，并表现出广泛的反应动力学。通过使用光遗传学方法，我能够识别胆碱能轴突的突触后靶点，并首次表征它们对内源性ACh的突触后反应的动力学。这些信息对揭示大脑皮层胆碱能活动的潜在机制至关重要，不能通过外源性胆碱能激动剂的应用来获得。这一建议的主要目的是检验一种假设，即胆碱能输入以不同的方式增强皮层对前馈感觉信息的处理，同时抑制来自小鼠感觉皮质其他皮质区域的反馈信息。层4是大脑皮层的主要输入层， 第四层锥体神经元从丘脑接受强大的前馈感觉输入。然而，前馈输入也与反馈输入整合到第5层锥体神经元上，这些神经元反过来形成皮质的初级输出层。在第一个目标中，我将准备丘脑皮质切片，以研究胆碱能输入如何调制前馈丘脑皮质突触到第四层锥体神经元。在第二个和第三个目标中，我将使用单个和成对的录音来研究胆碱能输入如何调节抑制神经元和突触，从而调节前馈和反馈输入到第5层锥体神经元。总之，这些实验将为乙酰胆碱如何调节在感觉处理中发挥作用的皮质回路提供新的见解，并可能为与胆碱能功能障碍相关的神经精神疾病提供新的见解。

DESCRIPTION (provided by applicant): Acetylcholine is an important neuromodulator in the brain and is essential for normal cognition. Behavioral studies suggest that cortical acetylcholine released from basal forebrain cholinergic axons play an important role in mediating the cognitive task of attention. Moreover, cholinergic dysfunction has been implicated in the cognitive disruption observed in Alzheimer's disease and schizophrenia. Despite the importance of the cortical cholinergic system, the synaptic mechanisms mediating cholinergic modulation of cortical circuits remain poorly understood. Basal forebrain cholinergic neurons project throughout the cortex where they provide the main source of cortical acetylcholine. However, understanding of how endogenously released acetylcholine affects cortical neurons and synapses is limited because it has not been possible to selectively stimulate cholinergic axons using conventional methods. By transducing cholinergic neurons in the basal forebrain with optogenetic constructs, I have demonstrated that I can overcome these technical challenges and selectively activate cholinergic axons in the cortex. Acetylcholine receptors are expressed in a cell-type specific manner and exhibit a wide range of response kinetics. By using an optogenetic approach, I am able to identify the postsynaptic targets of cholinergic axons and characterize the kinetics of their postsynaptic responses to endogenous ACh for the first time. This information is critical to uncovering the mechanisms underlying cholinergic activity in the cortex and cannot be obtained by exogenous application of cholinergic agonists. The primary goal of this proposal is to test the hypothesis that cholinergic inputs differentially enhance cortical processing of feedforward sensory information while suppressing feedback information from other cortical areas in sensory cortex of mice. Layer 4 is the main input layer of the cortex, and layer 4 pyramidal neurons receive strong feedforward sensory inputs from the thalamus. However, feedforward inputs are also integrated together with feedback inputs onto layer 5 pyramidal neurons, which in turn form the primary output layer of the cortex. In the first aim, I will prepare thalamocortical slices to study how cholinergic inputs modulate feedforward thalamocortical synapses onto layer 4 pyramidal neurons. In the second and third aims, I will then use single and paired recordings to investigate how cholinergic inputs modulate inhibitory neurons and synapses that regulate feedforward and feedback inputs onto layer 5 pyramidal neurons. Together, these experiments will provide new insight into how acetylcholine modulates cortical circuits that play a role in sensory processing, and may provide new insights into neuropsychiatric conditions associated with cholinergic dysfunction.