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

研究前外侧运动皮层在控制和执行顺序行为中的作用

基本信息

批准号：
10343630
负责人：
Susanne Elizabeth Ahmari
金额：
$ 42.76万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343630
关键词：
Anterior Anterolateral Area Behavior Behavioral Brain Brain region Childhood Color Complex Corpus striatum structure Data Detection Drops Electrophysiology (science)Fiber Generations Gilles de la Tourette syndrome Goals Grooming Homologous Gene Human Hyperactivity Image Individual Instinct Knock-out Knockout Mice Lateral Lead Length Link Microscopy Modeling Motor Motor Cortex Movement Neurons Obsessive-Compulsive Disorder Pattern Performance Photometry Play Preparation Prevention strategy Process Property Protocols documentation Ramp Regulation Resistance Rodent Role Slice Stereotyping Symptoms System Testing Thinking Wild Type Mouse Work autism spectrum disorder base comorbidity defined contribution in vivo learned behavior maladaptive behavior neuropsychiatric disorder novel optogenetics programs public health relevance recruit serial imaging stem theories

项目摘要

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.

项目概要/摘要尽管将单个动作顺利地连接成序列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了解仍然有限。积累中有证据表明纹状体活动模式与顺序行为的表现有关，但皮质输入在其启动和控制中的作用尚不清楚。因此，我们使用 SAPAP3 敲除（KO）小鼠实验系统，显示与中枢神经系统相关的重复梳理行为纹状体（CS）过度活跃，研究皮质和纹状体区域如何相互作用以产生正常的和持之以恒的行动模式。在我们最近的工作中，我们证明 SAPAP3-KO 不具有使用离体电生理学研究纹状体内在特性的异常。然而，我们观察到大（〜6 倍）从主要皮质输入到该区域的 CS 外在驱动力增加：前外侧运动区（ALM-也称为 M2）。（Corbit 等人，2019）。这些结果表明，重复选择电机程序可能是由 ALM 的过度驱动引起的，该区域的人类同源物（SMA/pre- SMA）与图雷特综合症（TS）和强迫症有关。我们的初步光遗传学和光度测定数据通过识别在梳理过程中增强的 ALM 活动来支持这一理论，并且在梳理停止时终止。总之，这些结果表明 ALM 可能是一个关键因素公认的调节先天序列行为的中心。然而，1）这个想法还没有经过严格测试，2）尚不清楚相同的原则是否适用于学习的序列行为。在这里，我们将使用状态依赖性光遗传学、离体电生理学和纵向体内 Ca+2 成像以确定 ALM 在正常和异常先天和后天生成中的作用有序的行为。在目标 1 中，我们将确定负责与梳理相关的 ALM 整体增加活动。在目标 2 中，我们将确定增加 ALM-CS 驱动器是否会导致重复选择先天和/或习得的顺序行为。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。这些研究的目标是确定皮质纹状体回路如何控制个体动作组装成有组织的序列，这最终可能导致针对持续行为的基于神经刺激的新治疗目标。