Dynamic GABAergic control of energy balance-regulating neurons in the VMH

项目摘要 能量平衡和体重控制来自协调的食欲和生理反应， 营养和激素信号告知动物的热量状态。复杂下丘脑神经网络 是组织这些反应的关键。我们以前的研究确定了脑源性的重要作用， 神经营养因子（BDNF）在中枢神经回路调节食物摄入量和体重。BDNF是一种主要的 突触传递和可塑性在成熟的大脑中的调节器，并通过兴奋性合成和释放。 神经元以活动依赖的方式。在已知的能量平衡中心中， 腹内侧下丘脑（VMH），在成年动物中起着所需的饱腹感作用。因此其 在该区域中，在进食状态和BDNF耗尽时，其表达及其受体TrkB的表达升高 导致小鼠过度进食和体重过度增加。VMH中的神经元主要是多巴胺能神经元 并在激活时介导食物摄入抑制。现在认识到，馈电电路不是硬接线的， 但高度可塑并响应于热量信号而重塑以满足动物的能量需求。这 下丘脑弓状核中的突触可塑性形式已得到很好的研究，但在VMH中还没有。 这个探索性的项目将调查GABA能传递的动态变化是否会发生在 VMH中的能量线索来调节能量平衡控制。虽然GABA能神经元大部分缺失， 在VMH中，起源于别处的抑制性GABA能纤维和GABAA受体在该区域中丰富。 我们将检验这一假设，即在进食状态下增加的阶段性（突触）GABA能抑制提供了 反馈控制VMH中的促凋亡BDNF+细胞，以防止神经元过度兴奋和延长 厌食症此外，我们将确定强直性（突触外）GABA能电流是否负调节 这些细胞处于禁食状态以恢复能量储存。总的来说，这些调查将告知如何稳态 突触和突触外GABA能传递的变化调节VMH BDNF+神经元， 能量平衡和代谢健康。

Project Summary Energy balance and body weight control result from coordinated appetitive and physiological responses to nutrient and hormonal signals informing the caloric status of the animal. Complex hypothalamic neural networks are critical in organizing these responses. Our previous studies identified an essential role for brain-derived neurotrophic factor (BDNF) in central neural circuits regulating food intake and body weight. BDNF is a major regulator of synaptic transmission and plasticity in the mature brain and is synthesized and released by excitatory neurons in an activity-dependent manner. Among known energy balance centers, it is most abundant in the ventromedial hypothalamus (VMH), where it plays a required satiety role in the adult animal. Accordingly, its expression and that of its receptor TrkB, is elevated there in the fed state and depletion of BDNF in this region results in over-eating and excessive weight gain in mice. Neurons in the VMH are predominantly glutamatergic and mediate food intake suppression when activated. It is now recognized that feeding circuits are not hardwired but highly plastic and remodel in response to caloric signals to meet the energy demands of the animal. This form of synaptic plasticity has been well studied in the arcuate nucleus of the hypothalamus but not in the VMH. This exploratory project will investigate whether dynamic changes in GABAergic transmission occur in response to energy cues in the VMH to mediate energy balance control. Although GABAergic neurons are largely absent in the VMH, inhibitory GABAergic fibers originating elsewhere and GABAA receptors are abundant in this region. We will test the hypothesis that increased phasic (synaptic) GABAergic inhibition in the fed state provides feedback control of anorexigenic BDNF+ cells in the VMH to prevent neuronal over excitation and extended anorexia. Furthermore, we will determine whether tonic (extrasynaptic) GABAergic currents negatively regulate these cells in the fasted state to restore energy stores. In total, these investigations will inform how homeostatic changes in synaptic and extrasynaptic GABAergic transmission regulate VMH BDNF+ neurons to promote energy balance and metabolic health.