Investigating the role of anterior lateral motor cortex in control and execution of sequenced behaviors

项目总结/摘要 虽然将单个动作平滑地链接到序列中对于执行复杂行为至关重要，但我们 对行为序列如何在大脑中编码的理解仍然有限。积累 有证据表明，纹状体的活动模式与序列行为的表现有关， 皮层输入在其启动和控制中的作用尚不清楚。因此，我们使用SAPAP 3敲除 (KO)小鼠实验系统，其显示与中枢神经系统相关的重复梳理行为。 纹状体（CS）活动过度，以研究皮质和纹状体区域如何相互作用，以产生正常的 和持续性行为模式在我们最近的工作中，我们证明了SAPAP 3-科斯不具有 使用离体电生理学的纹状体固有特性的异常。然而，我们观察到大（~6 从主要皮质输入到该区域的CS的外在驱动增加：前外侧运动区 (ALM-也称为M2）。（Corbit等人，2019）。这些结果表明，重复选择运动 程序可能是由过度驱动从ALM，一个区域，其人类同源物（SMA/前， SMA）与抽动秽语综合征（TS）和强迫症有关。我们初步的光遗传学和 测光数据通过识别在梳理期间斜升的ALM活动来支持该理论，并且 在梳理回合停止时终止。总之，这些结果表明，ALM可能是一个关键下- 公认的先天序列行为调控中心。（1）这个概念还没有 2）目前还不清楚同样的原则是否适用于习得的序列行为。 在这里，我们将使用状态依赖的光遗传学，离体电生理学和纵向体内Ca+2 成像以确定ALM在正常和异常先天性和后天性神经元生成中的作用。 有序的行为在目标1中，我们将识别负责疏导相关的ALM集合。 活动量增加在目标2中，我们将确定增加ALM-CS驱动是否会导致重复选择 先天和/或习得的序列行为。在目标3中，我们将定义ALM活动在 使用体内显微镜和光遗传学的学习序列的性能。这些研究的目的是 为了确定皮质-纹状体回路是如何控制个体动作组装成有组织的序列的， 这可能最终导致新的神经刺激为基础的治疗目标的持续行为。

PROJECT SUMMARY/ ABSTRACT Although smoothly linking individual actions into sequences is critical for execution of complex behaviors, we still have a limited understanding of how behavioral sequences are encoded in the brain. Accumulating evidence suggests that striatal activity patterns are linked to performance of sequenced behaviors, but the role of cortical inputs in their initiation and control is less clear. We therefore used the SAPAP3-knockout (KO) mouse experimental system, which displays repetitive grooming behavior associated with central striatal (CS) hyperactivity, to investigate how cortical and striatal regions interact to generate both normal and perseverative action patterns. In our recent work, we demonstrated that SAPAP3-KOs do not have abnormalities in striatal intrinsic properties using ex vivo electrophysiology. However, we observed large (~6 fold) increases in extrinsic drive to CS from the major cortical input to this region: anterolateral motor area (ALM- also known as M2). (Corbit et al, 2019). These results suggested that repeated selection of motor programs could be caused by excessive drive from ALM, an area whose human homologues (SMA/pre- SMA) have been linked to Tourette Syndrome (TS) and OCD. Our preliminary optogenetics and photometry data support this theory by identifying ALM activity that ramps up during grooming, and terminates at grooming bout cessation. Together, these results indicate that ALM may be a key under- recognized hub for the regulation of innate sequenced behaviors. However, 1) this idea has not yet been rigorously tested, and 2) it is unclear if the same principles apply to learned sequenced behaviors. Here we will use state-dependent optogenetics, ex vivo electrophysiology, and longitudinal in vivo Ca+2 imaging to determine the role of ALM in the generation of normal and abnormal innate and learned sequenced behaviors. In Aim 1, we will Identify the ALM ensemble responsible for grooming-associated ramping activity. In Aim 2, we will determine whether increasing ALM-CS drive leads to repeated selection of innate and/or learned sequenced behaviors. In Aim 3, we will define the role of ALM activity during performance of learned sequences using in vivo microscopy and optogenetics. The goal of these studies is to determine how cortico-striatal circuits control the assembly of individual actions into organized sequences, which could ultimately lead to new neurostimulation-based treatment targets for perseverative behaviors.