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: 10546498
• 负责人: Susanne Elizabeth Ahmari
• 金额: $ 42.34万
• 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/10546498
• 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; 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; comorbidity; defined contribution; in vivo; learned behavior; maladaptive behavior; motor learning; neuropsychiatric disorder; novel; optogenetics; programs; public health relevance; recruit; sequence learning; 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 尽管流畅地将单个动作链接到序列中对于执行复杂行为至关重要，但我们 对于行为序列在大脑中是如何编码的，仍有有限的理解。积累 有证据表明，纹状体的活动模式与有序行为的表现有关，但 皮质输入在它们的启动和控制中的作用还不是很清楚。因此，我们使用了SAPAP3基因敲除 (KO)小鼠实验系统，显示与中枢相关的重复梳理行为 纹状体(CS)多动，研究皮质和纹状体区域是如何相互作用产生正常的 和坚持不懈的行动模式。在我们最近的工作中，我们证明了SAPAP3-KO没有 用体外电生理学研究纹状体固有特性的异常。然而，我们观察到大量(~6 折叠)增加从主要皮质输入到该区域的对CS的外部驱动：前外侧运动区 (ALM-也称为M2)。(Corbit等人，2019年)。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，ALM是一个人类同源(SMA/PRE- SMA)与多发性抽动症(TS)和强迫症有关。我们初步的光遗传学和 光度学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 在梳理比赛结束时终止。综上所述，这些结果表明，ALM可能是一个关键因素。 公认的中枢，用于调节先天排序行为。然而，1)这个想法还没有 经过严格的测试，2)还不清楚同样的原则是否适用于习得的顺序行为。 在这里，我们将使用状态依赖的光遗传学、体外电生理学和体内纵向钙离子 成像确定ALM在正常和异常先天及后天习得性脑损伤发生中的作用 按顺序排列行为。在目标1中，我们将确定负责整容的ALM合唱团 坡道活动。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 先天的和/或后天习得的顺序行为。在目标3中，我们将定义ALM活动在 使用活体显微镜和光遗传学的学习序列的表现。这些研究的目标是 为了确定皮质-纹状体回路如何控制将单个动作组装成有组织的序列， 这最终可能导致以神经刺激为基础的持之以恒行为的新治疗目标。