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: 9898496
• 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/9898496
• 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元产生潜水员和强大的影响 动力学。但是，识别介导这些过程的细胞和电路底物已被证明 由于ACH动作的许多目标以及缺乏特定工具的挑战。 ACH被认为是对当地人的作用 皮质电路成分，特别是中间神经元，以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基因座 对于ACH对皮质动力学和行为的影响。通过利用一个新的针对性的新的 具有前所未有的特异性的药理学工具，我们将为ACHR依赖性的贡献进行。 皮质感觉运动计算的树突状机制。我们的初步证据表明毒蕈碱 乙酰胆碱受体（MACHR）可能调节第5层中盘式顶端树突的令人兴奋 皮质锥体神经元（L5 PNS）。这些树突暴露了一个可以驱动的主动上线机制 同时“自下而上”和“自上而下”皮质输入期间的高频体细胞尖峰。 L5 PN躯干 因此，树突有很好的位置，可以实现一个规范的皮质计算来组合多个 输入。在鼠标桶皮层中，自下而上的感觉信息与自上而下的电动机结合 这种亚细胞重合检测机制，产生了晶须对象定位信号。我们将使用 该系统通过表征MACHR激活对ACH在皮质功能中的新作用 L5 PN树突状集成（AIM 1）并识别其离子通道机制（AIM 2）。然后，我们将采用一个 具有前所未有的特异性的新型遗传靶向药理学策略，可为核心测试 MACHR依赖性树突机制对皮层感觉运动计算的贡献 行为（目标3）。这些实验将建立一个连接单个神经调节剂的新途径 - 其离子 通道目标（s）在一般定义的L5 PN细胞类型中 - 到细胞处理，电路计算和 行为，提供有关ACH如何调节大脑功能的关键见解。呢