Dissecting hypothalamic pathways that regulate sexually dimorphic behaviors

描述(由申请人提供)：这项资助申请旨在确定下丘脑腹内侧核(VMH)功能作用的遗传和神经回路基础。VMH在分子上是异质性的，相应地，它参与了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，摄食，以及性二态的社会和情感行为。一个吸引人的可能性是，这些不同的功能是由VMH神经元的离散子集控制的。我们和其他人已经在VMH内发现了一小群性二态神经元。我们假设这些神经元控制性二态的社会和情感行为。在目标1中，我们将使用我们培育的一种新的Cre重组酶小鼠品系来从基因上追踪这些二态VMH神经元之间的联系。我们还将测试这一假设，即从这些二态神经元发出的不同区域的投射在不同的行为过程中被激活。在目标2中，我们将利用一种新的Cre依赖的促凋亡基因来从基因上去除成年男性和女性的这些二态VMH神经元。随后，这些小鼠将接受二态社会和情感行为缺陷的测试。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依赖的异源受体(DREADD)来激活体内这些雄性和雌性VMH神经元的活动。这项实验将测试这些神经元的活动是否足以引发二态社交和情绪行为。综上所述，我们的分子遗传学方法将揭示哺乳动物前脑中性别二态神经元簇的连通性和功能相关性。与健康相关：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特定神经回路的功能障碍。VMH参与调节社会和情绪行为、神经内分泌功能、摄食、运动和内脏运动功能。VMH局部损害，如肿瘤，会导致认知改变、社会行为异常和代谢改变。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的机械论见解。这些发现可能最终允许开发更合理的针对性诊断和治疗方案，以治疗神经系统疾病中的VMH功能障碍。最后，我们在这项建议中使用的依赖Cre的、促凋亡的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“神经退行性变”模型。

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.