ESTROGEN-INDUCIBLE PNNS ENHANCE EXCITATORY SYNAPTIC STRENGTH ONTO GABA NEURONS IN THE MEPD TO PREVENT OBESITY AND METABOLIC DYSREGULATION

雌激素诱导的 PNNS 增强 MEPD 中 GABA 神经元的兴奋性突触强度，以预防肥胖和代谢失调

• 批准号: 10712725
• 负责人: Chunmei Wang
• 金额: $ 44.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-24 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712725
• 关键词: Adult; Age; Alzheimer' s Disease; American; Amygdaloid structure; Appetite Stimulants; Biology; Bipolar Disorder; Blood Glucose; Body Weight; Brain; Brain region; Buffers; Cells; Cellular Structures; Centers for Disease Control and Prevention (U.S.); Chemical Models; Child; Chronic; Digestion; Disease; Dorsal; Electrons; Equilibrium; Estradiol; Estrogen Receptor alpha; Estrogens; Etiology; Extracellular Matrix; Fatty acid glycerol esters; Female; Genetic; Genetic Models; Glucose; Glucose Intolerance; Glycosaminoglycans; Health; High Fat Diet; Homeostasis; Hyaluronan; Hyperglycemia; Hyperinsulinism; Hyperphagia; Hypothalamic structure; In Situ; Ions; Medial; Mediating; Metabolic; Metabolic syndrome; Metabolism; Modeling; Molecular; Molecular Conformation; Mus; Neurobiology; Neuroglia; Neurons; Neurosecretory Systems; Nutritional status; Obesity; Overweight; Pattern; Play; Population; Prevalence; Regulation; Reporting; Role; Schizophrenia; Signal Transduction; Structure; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Tomogram; Visualization; Weight; Weight Gain; addiction; adult obesity; behavioral response; blood glucose regulation; combat; comorbidity; effective therapy; feeding; follow-up; gain of function; gamma-Aminobutyric Acid; genetic approach; global health; hormonal signals; improved; insulin sensitivity; loss of function; male; mouse model; neural; neural circuit; obesity prevention; pandemic disease; paracrine; prevent; sex; targeted treatment

PROJECT SUMMARY Perineuronal nets (PNNs) are condensed extracellular matrix around a subset of neurons. PNNs can provide physical protection and ion buffering for neurons and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs enmesh GABA neurons in the arcuate nucleus of the hypothalamus (ARH) to regulate energy and glucose homeostasis. However, little is known about the potential metabolic function of PNNs in other brain regions that are also implicated in metabolic health. We observed abundant PNNs in the posterodorsal medial amygdala (MePD) and found that PNN-enmeshed neurons in the MePD are mostly GABA neurons. Digestion of PNNs drastically reduces excitability and synaptic activity of these GABAMePD neurons. Importantly, we showed that chronic disruption of MePD PNNs leads to hyperphagia and modest weight/fat gain in chow-fed mice. On the other hand, chronic increases in MePD PNNs result in lower body weight/fat in chow-fed mice. These results suggest that MePD PNNs and PNNs-enmeshed GABAMePD neurons are required to prevent overeating and obesity. We will follow up these findings to establish the function of MePD PNNs (Aim 1) and GABAMePD (Aim 2) neurons in energy and glucose homeostasis. Meanwhile, we will delineate the mechanisms by which PNNs regulate excitability and synaptic activity of GABAMePD neurons. 17β-estradiol (E2) can act on estrogen receptor-α (ERα) to regulate energy and glucose balance in both females and males. Previous reports showed that ERα in many brain regions mediates the metabolic effects of E2 only in female mice, but not male mice. Our pilot observations indicate that E2 can increase PNNs in MePD in both male and female mice. Importantly, loss of ERα in the medial amygdala (containing the MePD) causes obesity not only in female mice, but also in male mice, suggesting the potential metabolic role of MePD in male metabolic health. In Aim 3, we will follow up these findings to test whether E2 induces PNNs to facilitate GABA neurons in the MePD to prevent obesity and metabolic dysregulation in both male and female mice. Together, we will reveal a new metabolic regulation mechanism: E2-ERα-PNNs-GABAMePD-energy/glucose homeostasis. Our studies will advance our understanding about the estrogen biology in both female and male metabolism and the metabolic role of PNNs in a new brain region MePD. Finally, we will identify a unique anorexigenic GABA population, which is different from previous reported orexigenic GABA neural populations in many other brain regions.

项目概要 神经周围网 (PNN) 是 PNN 神经元子集周围的浓缩细胞外基质。 对神经元的物理保护和离子缓冲，并调节其突触可塑性和细胞内信号传导。 最近的证据表明，PNN 与下丘脑弓状核 (ARH) 中的 GABA 神经元啮合 调节能量和葡萄糖稳态然而，人们对潜在的代谢功能知之甚少。 其他大脑区域的 PNN 也与代谢健康有关。 我们在后背内侧杏仁核 (MePD) 中观察到丰富的 PNN，并发现 PNN 交织 MePD 中的神经元主要是 GABA 神经元，PNN 的消化显着降低了兴奋性和突触。 重要的是，我们发现 MePD PNN 的慢性破坏会导致 GABAMePD 神经元的活性。 食物喂养的小鼠食欲亢进和适度的体重/脂肪增加另一方面，MePD PNN 的慢性增加。 导致喂食小鼠的体重/脂肪较低。这些结果表明 MePD PNN 和 PNN 相互交织。 GABAMePD 神经元是防止暴饮暴食和肥胖所必需的，我们将跟踪这些发现以确定。 MePD PNN（目标 1）和 GABAMePD（目标 2）神经元在能量和葡萄糖稳态中的功能。 同时，我们将描述 PNN 调节神经元兴奋性和突触活动的机制。 GABAMePD 神经元。 17β-雌二醇（E2）可以作用于雌激素受体-α（ERα）来调节能量和葡萄糖平衡 先前的报告表明，许多大脑区域的 ERα 介导代谢作用。 E2 仅适用于雌性小鼠，但不适用于雄性小鼠。我们的初步观察表明，E2 可以增加 MePD 中的 PNN。 重要的是，在雄性和雌性小鼠中，内侧杏仁核（含有 MePD）中 ERα 的缺失都会导致这种情况。 肥胖不仅出现在雌性小鼠中，而且出现在雄性小鼠中，这表明 MePD 在雄性小鼠中的潜在代谢作用 在目标 3 中，我们将跟踪这些发现，以测试 E2 是否诱导 PNN 促进 GABA。 MePD 中的神经元可预防雄性和雌性小鼠的肥胖和代谢失调。 我们将共同揭示一种新的代谢调节机制：E2-ERα-PNNs-GABAMePD-energy/glucose 我们的研究将增进我们对女性和男性雌激素生物学的理解。 代谢和 PNN 在新的大脑区域 MePD 中的代谢作用最后，我们将确定一个独特的区域。 厌食性 GABA 群体，与之前报道的厌食性 GABA 神经群体不同 许多其他大脑区域。