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.

在理解皮质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。这种知识差距阻碍了我们对决策功能障碍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- 术语目标是阐明从基因到电路和系统的复杂联系并揭示病理学，与特定回路及其水平的精神障碍有关的病理生理学和行为缺陷细胞成分。该提案旨在确定基因组如何指导细胞的组织和功能前运动皮层支持决策。小鼠的前运动皮质与非人类的相似灵长类动物和人类，说明了它们在高级认知功能中进化上保守的作用。在此外，我们还开发了小鼠的行为范例，以允许解剖潜在的神经回路使用许多其他物种无法使用的强大分子工具来进行复杂的行为。中心假设是分子特征和连接模式共同驱动前运动皮层神经元获得支持决策的不同功能。这个假设是根据之前的工作和申请人提供的初步数据。拟议研究的基本原理是，本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途径来理解和治疗与精神疾病有关的认知缺陷。该假设将通过追求两个具体目标来检验： 1）确定前运动皮层分子细胞类型在决策中的功能； 2) 建立前运动皮层传入输入的功能作用。在第一个目标下，神经反应通过结合体内成像和空间成像，将单个神经元映射到其分子身份转录组学。此外，将操纵分子身份来确定它们对功能。接下来，由特定传入输入定义的前运动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。的功能作用这些传入输入将通过特定路径的光遗传学操作进一步表征。这种做法具有创新性，因为它将体内成像与空间转录组学相结合并利用移植方法和最新的电路映射工具揭示前运动电路在决策中的新颖的认知作用制作。这项研究意义重大，因为它回答了有关结构的长期存在的问题皮质回路和功能：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的动力。最终，这些知识有可能揭示具体的细胞类型和大脑通路是决策的基础，可以更好地理解、干预和治疗精神疾病中普遍存在的决策功能障碍。