Molecular and functional architecture of a premotor circuit for decision making

用于决策的前运动电路的分子和功能架构

基本信息

批准号：
10651389
负责人：
Zheng Herbert Wu
金额：
$ 72.41万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651389
关键词：
Address Amygdaloid structure Anterolateral Architecture Area Atlases Behavior Behavioral Behavioral Paradigm Biological Brain Calcium Cells Censuses Characteristics Cognition Cognitive Cognitive deficits Complex Coupling Data Decision Making Disease Dissection Eating Disorders Exhibits Functional disorder Genes Genome Goals Human Image Impaired cognition Interneurons Interoception Intervention Knowledge Link Location Major Depressive Disorder Maps Mediating Mental disorders Methods Molecular Molecular Profiling Motor Motor Cortex Movement Mus Neurons Odors Parietal Lobe Parvalbumins Pathology Pathway interactions Pattern Population Dynamics Post-Traumatic Stress Disorders Prefrontal Cortex Preparation Primates Process Research Rewards Role Sampling Short-Term Memory Somatostatin Source Stimulus Structure System Taxonomy Testing Tracer Translating Transplantation Vasoactive Intestinal Peptide Work addiction brain pathway cell cortex cell type cognitive function data to knowledge endophenotype excitatory neuron expectation experimental study hippocampal pyramidal neuron in vivo in vivo imaging individual response inhibitory neuron innovation insight motor control neural neural circuit neuromechanism new technology nonhuman primate novel optogenetics response sensory stimulus single-cell RNA sequencing tool transcriptomics

项目摘要

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.

理解皮质细胞类型和连通性模式的多样性如何有根本的差距转化为电路的功能动力学，以支持认知行为。这个知识差距篮板我们对决策和其他使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，重度抑郁症和饮食失调。我的长期术语目标是揭示从基因到电路和系统的复杂联系，并揭示病理，病理生理学和在特定电路及其级别涉及精神障碍的行为缺陷及其细胞成分。该建议旨在确定基因组如何指导的组织和功能支持决策的前皮层。小鼠中的前皮质类似于非人类的皮质灵长类动物和人类，说明了它们在高级认知功能中的进化保守作用。在此外，我们在小鼠中开发了行为范例，以允许解剖神经回路在许多其他物种中使用强大的分子工具使用强大的分子工具的复杂行为。中心假设是分子特征和连通性模式集体驱动前皮层神经元获得支持决策的不同功能。该假设是根据以前的工作提出的申请人产生的初步数据。拟议研究的理由是，这项研究将提供一个新的目标大脑区域以及特定的细胞类型和理解和治疗的途径与精神病有关的认知缺陷。该假设将通过追求两个具体目标来检验： 1）确定前皮层的分子细胞类型在决策中的功能； 2）建立前皮层传入输入的功能作用。在第一个目标下，神经反应单个神经元将通过体内成像和空间耦合将其映射到其分子身份转录组学。此外，将操纵分子身份以确定其因果关系的贡献功能。接下来，由特定传入输入定义的前前皮层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。功能的作用这些传入输入将进一步以特异性的光遗传操作为特征。这种方法之所以创新，是因为它将体内成像与空间转录组学结合在一起并利用移植方法和最新的电路映射工具，以揭示前门电路在决策中的新颖，认知的作用制作。这项拟议的研究很重要，因为它回答了有关结构的长期问题皮质电路的功能：不同身份的神经元如何连接并相互作用以产生网络高级认知的动态。最终，这种知识有可能揭示特定的细胞类型和大脑通路的潜在决策和更好地理解，干预和治疗决策功能障碍在精神病中普遍存在。