Molecular and functional architecture of a premotor circuit for decision making

在理解大脑皮层细胞类型和连接模式的多样性如何 转化为电路的功能动力学，以支持认知行为。这一知识鸿沟阻碍了 我们对决策障碍和其他令人衰弱的认知异常的理解 与大多数精神疾病有关，包括成瘾、严重抑郁和饮食失调。我的龙- 学期目标是解开从基因到电路再到系统的复杂联系，并揭示其病理机制， 病理生理学和行为缺陷涉及特定回路水平的精神障碍和他们的 细胞成分。这项建议旨在确定基因组如何指示组织和功能 运动前皮质支持决策。小鼠的运动前皮质与非人类的运动前皮质相似 灵长类动物和人类，说明它们在高级认知功能中进化保守的作用。在……里面 此外，我们在小鼠身上开发了行为范例，以允许解剖潜在的神经回路 使用许多其他物种所没有的强大分子工具的复杂行为。中心假说 分子签名和连接模式共同驱动运动前皮质神经元获得 支持决策的不同职能。这一假说是在以前的工作基础上提出的 申请者提供的初步数据。提出这项研究的理由是，这项研究将 提供新的靶向脑区以及特定的细胞类型和途径，以了解和治疗 与精神疾病有关的认知缺陷。这一假设将通过追求两个具体目标来检验： 1)确定运动前皮质分子细胞类型在决策中的功能；以及2)建立 运动前皮质传入信息的功能作用。在第一个目标下，神经反应 通过体内成像和空间耦合，单个神经元将被映射到它们的分子身份 转录学。此外，分子同一性将被操纵以确定它们对 功能。其次，由特定的传入输入定义的运动前皮质神经元的分子身份和功能 将在决策过程中通过单细胞RNA测序和成像来确定。的职能作用 这些传入输入将通过特定于路径的光遗传操作来进一步表征。这种方法 是创新的，因为它结合了体内成像和空间转录，并利用移植 方法和最新的电路映射工具来揭示运动前电路在决策中的新的认知作用 制作。这项拟议的研究具有重要意义，因为它回答了长期以来关于结构的问题 大脑皮层回路的功能：不同身份的神经元如何连接和相互作用以产生网络 更高层次认知背后的动力学。最终，这样的知识有可能揭示出具体的 决策的细胞类型和大脑通路，以及更好地理解、干预和治疗 在精神疾病中普遍存在的决策障碍。

There is a fundamental gap in understanding how the diversity of cortical cell types and connectivity patterns translates into functional dynamics of the circuits to support cognitive behaviors. This knowledge gap hampers our understanding of the dysfunctions of decision making and other debilitating cognitive abnormalities associated with most psychiatric illnesses, including addiction, major depression, and eating disorders. My long- term goal is to unravel the intricate link from genes to circuits and to systems and reveal the pathology, pathophysiology, and behavioral deficits involved in mental disorders at the level of specific circuits and their cellular constituents. This proposal aims to determine how the genome instructs the organization and function of the premotor cortex to support decision making. The premotor cortex in mice resembles those of the non-human primates and humans, illustrating their evolutionarily conserved role in higher-level cognitive functions. In addition, we have developed behavior paradigms in mice to permit the dissection of neural circuits underlying complex behaviors using the powerful molecular tools unavailable in many other species. The central hypothesis is that molecular signatures and connectivity patterns collectively drive premotor cortex neurons to acquire distinct functions to support decision making. This hypothesis has been formulated based on previous work and the preliminary data produced by the applicants. The rationale for the proposed research is that this study will provide a new target brain area together with specific cell types and pathways for understanding and treating the cognitive deficits implicated in psychiatric illnesses. This hypothesis will be tested by pursuing two specific aims: 1) Determine the function of the molecular cell types of the premotor cortex in decision making; and 2) Establish the functional role of the afferent inputs of the premotor cortex. Under the first aim, the neural responses of individual neurons will be mapped to their molecular identity by coupling in vivo imaging and spatial transcriptomics. Further, the molecular identity will be manipulated to determine their causal contribution to function. Next, the molecular identity and function of premotor cortex neurons defined by specific afferent inputs will be established by single-cell RNA sequencing and imaging during decision making. The functional role of these afferent inputs will be further characterized by pathway-specific optogenetic manipulations. This approach is innovative because it combines in vivo imaging with spatial transcriptomics and utilizes transplantation methods and the latest circuit mapping tools to reveal the novel, cognitive role of the premotor circuit in decision making. This proposed research is significant because it answers the long-standing question about the structure and function of cortical circuits: How do neurons of distinct identities connect and interact to produce network dynamics underlying higher-level cognition. Ultimately, such knowledge has the potential to reveal the specific cell types and brain pathways underlying decision making and to better understand, intervene, and treat dysfunctions of decision making that are prevalent in psychiatric illnesses.