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：
8562357
负责人：
Nirao Mahesh Shah
金额：
$ 34.82万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8562357
关键词：
Ablation Acute Adult Affect Aggressive behavior Anxiety Apoptotic Applications Grants Area Behavior Behavioral Behavioral Assay Biological Assay Brain Cell Nucleus Cells Cholera Toxin Clinical Clozapine Cognition Designer Drugs Development Diagnostic Emotional FOS gene Feeding behaviors Female Functional disorder Genes Genetic Goals Health Hypothalamic structure Internal Ribosome Entry Site Knock-in Mouse Label Ligands Link Localized Lesion Maps Mental disorders Metabolic Modeling 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 Physiological Progesterone Receptors Prosencephalon Reagent Regulation Research Project Grants Retrieval Role Sex Characteristics Social Behavior Social Controls Structure Testing Therapeutic Tracer Virus Work anthrax lethal factor base behavior test cell type cognitive function feeding in vivo innovation insight male maternal aggression motor control nervous system disorder neural circuit novel novel diagnostics novel therapeutic intervention public health relevance pup receptor recombinase relating to nervous system research study sex social 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）：本拨款申请旨在定义腹内侧下丘脑（VMH）功能的遗传和神经回路基础。 VMH 具有分子异质性，相应地，它涉及多种行为和生理功能的调节：运动和内脏运动功能、神经内分泌功能、进食以及性别二态性社交和情感行为。一种吸引人的可能性是，这些不同的功能是由 VMH 神经元的离散子集控制的。我们和其他人在 VMH 内发现了一小群性二态性神经元。我们假设这些神经元控制性别二态性的社交和情感行为。在目标 1 中，我们将使用我们培育的新型 Cre 重组酶小鼠品系来对这些二态性 VMH 神经元的连接进行基因追踪。我们还将测试以下假设：这些二态神经元向不同区域发出的投射在不同的行为期间被激活。在目标 2 中，我们将利用一种新的 Cre 依赖性促凋亡基因来基因消融成年男性和女性中的这些二态性 VMH 神经元。随后将测试这些小鼠的二态性社交和情感行为缺陷。在目标 3 中，我们将利用由异源配体（氯氮平-N-氧化物）激活的 Cre 依赖性异源受体（DREADD）来开启男性和女性体内这些 VMH 神经元的活性。该实验将测试这些神经元的活动是否足以引发二态性社交和情绪行为。总而言之，我们的分子遗传学方法将揭示哺乳动物前脑中性二态性神经元簇的连接性和功能相关性。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、进食、运动和内脏运动功能的调节有关。 VMH 局部病变（例如肿瘤）会导致认知改变、社会行为异常和代谢变化。我们的研究将为 VMH 及其参与健康的回路的功能相关性提供新颖的机制见解。这些发现最终可能会为神经系统疾病中的 VMH 功能障碍开发出更有针对性的诊断和治疗方案。最后，我们在本提案中使用的 Cre 依赖性促凋亡基因编码试剂将有助于开发任何神经元（或其他细胞）类型的“神经变性”模型。