Feedback and feedforward gating of sensory signaling through timing in the thalamocortical loop

通过丘脑皮层环路中的定时对感觉信号的反馈和前馈门控 几乎所有的感觉体验都是从外周开始的，产生的感觉信号通过丘脑传播 才能到达大脑皮层尽管对前馈进行了大量的解剖和功能研究， 从丘脑到初级感觉皮层（TC）的投射，对广泛的 皮质丘脑（CT）反馈通路，向丘脑提供约40%的输入。一个提议的 CT反馈的作用是控制上升感觉信号相对于背景活动的显著性，从而 调节感官刺激的选择性可检测性和可辨别性，但尚未明确测试 由于底层电路的复杂性、解开这种性质的环路的困难以及唯一的 专门针对电路关键元件设计的工具的最新可用性。该项目将利用 一系列工具可精确测量和光遗传学操纵胡须中TC-CT电路的元件 触觉感知过程中清醒的头部固定小鼠的体感通路，以制定一套规则 皮层反馈控制丘脑皮层回路中的信号处理。一、L6CT的作用 将确定丘脑中感觉信号的反馈投射（Aim 1）。L6CT神经元将 光遗传学操作，同时记录L6CT中的细胞外群体加标活性， VPm和TRN，同时提供受控的感官刺激。第二，L6CT反馈对感觉的影响 将确定S1皮层中的信号传导（Aim 2）。在一系列靶向的光遗传学操作中， 通过一种新的实时闭环光遗传学控制， 框架，同时记录跨皮质层。第三，双向的，皮质丘脑控制的， 将评估感觉输入感知中感觉诱发活动的显著性（目标3）。小鼠将被 接受触觉任务训练，同时监测丘脑和皮层的群体单单位活动， L6CT神经元活动的光遗传学操纵。意义前馈丘脑皮层回路是 被认为在控制感知相关信息流方面发挥着动态和关键作用，但皮质丘脑 丘脑的输入是广泛的，提供了对通路信号处理的精确控制， 我们对它知之甚少。该项目的成功可以大大促进对 在所有的感觉通路的基本功能，并提供了一套规则，反馈的行为，以动态门的 信号处理对于复杂环境的导航至关重要。更广泛的影响。反馈循环播放 在一系列神经系统疾病和障碍中起着关键作用，从涉及的复杂反馈回路， 帕金森氏病，涉及某些形式的癫痫电路的兴奋性， 创伤性脑损伤中的脑结构，以及许多其他方面。因此，该项目的成功可以揭示 这是在正常和疾病状态下塑造功能的关键基本原则。

Feedback and feedforward gating of sensory signaling through timing in the thalamocortical loop Nearly all sensory experience begins in the periphery, generating sensory signals travelling through the thalamus before reaching neocortex. Despite numerous anatomical and functional investigations into the feedforward projections from thalamus to primary sensory cortex (TC), significantly less is known about the extensive reciprocal corticothalamic (CT) feedback pathway that provides ~40% of input to the thalamus. One proposed role of CT feedback is to control the salience of ascending sensory signals relative to background activity, thereby regulating the selective detectability and discriminability of sensory stimuli, but this has not been explicitly tested due to the complexity of the underlying circuit, the difficulty in disentangling loops of this nature, and the only recent availability of tools designed to specifically target key elements of the circuit. This project will utilize a range of tools to precisely measure and optogenetically manipulate elements of the TC-CT circuit in the whisker somatosensory pathway of the awake head-fixed mouse during tactile perception, to develop the set of rules by which cortical feedback gates signal processing in the thalamocortical circuit. First, the effect of L6CT feedback projections on sensory signaling in the thalamus will be determined (Aim 1). L6CT neurons will be optogenetically manipulated while recording extracellular population spiking activity in L6CT and across both VPm and TRN, while delivering controlled sensory stimuli. Second, the effect of L6CT feedback on sensory signaling in S1 cortex will be determined (Aim 2). In a range of targeted optogenetic manipulations, activity in thalamus will be forced to desired baseline firing rates via a novel real-time closed-loop optogenetic control framework, while recording across cortical laminae. Third, the bi-directional, corticothalamic control of the salience of sensory evoked activity in the perception of sensory inputs will be assessed (Aim 3). Mice will be trained in tactile tasks while monitoring population single unit activity across thalamus and cortex in the presence of optogenetic manipulation of L6CT neuron activity. Significance. The feedforward thalamocortical circuit is thought to play a dynamic and pivotal role in controlling perceptually relevant information flow, but corticothalamic input to thalamus is extensive, providing an exquisite level of control of the signal processing of the pathway that is very poorly understood. Success in this project could provide a significant advance in the understanding of basic function in all sensory pathways, and provide a set of rules by which feedback acts to dynamically gate the signal processing that is vital for navigating complex environments. Broader Impacts. Feedback loops play critical roles in a range of neurological diseases and disorders, from the complex feedback loops involved in Parkinson’s disease, to the excitability of circuits involved in certain forms of epilepsy, to the interaction between brain structures in traumatic brain injury, and many others. Success in this project could therefore shed light on a fundamental principle critical for shaping function in normal and disease states.