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通过涉及这些稳态功能的信号和脑区域的多样性来强调。在下丘脑中，室旁核是参与代谢和自主神经功能调节的关键区域。PVH的破坏与摄食过多、体重过度增加、葡萄糖和胰岛素稳态的改变以及心血管功能有关。虽然PVH在内分泌和自主神经功能中的重要性被广泛接受，但对这种异质性神经元群介导这些作用的具体机制知之甚少。该提议旨在检验PVH神经元的离散子集在代谢调节中发挥独特作用的假设。我们重点分析位于PVH内的胰岛素受体底物-4神经元的神经回路、生理功能和转录谱。为了实现这些目标，已经产生了一种新的IRS 4-Cre驱动线。Cre依赖性神经元示踪剂和神经元调节剂将立体定位地注射到IRS 4-Cre小鼠的PVH中以映射PVHIRS 4神经元连接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.