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.

项目总结 神经周围神经网络(PNN)是一种凝聚在神经元周围的细胞外基质。PNNS可以提供 对神经元的物理保护和离子缓冲，并调节它们的突触可塑性和细胞内信号。 最近的证据表明，PNNS与下丘脑弓状核(ARH)内的GABA神经元交织。 调节能量和葡萄糖的动态平衡。然而，人们对其潜在的代谢功能知之甚少。 也与代谢健康有关的其他大脑区域的PNNS。 我们观察到杏仁内侧后背侧核(MePD)内有丰富的PNN，并发现PNN网状分布 MePD内的神经元主要是GABA神经元。消化三叉神经核团显著降低兴奋性和突触 这些GABAMePD神经元的活动。重要的是，我们发现，慢性破坏MePD PNNS会导致 喂食小鼠的过度吞噬和适度的体重/脂肪增加。另一方面，MePD PNNS的慢性增加 导致喂食食物的小鼠体重/脂肪比降低。这些结果表明，MePD PNNS和PNNS是相互联系的 GABAMePD神经元是防止暴饮暴食和肥胖所必需的。我们将跟进这些调查结果，以确定 MePD PNNS(Aim 1)和GABAMePD(Aim 2)神经元在能量和血糖稳态中的作用。 同时，我们将描述PNNS调节兴奋性和突触活性的机制。 GABA-PD神经元。 17雌二醇(17β-estadiol，E_2)作用于雌激素受体-受体(ER-α，ER-α)，调节二者的能量和糖平衡。 雌性和雄性。以往的报道表明，ERα在许多脑区中介导了 雌二醇只在雌性小鼠体内存在，而雄性小鼠则不存在。我们的初步观察表明，E2可以增加MePD患者的PNNS 在雄性和雌性小鼠中都是如此。重要的是，杏仁内侧核内ERα的缺失(包含甲状旁腺素)导致 肥胖不仅在雌性小鼠身上，在雄性小鼠中也是如此，这表明MePD在雄性小鼠中的潜在代谢作用 新陈代谢健康。在目标3中，我们将跟进这些发现，以测试E2是否诱导PNN促进GABA 在雄性和雌性小鼠中，MePD中的神经元用于预防肥胖和代谢失调。 我们将共同揭示一种新的代谢调节机制：E2-ERα-PNNS-GABA-PD-能量/葡萄糖 动态平衡。我们的研究将促进我们对女性和男性雌激素生物学的理解 PNNS在新的脑区MePD中的代谢和代谢作用。最后，我们将确定一个唯一的 厌食性GABA群体，不同于以往报道的厌食性GABA神经群体 还有许多其他的大脑区域。