A dendritic mechanism for cholinergic neuromodulation of cortical function

皮质功能胆碱能神经调节的树突机制

• 批准号: 10374876
• 负责人: Mark Thomas Harnett
• 金额: $ 34.78万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374876
• 关键词: Acetylcholine; Acute; Address; Adult; Alzheimer' s Disease; Anatomy; Animal Behavior; Apical; Attention deficit hyperactivity disorder; Behavior; Behavioral; Brain; Cells; Dendrites; Detection; Disease; Distal; Electrophysiology (science); Exhibits; Frequencies; Functional disorder; Health; Hybrids; Image; Interneurons; Ion Channel; Link; Mediating; Motor; Mus; Muscarinic Acetylcholine Receptor; Neuromodulator; Neurons; Patch-Clamp Techniques; Pathway interactions; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Play; Positioning Attribute; Potassium Channel; Process; Receptor Activation; Rodent; Role; Schizophrenia; Sensory; Signal Transduction; Site; Slice; Specificity; System; Testing; Therapeutic; Time; Vibrissae; Voltage-Gated Potassium Channel; barrel cortex; base; behavior influence; cell type; cholinergic; experimental study; genetic approach; hippocampal pyramidal neuron; in vivo; insight; neural circuit; neuroregulation; neurotransmission; novel; operation; patch clamp; recruit; relating to nervous system; response; sensor; tool; two photon microscopy; two-photon; voltage

Acetylcholine (ACh) exerts diverse and powerful effects on animal behavior and underlying cortical neural dynamics. However, identifying the cellular and circuit substrates mediating these processes has proved challenging due to the many targets of ACh action and the lack of specific tools. ACh is thought to act on local cortical circuit components, specifically interneurons, to indirectly influence pyramidal neuron dynamics. We hypothesize that direct cholinergic neuromodulation of pyramidal neurons dendrites is an important new locus for the effects of ACh on cortical dynamics and behavior. By leveraging a new genetically targeted pharmacological tool with unprecedented specificity, we will causally test the contribution of AChR-dependent dendritic mechanisms to a cortical sensorimotor computation.!Our preliminary evidence shows that muscarinic acetylcholine receptors (mAChRs) potently modulate the excitability of distal apical trunk dendrites in layer 5 cortical pyramidal neurons (L5 PNs). These dendrites exhibit an active supralinear mechanism that can drive high frequency somatic spiking during coincident “bottom-up” and “top-down” cortical input. L5 PN trunk dendrites are therefore well positioned to implement a canonical cortical computation for combining multiple inputs. In the mouse barrel cortex, bottom-up sensory information is combined with top-down motor input via this subcellular coincidence detection mechanism to produce a whisker object localization signal. We will use this system to test a novel role for ACh in cortical function by characterizing the effect of mAChR activation on L5 PN dendritic integration (Aim 1) and identifying its ion channel mechanism (Aim 2). We will then employ a novel genetically-targeted pharmacology strategy with unprecedented specificity to causally test the contributions of mAChR-dependent dendritic mechanisms to a cortical sensorimotor computation during behavior (Aim 3). These experiments will establish a new pathway linking a single neuromodulator – and its ion channel target(s) in a genetically defined L5 PN cell type – to cellular processing, circuit computation, and behavior, providing critical insight into how ACh modulates brain function. !

乙酰胆碱 (ACh) 对动物行为和潜在的皮质神经产生多种强大的影响 动力学。然而，识别介导这些过程的细胞和电路基质已证明 由于乙酰胆碱作用目标众多且缺乏具体工具，因此具有挑战性。 ACh 被认为作用于局部 皮质回路组件，特别是中间神经元，间接影响锥体神经元动力学。我们 假设锥体神经元树突的直接胆碱能神经调节是一个重要的新位点 了解乙酰胆碱对皮质动力学和行为的影响。通过利用新的基因靶向 具有前所未有的特异性的药理学工具，我们将因果测试 AChR 依赖性的贡献 皮质感觉运动计算的树突机制。！我们的初步证据表明毒蕈碱 乙酰胆碱受体 (mAChR) 有效调节第 5 层远端顶端树突的兴奋性 皮质锥体神经元 (L5 PN)。这些树突表现出一种主动的超线性机制，可以驱动 “自下而上”和“自上而下”皮层输入同时发生时的高频体细胞尖峰。 L5 PN 中继 因此，树突能够很好地实现典型的皮层计算，以组合多个 输入。在小鼠桶状皮层中，自下而上的感觉信息通过自上而下的运动输入相结合 这种亚细胞重合检测机制可产生晶须物体定位信号。我们将使用 该系统通过表征 mAChR 激活对皮质功能的影响来测试 ACh 在皮质功能中的新作用 L5 PN 树突整合（目标 1）并确定其离子通道机制（目标 2）。然后我们将雇用一个 新颖的基因靶向药理学策略具有前所未有的特异性，可用于因果测试 mAChR 依赖的树突机制对皮质感觉运动计算的贡献 行为（目标 3）。这些实验将建立一条连接单个神经调节剂及其离子的新途径 基因定义的 L5 PN 细胞类型中的通道目标 – 细胞处理、电路计算和 行为，为乙酰胆碱如何调节大脑功能提供重要的见解。 ！