Bidirectional circuits of locus ceruleus and motor cortex neurons

蓝斑和运动皮层神经元的双向回路

• 批准号: 10447235
• 负责人: Gordon M Shepherd
• 金额: $ 71.64万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447235
• 关键词: Address; Anatomy; Arousal; Attention; Axon; Back; Behavioral; Brain; Brain Stem; Cell Nucleus; Cell model; Communication; Complement; Disease; Electrophysiology (science); Feedback; Foundations; Future; Generations; Glutamates; Goals; Health; Impairment; Interneurons; Ion Channel Gating; Knowledge; Label; Lead; Link; Mammals; Mediating; Methods; Mission; Modeling; Monitor; Motor; Motor Cortex; Movement; Mus; Neocortex; Neuraxis; Neurons; Norepinephrine; Outcome; Output; Pathology; Pathway interactions; Pharmacology; Positioning Attribute; Property; Public Health; Pyramidal Tracts; Recurrence; Research; Role; Signal Transduction; Slice; Spinal Cord; Synapses; System; Testing; United States National Institutes of Health; Viral; Volition; Whole-Cell Recordings; base; cell type; cellular targeting; disability; excitatory neuron; experimental study; improved; in vivo; inhibitory neuron; motor behavior; motor control; neuroregulation; noradrenergic; novel strategies; optogenetics; postsynaptic; presynaptic; programs; tool; transmission process; voltage

Project Summary Primary motor cortex (M1) and the locus ceruleus (LC) both contribute in essential ways to the generation of purposive movements – with M1 and its pyramidal tract (PT) neurons involved in action planning and execution, the and LC and its noradrenergic axonal projections involved in aspects relating to arousal and attention. The cellular- and circuit-level mechanisms by which these two major brain systems communicate and interact are not well understood. Prior anatomical studies have described axonal projections and virally traced putative synaptic connections between the LC and neocortex that include M1, but functional aspects of LC inputs to M1 have not been characterized, and still unexplored is the possibility of direct bidirectional interactions between M1 and LC. Yet, there is growing evidence, though mostly indirect, to suggest such a circuit mediating direct LC-M1 communication. Here we will develop and test the hypothesis that LC→M1 and M1→LC projections are tightly linked to form a reciprocal, looping circuit. We posit that pyramidal tract (PT) neurons in M1 are the key cortical cell type mediating these interactions, receiving neuromodulatory inputs from the norepinephrine-releasing LC axons – and quite possibly also excitatory inputs from co-released glutamate – and sending excitatory afferents back to the brainstem, including branches to the LC neurons to close a recurrent loop. To investigate these possibilities, we will apply multiple methods for cell-type-specific circuit analysis in the mouse. In the ascending LC→M1 pathway, we will optogenetically label and excite presynaptic LC axons while recording from identified classes of M1 neurons, to characterize noradrenergic and synaptic actions on PT neurons and other potential cellular targets. In the descending M1→LC pathway, we will adapt the methods to assess glutamatergic synaptic connectivity to LC neurons, including those with recurrent projections to M1. In both pathways we will test and quantitatively characterize the monosynaptic excitatory and disynaptic inhibitory circuits. The overall outcome will be detailed new framework delineating the cellular mechanisms mediating direct LC-M1 interactions. Results from this discovery-oriented research program will lay the groundwork for future hypothesis-oriented studies to investigate – at the mechanistically important level of specific cell types and their synaptic connections and neuromodulatory properties – how signaling in ceruleo-cortical circuits contributes to mammalian motor function in vivo.

项目概要 初级运动皮层 (M1) 和蓝斑 (LC) 都对生成 有目的的运动——M1 及其锥体束 (PT) 神经元参与行动计划和执行， 和 LC 及其去甲肾上腺素能轴突投射涉及与唤醒和注意力相关的方面。 这两个主要大脑系统沟通和相互作用的细胞和电路水平机制是 之前的解剖学研究描述了轴突投影和病毒追踪的假定。 LC 和新皮质之间的突触连接（包括 M1），但 LC 输入到 M1 的功能方面 尚未被表征，并且仍未探索 M1 之间直接双向相互作用的可能性 然而，越来越多的证据（尽管大多是间接的）表明存在这样一个直接介导 LC-M1 的电路。 在这里，我们将开发并测试 LC→M1 和 M1→LC 投影是紧密的假设。 我们假设 M1 中的锥体束 (PT) 神经元是关键的皮质。 介导这些相互作用的细胞类型，接收来自释放去甲肾上腺素的 LC 的神经调节输入 轴突 - 很可能还有来自共同释放的谷氨酸的兴奋性输入 - 并发送兴奋性传入 回到脑干，包括连接 LC 神经元的分支以闭合循环以研究这些。 可能性，我们将应用多种方法进行小鼠细胞类型特异性电路分析。 LC→M1 通路，我们将通过光遗传学标记和激发突触前 LC 轴突，同时记录已识别的 M1 神经元类别，用于表征 PT 神经元和其他潜在神经元的去甲肾上腺素能和突触作用 在下行 M1→LC 通路中，我们将调整方法来评估谷氨酸能突触。 与 LC 神经元的连接，包括那些反复投射到 M1 的神经元，我们将在这两条通路中进行测试和验证。 定量表征单突触兴奋性和双突触抑制回路的总体结果。 将详细描述介导直接 LC-M1 相互作用的细胞机制的新框架。 这个以发现为导向的研究计划将为未来以假设为导向的研究奠定基础 研究——在特定细胞类型及其突触连接的机械重要水平上 神经调节特性——蓝皮层回路中的信号传导如何促进哺乳动物的运动功能 体内。