Bidirectional circuits of locus ceruleus and motor cortex neurons

项目摘要 初级运动皮层（M1）和蓝斑（LC）都以重要的方式参与了 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参与有关方面的觉醒和注意。的 这两个主要的大脑系统通过细胞和电路水平的机制进行通信和相互作用， 没有被很好地理解。先前的解剖学研究已经描述了轴突投射和病毒追踪的假定的神经元投射。 LC和包括M1在内的新皮层之间的突触连接，但LC输入到M1的功能方面 还没有被描述，仍然没有探索的是M1之间直接双向相互作用的可能性。 和LC。然而，有越来越多的证据，虽然大多是间接的，建议这样的电路介导直接LC-M1 通信在这里，我们将开发和测试的假设，LC→M1和M1→LC的预测是紧密的 连接形成一个相互的循环回路。我们认为M1区锥体束神经元是皮层神经元中的关键神经元， 介导这些相互作用的细胞类型，从释放去甲肾上腺素的LC接收神经调节输入 轴突-很可能也是共同释放谷氨酸的兴奋性输入-并发送兴奋性传入 回到脑干，包括LC神经元的分支，以关闭循环回路。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通路，我们将光遗传学标记和激发突触前LC轴突，同时记录从鉴定的 M1类神经元，以表征对PT神经元的去甲肾上腺素能和突触作用以及其他潜在的 细胞目标。在下行的M1→LC通路中，我们将调整方法来评估突触能突触的功能。 连接LC神经元，包括那些经常性的投射到M1。在这两种途径中，我们将测试和 定量表征单突触兴奋和双突触抑制回路。总体结果 将详细描述新的框架介导直接LC-M1相互作用的细胞机制。结果 从这个发现导向的研究计划将奠定基础，为未来的假设导向的研究， 研究-在特定细胞类型及其突触连接的重要机制水平上， 神经调节特性：蓝斑皮层回路中的信号传导如何促进哺乳动物的运动功能 in vivo.

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.