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.

项目摘要 一级运动皮层（M1）和基因座ceruleus（LC）都以基本的方式贡献 目的运动 - M1及其锥体区（PT）神经元参与行动计划和执行， 和LC及其去甲肾上腺素能的轴突投影涉及与唤醒和关注有关的方面。这 这两个主要大脑系统通信和相互作用的细胞和电路级机制是 不太了解。先前的解剖学研究描述了轴突项目，并实际上追踪了推定 LC和Neofortex之间的突触连接，包括M1，但LC输入到M1的功能方面 尚未表征，仍然出乎意料是M1之间直接双向相互作用的可能性 和LC。然而，越来越多的证据表明，这种介导直接LC-M1的电路介导 沟通。在这里，我们将开发并测试LC→M1和M1→LC项目紧密的假设 链接到形成倒数循环电路。我们肯定M1中的锥体道（PT）神经元是关键皮质 介导这些相互作用的细胞类型，从非肾上腺素释放LC接收神经调节输入 轴突 - 很可能还来自共同发行的谷氨酸的兴奋性输入 - 并发送兴奋性传入 回到脑干，包括到LC神经元的分支以关闭复发环。调查这些 可能性，我们将在小鼠中应用多种方法进行细胞类型特异性电路分析。在上升 LC→M1途径，我们将在鉴定的时录制时，将其上标记和令人兴奋的突触前LC轴突 M1神经元的类别，以表征对PT神经元和其他潜力的Nor义肾上腺素和突触作用 细胞靶标。在下降的M1→LC途径中，我们将适应评估谷氨酸能突触的方法 与LC神经元的连通性，包括具有M1的经常性项目的连通性。在这两种途径中，我们都将测试和 定量地表征了单突触兴奋性和无突触抑制回路。总体结果 将详细介绍新框架，描述介导直接LC-M1相互作用的细胞机制。结果 从这个以发现为导向的研究计划将为未来的以假设为导向的研究奠定基础 调查 - 在机械上重要的特定细胞类型及其突触连接的水平和 神经调节特性 - Ceruleo-cortical电路中的信号传导如何促进哺乳动物运动功能 体内。