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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.

项目总结