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

• 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
• 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

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.

项目摘要/摘要 尽管将单个动作顺利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方式仍然有限。累积 有证据表明，纹状体活动模式与测序行为的性能有关，但是 皮质输入在其启动和控制中的作用尚不清楚。因此，我们使用了SAPAP3-KNOCKOUT （KO）鼠标实验系统，该系统显示与中央相关的重复修饰行为 纹状体（CS）多动症，以研究皮质和纹状体区域如何相互作用以产生正常 和持久的行动模式。在最近的工作中，我们证明了SAPAP3-KOS没有 使用离体电生理学的纹状体内在特性异常。但是，我们观察到很大（〜6 折叠）从主要皮质输入到该区域的外部驱动器增加到CS：前外侧运动区域 （ALM-也称为M2）。 （Corbit等，2019）。这些结果表明，重复选择电动机 程序可能是由ALM过度开车引起的。 SMA）与Tourte综合征（TS）和OCD有关。我们的初步光遗传学和 光度法数据通过识别在修饰过程中增加的ALM活动来支持该理论，并且 终止于修饰戒烟。总之，这些结果表明ALM可能是低下的关键 公认的枢纽，以调节先天测序行为。但是，1）这个想法尚未 经过严格测试，2）目前尚不清楚同样的原理是否适用于学习的测序行为。 在这里，我们将使用状态依赖性的光遗传学，离体电生理学和体内纵向CA+2 成像以确定ALM在正常和异常先天的产生中的作用 测序行为。在AIM 1中，我们将确定负责与修饰相关的ALM合奏 坡道活动。在AIM 2中，我们将确定增加ALM-CS驱动器是否导致重复选择 先天和/或学到的序列行为。在AIM 3中，我们将定义ALM活动的作用 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 确定皮质 - 纹状体电路如何控制单个作用的组装到有组织的序列中， 最终可能导致新的基于神经刺激的治疗目标，以实现持久行为。