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

VMH 能量平衡调节神经元的动态 GABA 控制

基本信息

批准号：
10536368
负责人：
Maribel Rios
金额：
$ 44.21万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10536368
关键词：
Animals Anorexia Behavior Body Weight Brain Brain-Derived Neurotrophic Factor CRISPR/Cas technology Cells Clinical Complex Cues Desire for food Diabetes Mellitus Disease Eating Epidemic Equilibrium Exhibits Fasting Feedback Fiber Food deprivation (experimental)Glucose Glutamates Health Heart Diseases Human Hyperglycemia Hypothalamic structure Inhibitory Synapse Insulin Resistance Investigation Mediating Metabolic Metabolic Diseases Morbid Obesity Mus Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Phase Physiological Pilot Projects Play Population Regulation Role Satiation Signal Transduction Structure of nucleus infundibularis hypothalami Synapses Synaptic Transmission Synaptic plasticity Testing United States Variant Weight maintenance regimen density energy balance excessive weight gain excitatory neuron feeding gamma-Aminobutyric Acid global health glucose disposal glycemic control hormonal signals mature animal mind control neural circuit neural network neurotransmission obesity treatment presynaptic prevent receptor release factor response transmission process

项目摘要

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.

项目概要能量平衡和体重控制是食欲和生理反应协调的结果营养和激素信号告知动物的热量状态。复杂的下丘脑神经网络对于组织这些回应至关重要。我们之前的研究确定了脑源性的重要作用神经营养因子（BDNF）在调节食物摄入和体重的中枢神经回路中。 BDNF 是一个主要成熟大脑中突触传递和可塑性的调节剂，由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，它最丰富的是下丘脑腹内侧区（VMH），在成年动物中发挥所需的饱腹感作用。据此，其在进食状态下，该区域的 BDNF 表达及其受体 TrkB 的表达升高导致小鼠暴饮暴食和体重过度增加。 VMH 中的神经元主要是谷氨酸能神经元并在激活时介导食物摄入抑制。现在人们认识到馈电电路不是硬连线的但具有高度可塑性，可以根据热量信号进行重塑，以满足动物的能量需求。这突触可塑性的形式在下丘脑的弓状核中已经得到了很好的研究，但在 VMH 中却没有。该探索性项目将调查 GABA 能传输是否会因响应而发生动态变化 VMH 中的能量线索来调节能量平衡控制。尽管 GABA 能神经元基本上不存在在VMH中，来自其他地方的抑制性GABA能纤维和GABAA受体在该区域丰富。我们将检验以下假设：进食状态下增加的阶段性（突触）GABA 能抑制可提供 VMH 中厌食 BDNF+ 细胞的反馈控制，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（突触外）GABA能电流是否负向调节这些细胞在禁食状态下恢复能量储存。总的来说，这些研究将揭示体内平衡如何突触和突触外 GABA 能传递的变化调节 VMH BDNF+ 神经元以促进能量平衡和代谢健康。