Cholinergic modulation of cortical circuits.

皮质回路的胆碱能调节。

• 批准号: 8636328
• 负责人: Sergio Estevan Arroyo
• 金额: $ 1.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-06 至 2014-06-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636328
• 关键词: Acetylcholine; Affect; Alzheimer' s Disease; Animals; Area; Attention; Axon; Behavior; Behavioral; Brain; Cells; Cholinergic Agonists; Cholinergic Fibers; Cholinergic Receptors; Cognition; Cognitive; Cues; Dendrites; Disease; Disinhibition; Distal; Elements; Exhibits; Feedback; Fiber; Frequencies; Functional disorder; Goals; Individual; Inhibitory Synapse; Interneurons; Kinetics; Lead; Lesion; Mediating; Methods; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Neuromodulator; Neurons; Nicotinic Agonists; Nicotinic Receptors; Output; Performance; Play; Process; Receptor Activation; Research; Role; Schizophrenia; Sensory; Sensory Process; Signal Transduction; Slice; Source; Synapses; System; Testing; Thalamic structure; Time; basal forebrain; basal forebrain cholinergic neurons; cell type; cholinergic; cholinergic neuron; hippocampal pyramidal neuron; inhibitory neuron; insight; neuropsychiatry; novel therapeutic intervention; optogenetics; postsynaptic; research study; response; selective attention; sensory cortex; transmission process

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.

描述（由申请人提供）：乙酰胆碱是大脑中重要的神经调节剂，对于正常认知至关重要。行为研究表明皮质乙酰胆碱 从基底前脑胆碱能轴突释放出来，在介导注意力的认知任务中起着重要作用。此外，胆碱能功能障碍与在阿尔茨海默氏病和精神分裂症中观察到的认知破坏有关。尽管皮质胆碱能系统的重要性，但介导皮质回路胆碱能调节的突触机制仍然鲜为人知。基底前脑胆碱能神经元在整个皮质中都提供了皮质乙酰胆碱的主要来源。但是，了解内源释放的乙酰胆碱如何影响皮质神经元和突触是有限的，因为不可能使用常规方法选择性地刺激胆碱能轴突。通过使用光遗传构建体将胆碱能神经元转导胆碱能神经元，我证明我可以克服这些技术挑战并选择性地激活皮质中的胆碱能轴突。乙酰胆碱受体以细胞类型的特异性表达，并表现出广泛的反应动力学。通过使用光遗传学方法，我能够鉴定胆碱能轴突的突触后靶标，并首次表征其突触后ACH的动力学。这些信息对于揭示皮质中胆碱能活性的机制至关重要，无法通过外源应用胆碱能激动剂来获得。该提案的主要目的是检验以下假设：胆碱能输入差异化增强了进食感官信息的皮质处理，同时抑制了小鼠感觉皮质中其他皮质区域的反馈信息。第4层是皮质的主要输入层 和第4层锥体神经元从丘脑接收强有力的进发感觉输入。但是，进料输入还与反馈输入一起集成到第5层锥体神经元上，这又构成了皮质的主要输出层。在第一个目的中，我将准备丘脑皮质切片，以研究胆碱能输入如何调节前丘脑皮质突触到4层锥体神经元。然后，在第二和第三目标中，我将使用单个和配对的记录来研究胆碱能输入如何调节抑制性神经元和突触，这些神经元和突触调节前馈和反馈输入到5层金字塔神经元上。总之，这些实验将提供有关乙酰胆碱如何调节在感觉过程中发挥作用的皮质回路的新见解，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。