A dendritic mechanism for cholinergic neuromodulation of cortical function

乙酰胆碱（Acetylcholine，ACh）对动物行为和潜在的皮层神经元具有多种和强大的影响， 动力学然而，确定介导这些过程的细胞和电路基板已经证明， 由于乙酰胆碱行动的许多目标和缺乏具体的工具，这是一项具有挑战性的工作。ACh被认为是作用于局部 皮质电路组件，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直接胆碱能神经调节是一个重要的新位点 乙酰胆碱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 药理学工具具有前所未有的特异性，我们将因果检验AChR依赖性 皮层感觉运动计算的树突机制我们的初步证据显示毒蕈碱 乙酰胆碱受体（mAChRs）有效地调节第5层远端顶干树突的兴奋性 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， 在同时的“自下而上”和“自上而下”皮层输入期间的高频躯体尖峰。L5 PN中继 因此，树突被很好地定位以实现用于组合多个 输入。在老鼠的桶状皮层中，自下而上的感觉信息与自上而下的运动输入通过 该亚细胞符合检测机制产生触须对象定位信号。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（目的1）和确定其离子通道机制（目的2）。然后我们将使用一个 新的遗传靶向药理学策略，具有前所未有的特异性，可以因果检验 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新的途径连接一个单一的神经调质-和它的离子 遗传定义的L5 PN小区类型中的信道目标-到蜂窝处理、电路计算，以及 行为，提供关键的洞察乙酰胆碱如何调节大脑功能。!

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. !