Dissecting hypothalamic pathways that regulate sexually dimorphic behaviors

剖析调节性二态性行为的下丘脑通路

• 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
• 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

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.

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.