Unique Roles for Defined PVH Neurons in the Control of Energy Balance

 描述(由申请人提供)：中枢神经系统调节能量平衡和代谢稳态的复杂性被与这些稳态功能有关的各种信号和大脑区域所强调。在下丘脑中，室旁核被认为是参与新陈代谢和自主神经功能调节的关键区域。PVH的破坏与吞噬功能亢进、体重过度增加、血糖和胰岛素稳态改变以及心血管功能有关。尽管PVH在内分泌和自主神经功能中的重要性已被广泛接受，但对于这种异质神经元介导这些作用的具体机制还知之甚少。这一建议旨在检验PVH神经元的离散亚群在代谢调节中发挥独特作用的假设。我们重点分析了位于下丘脑室旁核内的胰岛素受体底物-4神经元的神经回路、生理功能和转录图谱。为了实现这些目标，产生了一种新颖的Irs4-CRE驱动器线。CRE依赖的神经元示踪剂和神经元调节剂将被立体定向注射到Irs4-CRE小鼠的PVH中，以绘制PVHIRS4神经元的联系图，并直接测试这些神经元在能量平衡和代谢控制中的作用。阐明PVH调节新陈代谢和内分泌功能的解剖和细胞机制将为肥胖和糖尿病的治疗提供新的见解和潜在的靶点。

 DESCRIPTION (provided by applicant): The complexity of central nervous system regulation of energy balance and metabolic homeostasis is underscored by the variety of the signals and brain areas that have been implicated in these homeostatic functions. Within the hypothalamus, the paraventricular nucleus is known to be a critical region involved in the regulation of metabolism and autonomic function. Destruction of the PVH has been associated with hyperphagia, excessive weight gain, alterations in glucose and insulin homeostasis, and cardiovascular function. Although the importance of the PVH in endocrine and autonomic function is widely accepted, relatively little is known about the specific mechanisms through which this heterogeneous group of neurons mediates these effects. This proposal aims to test the hypothesis that discrete subsets of PVH neurons play unique roles in metabolic regulation. We focus on analyzing the neural circuitry, physiologic function and transcriptional profile of insulin receptor substrate-4 neurons located within the PVH. To achieve these goals, a novel IRS4-Cre driver line has been generated. Cre-dependent neuronal tracers and neuron modulators will be injected stereotaxically into the PVH of IRS4-Cre mice to map PVHIRS4 neuronal connections and directly test the role of these neurons in energy balance and metabolic control. Elucidation of the anatomic and cellular mechanisms through which the PVH regulates metabolism and endocrine function will yield new insights and potential targets for the treatment of obesity and diabetes.