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有多种强大的影响 动力学。然而，鉴定参与这些过程的细胞和电路底物已经证明 由于ACH行动的目标众多，而且缺乏具体的工具，因此具有挑战性。ACH被认为作用于当地 皮质回路成分，特别是中间神经元，间接影响锥体神经元的动力学。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 ACh对大脑皮层动力学和行为的影响。通过利用一种新的基因靶向 以前所未有的特异性，我们将因果检验AChR依赖的贡献 大脑皮层感觉运动计算的树突机制。！我们的初步证据表明，毒鼠强 乙酰胆碱受体(MAChRs)有效地调节第5层远端心尖干树突的兴奋性 皮质锥体神经元(L5 PNS)。这些树突表现出一种活跃的超线性机制，可以驱动 在一致的“自下而上”和“自上而下”的皮质输入过程中的高频躯体刺激波。L5 PN中继线 因此，树突很好地实现了用于组合多个 投入。在小鼠桶状皮质中，自下而上的感觉信息与自上而下的运动输入通过 这种亚细胞符合检测机制以产生胡须对象定位信号。我们将使用 该系统旨在通过表征mAChR激活对皮层功能的影响来测试ACh在皮质功能中的新作用 L5PN树突整合(Aim 1)及其离子通道机制的确定(Aim 2)。然后，我们将聘请一名 具有前所未有的特异性的新的基因靶向药理学策略，用于因果测试 依赖mAChR的树突机制对大脑皮层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一神经调节剂及其离子的新途径 遗传定义的L5 PN信元类型中的通道目标(S)-到信元处理、电路计算和 行为，为ACh如何调节大脑功能提供了关键的见解。好了！