Dissecting hypothalamic pathways that regulate sexually dimorphic behaviors

描述（由申请人提供）：本资助申请旨在定义下丘脑腹内侧（VMH）功能作用的遗传和神经回路基础。VMH具有分子异质性，与多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、摄食和两性二态的社会和情感行为。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。我们和其他研究人员已经确定了VMH内的一小簇两性二态神经元。我们假设这些神经元控制着两性二态的社会和情感行为。在Aim 1中，我们将使用我们产生的一种新的Cre重组酶小鼠菌株来遗传追踪这些二态VMH神经元的连接。我们还将验证这样一个假设，即在不同的行为中，这些二形神经元向不同区域发出的投射被激活。在目的2中，我们将利用一种新的cre依赖的促凋亡基因，从基因上切除成年雄性和雌性的这些二态VMH神经元。随后将对这些小鼠进行二态社会和情感行为缺陷测试。在Aim 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）来激活雄性和雌性VMH神经元的活性。这个实验将测试这些神经元的活动是否足以引发二态社会和情感行为。综上所述，我们的分子遗传学方法将揭示哺乳动物前脑中两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往往反映特定神经回路的功能障碍。下丘脑下丘脑与社会和情感行为、神经内分泌功能、摄食、运动和内脏运动功能的调节有关。vmh局部病变如肿瘤导致认知改变、社会行为异常和代谢变化。我们的研究将为下颌下颌血管瘤的功能相关性及其参与健康的回路提供新的机制见解。这些发现可能最终允许对神经系统疾病的VMH功能障碍进行更合理的诊断和治疗选择。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。

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.