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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘