Functional dissection of a molecularly identified female-specific neural pathway in mice

分子鉴定的小鼠雌性特异性神经通路的功能解剖

• 批准号: 10503353
• 负责人: Nirao Mahesh Shah
• 金额: $ 44万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503353
• 关键词: Address; Aggressive behavior; Anxiety; Behavior; Behavior Control; Behavioral; Biological; Brain; Case Study; Cell Nucleus; Clinical; Communication; Complex; Courtship; Development; Diagnosis; Disease; Dissection; Estrogen Receptor alpha; Estrogen Receptors; Female; Fiber; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Expression Profile; Genetic Transcription; Goals; Halorhodopsins; Health; Heterogeneity; Hypothalamic structure; Image; Individual; Intervention; Knowledge; Language; Lesion; Light; Link; Major Depressive Disorder; Maps; Maternal Behavior; Mental disorders; Modernization; Molecular; Mouse Strains; Mus; Nerve Degeneration; Neural Pathways; Neurodegenerative Disorders; Neurologic; Neurons; Neurosciences; Neurosecretory Systems; Output; Partner in relationship; Pathway interactions; Performance; Phenotype; Population; Progesterone Receptors; Reporter; Research; Role; Sampling; Satiation; Sex Bias; Sex Differences; Signal Transduction; Social Behavior; Social Controls; Social Interaction; Specific qualifier value; Specificity; Symptoms; Testing; Tracer; Viral; Well in self; Work; base; behavior test; cell type; deep sequencing; emotional behavior; genetic approach; insight; interest; mating behavior; neural circuit; novel; optogenetics; reduce symptoms; reproductive success; sex; sexual dimorphism; single-cell RNA sequencing; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT A central goal of modern neuroscience is to link genetically defined neural circuits with specific behaviors. Deep sequencing studies have revealed an incredible transcriptional heterogeneity of neuronal subtypes within populations previously thought to be homogeneous. Despite the discovery of such molecular heterogeneity, the functional and behavioral relevance of these recently genetically defined neuronal cell types is largely unknown. Our application addresses this gap in knowledge by focusing on the neuronal control of social behaviors. Social interactions, ranging from non-vocal communication to complex language to core behaviors such as courtship or aggression, are important for mental well-being and reproductive success. The neural circuits underpinning these diverse behaviors have been difficult to disentangle, with non-genetically targeted approaches yielding phenotypes in multiple behavioral domains. Here we propose to characterize how progesterone and estrogen receptor alpha expressing neurons (Pvl neurons) in the ventromedial hypothalamus ventrolateralis (VMHvl) regulate social behaviors. Our deep sequencing studies reveal distinct neuronal cell types within the population of Pvl neurons, with one of them restricted exclusively to females. Using newly developed Cre and Flpo mouse strains that mark this female-restricted neuronal cell type within Pvl neurons, we will determine its activity (Specific Aim 1), behavioral function (Specific Aim 2), and functional connectivity (Specific Aim 3) as these relate to female social behaviors. Together, our studies will uncover the activity dynamics, function, and connectivity of a genetically defined neuronal cell type of Pvl neurons; in parallel, we will also characterize the complementary set of remaining Pvl neurons and test their participation ins social behaviors. Thus, our research aims to understand how genetically defined cellular heterogeneity within a neuronal population relates to functional specificity in the control of social behaviors, a critical issue in neuroscience. Health Relatedness: Diverse neurodegenerative conditions and mental illnesses manifest with devastating clinical symptoms as well as a range of deficits in social and emotional behaviors. Pvl neurons within the VMHvl represent a critical hub that regulates diverse core, developmentally programmed social behaviors that differ between the sexes. Rare case reports of lesions in proximity to this region show dramatic alterations in social behaviors. Our studies therefore will provide new insights into fundamental questions in neuroscience, and they also have the potential to shed light on how dysfunction in pathways emanating from the VMHvl alters social behavior in disease states.

项目概要/摘要 现代神经科学的一个中心目标是将基因定义的神经回路与特定行为联系起来。深的 测序研究揭示了群体内神经元亚型令人难以置信的转录异质性 以前认为是同质的。尽管发现了这种分子异质性，但功能和 这些最近基因定义的神经元细胞类型的行为相关性在很大程度上是未知的。我们的应用 通过关注社会行为的神经元控制来解决这一知识差距。社交互动，范围从 从非语音交流到复杂的语言，再到求爱或攻击等核心行为，对于 心理健康和生殖成功。支撑这些不同行为的神经回路一直很困难 通过非基因靶向方法来解开在多个行为领域产生表型的问题。在这里我们 建议描述孕激素和雌激素受体α表达神经元（Pvl神经元）在 下丘脑腹外侧肌 (VMHvl) 调节社会行为。我们的深度测序研究表明 Pvl 神经元群体中有不同的神经元细胞类型，其中一种仅限于雌性。使用 新开发的 Cre 和 Flpo 小鼠品系在 Pvl 神经元内标记了这种雌性限制性神经元细胞类型，我们 将确定其活动（具体目标 1）、行为功能（具体目标 2）和功能连接（具体目标 3）因为这些与女性社会行为有关。我们的研究将共同​​揭示活动动态、功能和 Pvl 神经元的基因定义的神经元细胞类型的连接性；与此同时，我们还将描述 剩余 Pvl 神经元的互补组并测试它们对社会行为的参与。因此，我们的研究旨在 了解神经元群体内遗传定义的细胞异质性如何与功能特异性相关 社会行为的控制是神经科学的一个关键问题。 健康相关性：多种神经退行性疾病和精神疾病具有毁灭性的临床表现 症状以及一系列社交和情感行为缺陷。 VMHvl 内的 Pvl 神经元代表 调节不同性别之间不同的核心、发展规划的社会行为的关键枢纽。稀有的 该区域附近病变的病例报告显示社会行为发生了巨大变化。因此我们的研究将 为神经科学的基本问题提供了新的见解，并且它们还有可能揭示如何 VMHvl 通路的功能障碍会改变疾病状态下的社会行为。