Coordinated modulation of cortical circuits by serotonin and acetylcholine

血清素和乙酰胆碱对皮质回路的协调调节

• 批准号: 10665047
• 负责人: Allan T Gulledge
• 金额: $ 41万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-13 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665047
• 关键词: Acetylcholine; Action Potentials; Advanced Development; Area; Automobile Driving; Axon; Behavior; Brain Stem; Cells; Cerebral cortex; Choline; Cognition; Communication; Contralateral; Corpus striatum structure; Data; Distant; Etiology; Excitatory Synapse; Exhibits; G-Protein-Coupled Receptors; Generations; Glutamates; Hippocampus; Impaired cognition; Maps; Measures; Medial; Medial Dorsal Nucleus; Mental disorders; Mission; Mus; National Institute of Mental Health; Neocortex; Neurons; Neurotransmitters; Optics; Output; Patients; Pattern; Performance; Physiological; Pilot Projects; Prefrontal Cortex; Public Health; Pyramidal Tracts; Regulation; Reporting; Research; Research Proposals; Reuniens Thalamic Nucleus; Serotonin; Signal Transduction; Source; Synapses; System; Testing; Thalamic structure; Viral; Whole-Cell Recordings; cholinergic; clinically relevant; cognitive function; cognitive task; excitatory neuron; hippocampal pyramidal neuron; innovation; insight; neocortical; neural circuit; neuronal circuitry; neuronal excitability; neuropsychiatric disorder; neuroregulation; novel therapeutic intervention; optogenetics; postsynaptic; postsynaptic neurons; presynaptic; segregation; serotonergic regulation

Abstract Cortical circuits, comprising specialized neuron subpopulations and their selective synaptic connections, send output to long-distance cortical and subcortical targets via two distinct classes of projection neurons: intratelencephalic (IT) neurons that project primary within and across cortical hemispheres, and pyramidal tract (PT) neurons that project to deep subcortical targets (e.g., the thalamus and brainstem). Cortical circuits are regulated by a variety of modulatory neurotransmitters, such as serotonin (5-HT) and acetylcholine (ACh), that optimize circuit performance for different cognitive tasks. Indeed, disruption of serotonergic or cholinergic signaling in the cortex impairs cognition and normal behavior, and both transmitter systems are implicated in a range of psychiatric diseases. Therefore, revealing the physiological mechanisms by which 5-HT and ACh influence cortical processing will enhance our understanding of normal cognition, and will advance the development of novel therapeutic strategies for psychiatric patients. In the mouse prefrontal cortex (PFC), 5-HT and ACh act via G-protein-coupled receptors to reciprocally regulate the postsynaptic excitability of IT and PT neurons. 5-HT promotes IT neuron output, but suppresses PT neurons. Conversely, ACh preferentially excites PT neurons, but has limited impact on IT neurons. Regardless of neuromodulatory state, action potential generation in IT and PT neurons requires excitatory synaptic drive that may also be regulated, at the presynaptic level, by 5-HT and/or ACh. Our pilot studies suggest that 5-HT and ACh act differentially to regulate key excitatory afferents to IT and PT neurons. This current project will test the overarching hypothesis that 5-HT and ACh bias the “throughput” of cortical circuits via coordinated pre- and postsynaptic regulation of specific combinations of excitatory afferent and cortical projection target neuron subtype. Our first aim is to map the relative targeting, and functional excitatory drive, of IT and PT neurons by key extrinsic excitatory afferents to the mouse medial PFC. Our second aim is to test for afferent-specific presynaptic regulation by 5-HT and ACh, thereby determining whether pre- and postsynaptic neuromodulation is coordinated to facilitate specific combinations of afferent input and cortical projection output. Our third aim is to test whether 5-HT and/or ACh regulate local circuit communication between IT and PT neurons in a manner consistent with the opposing postsynaptic impacts of these modulators on excitability. Completion of these aims will establish a rigorous, circuit-based framework for understanding cholinergic and serotonergic regulation of cognitive function, and will provide insight into how disruptions of neuromodulatory circuits contribute to psychiatric disease.

摘要 皮层回路，包括专门的神经元亚群和它们的选择性突触连接， 通过两类不同的投射神经元将输出发送到远距离皮层和皮层下目标： 端脑内（IT）神经元，主要投射在皮质半球和锥体束内 (PT)投射到深层皮层下目标的神经元（例如，丘脑和脑干）。大脑皮层回路 由多种调节性神经递质调节，如血清素（5-HT）和乙酰胆碱（ACh）， 针对不同的认知任务优化电路性能。事实上，干扰肾上腺素能或胆碱能 皮质中的信号传导会损害认知和正常行为，而这两个递质系统都与大脑的活动有关。 一系列精神疾病。因此，揭示5-HT和ACh在神经细胞中的作用机制， 影响皮层处理将增强我们对正常认知的理解， 为精神病患者开发新的治疗策略。 在小鼠前额叶皮层（PFC），5-HT和ACh通过G蛋白偶联受体作用于大脑皮层， 调节IT和PT神经元的突触后兴奋性。5-HT促进IT神经元输出，但抑制 PT神经元。相反，ACh优先兴奋PT神经元，但对IT神经元的影响有限。 不管神经调节状态如何，IT和PT神经元中的动作电位产生需要兴奋性的刺激。 在突触前水平，5-HT和/或ACh也可以调节突触驱动。我们的试点研究 表明5-HT和ACh对IT和PT神经元关键兴奋性传入的调节作用不同。这 目前的项目将测试总体假设，即5-HT和ACh偏置皮层回路的“吞吐量 通过兴奋性传入和皮层神经元的特定组合的协调的突触前和突触后调节， 投射靶神经元亚型。我们的第一个目标是绘制相对目标，和功能性兴奋性驱动， 的IT和PT神经元的关键外部兴奋性传入小鼠内侧PFC。我们的第二个目的是测试 用于5-HT和ACh的传入特异性突触前调节，从而确定前和 突触后神经调节被协调以促进传入输入和皮层神经元之间的特定组合。 投影输出我们的第三个目的是测试5-HT和/或ACh是否调节局部电路通信 在IT和PT神经元之间，以与这些神经元的相反突触后影响一致的方式， 兴奋性调节剂。 这些目标的完成将建立一个严格的，基于电路的框架，了解胆碱能 以及对认知功能的神经递质调节，并将提供关于神经递质的破坏如何影响认知功能的见解。 神经调节回路导致精神疾病。