Dissecting hypothalamic pathways that regulate sexually dimorphic behaviors

剖析调节性二态性行为的下丘脑通路

基本信息

批准号：
9351259
负责人：
Nirao Mahesh Shah
金额：
$ 35.41万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9351259
关键词：
Ablation Acute Adult Affect Aggressive behavior Anxiety Apoptotic Applications Grants Area Behavior Behavior Control Behavioral Behavioral Assay Biological Assay Brain Cell Nucleus Cells Cholera Toxin Clinical Clozapine Cognition Development Diagnostic FOS gene Female Functional disorder Genes Genetic Genetic study Goals Health Hypothalamic structure Internal Ribosome Entry Site Knock-in Mouse Label Ligands Link Localized Lesion Maps Mental disorders Metabolic Modeling Molecular Molecular Genetics Motor Mouse Strains Mus Nerve Degeneration Neurodegenerative Disorders Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neuroglia Neurons Neurosecretory Systems Oxides Partner in relationship Pathway interactions Pharmacology Study Physiological Progesterone Receptors Prosencephalon Reagent Regulation Research Project Grants Retrieval Role Sex Characteristics Social Behavior Social Controls Structure Territoriality Testing Therapeutic Tracer Viral Virus Work anthrax lethal factor behavior test cell type cognitive function designer receptors exclusively activated by designer drugs emotional behavior experimental study feeding genetic approach in vivo innovation insight male maternal aggression motor control mouse Cre recombinase nervous system disorder neural circuit novel novel diagnostics novel therapeutic intervention progesterone receptor A public health relevance pup receptor relating to nervous system sex tumor

项目摘要

DESCRIPTION (provided by applicant): This grant application seeks to define the genetic and neural circuit basis of the functional role of the ventromedial hypothalamus (VMH). The VMH is molecularly heterogeneous and correspondingly, it has been implicated in the regulation of diverse behaviors and physiological function: motor and visceromotor functions, neuroendocrine function, feeding, and sexually dimorphic social and emotional behaviors. One appealing possibility is that these diverse functions are controlled by discrete subsets of VMH neurons. We and others have identified a small cluster of sexually dimorphic neurons within the VMH. We hypothesize that these neurons control sexually dimorphic social and emotional behaviors. In Aim 1, we will use a novel Cre recombinase mouse strain we have generated to genetically trace the connections of these dimorphic VMH neurons. We will also test the hypothesis that projections to different areas emanating from these dimorphic neurons are activated during distinct behaviors. In Aim 2, we will utilize a novel Cre-dependent, pro-apoptotic gene to genetically ablate these dimorphic VMH neurons in adult males and females. These mice will subsequently be tested for deficits in dimorphic social and emotional behaviors. In Aim 3, we will utilize a Cre- dependent heterologous receptor (DREADD) activated by a heterologous ligand (clozapine-N-oxide) to switch on activity in these VMH neurons in vivo in males and females. This experiment will test whether activity in these neurons is sufficient to elicit dimorphic socia and emotional behavior. Taken together, our molecular genetic approaches will uncover the connectivity and functional relevance of a sexually dimorphic neuronal cluster in the mammalian forebrain. Health Relatedness: The devastating clinical manifestations of common neurodegenerative conditions and psychiatric conditions often reflect dysfunction of specific neural circuits. The VMH has been implicated in the regulation of social and emotional behaviors, neuroendocrine function, feeding, and motor and visceromotor function. VMH-localized lesions such as tumors result in altered cognition, abnormal social behaviors, and metabolic changes. Our studies will provide novel mechanistic insight into the functional relevance of the VMH and the circuits in which it participates in health. These findings may ultimately allow development of more rationally-targeted diagnostic and therapeutic options for VMH dysfunction in neurological disorders. Finally, the Cre-dependent, pro-apoptotic genetically encoded reagent that we use in this proposal will be useful in developing models of "neurodegeneration" in any neuronal (or other cell) type.

描述（由申请人提供）：本赠款申请旨在定义腹侧下丘脑（VMH）功能作用的遗传和神经回路基础。 VMH是分子异质的，相应地，它与各种行为和生理功能的调节有关：运动和内脏运动功能，神经内分泌功能，喂养以及性二态性的社交和情感行为。一种有吸引力的可能性是这些多样化的功能受VMH神经元的离散子集控制。我们和其他人在VMH中确定了一小部分性二态神经元。我们假设这些神经元控制了性二态社会和情感行为。在AIM 1中，我们将使用一种新型的CRE重组酶小鼠菌株，从而从遗传上追踪这些双态VMH神经元的连接。我们还将检验以下假设：在不同的行为中，对这些二态神经元发出的不同区域的投影被激活。在AIM 2中，我们将利用一种新型的CRE依赖性，促凋亡基因在遗传上消除成年男性和女性的这些双态VMH神经元。随后，这些小鼠将在二态社会和情感行为中测试缺陷。在AIM 3中，我们将利用由异源配体（氯氮平-N-氧化物）激活的依赖性异源受体（Dreadd）在男性和女性中的这些VMH神经元中开启活性。该实验将测试这些神经元中的活动是否足以引起双态社会和情感行为。综上所述，我们的分子遗传方法将揭示哺乳动物前脑中性二态神经元簇的连通性和功能相关性。健康相关性：常见神经退行性疾病和精神疾病的破坏性临床表现通常反映了特定神经回路的功能障碍。 VMH与社会和情绪行为，神经内分泌功能，喂养以及运动和内脏运动功能有关。 VMH定位的病变（例如肿瘤）会导致认知，社会行为异常和代谢变化改变。我们的研究将为VMH的功能相关性及其参与健康的电路提供新的机械洞察力。这些发现最终可能允许为神经系统疾病中VMH功能障碍而开发更理性的诊断和治疗选择。最后，我们在该提案中使用的CRE依赖性，促凋亡的遗传编码试剂将有助于在任何神经元（或其他细胞）类型中开发“神经变性”模型。