The Role of BDNF in VMH astrocytes influencing energy and glucose homeostasis

 描述(由申请人提供)：肥胖是2型糖尿病、心血管疾病和其他疾病发展的危险因素。我们之前的研究发现，脑源性神经营养因子(BDNF)在控制食物摄入量和体重的中枢神经回路中扮演着一个新的关键角色。与此一致的是，具有全局中枢(BDNF2L/2LCk-cre)或成人下丘脑腹内侧部(VMH)选择性BDNF缺失的小鼠表现出过度摄食、肥胖和代谢障碍。脑源性神经营养因子功能的减弱也与人类的吞噬行为和严重肥胖有关。这些发现具有重要的临床意义，因为干扰BDNF信号的BdnfVal66Met变体在美国人中非常普遍。在这里，我们建议研究BDNF是否调节星形胶质细胞的结构可塑性和功能，以增加VMH中厌食神经元的兴奋驱动，VMH是一个饱足中心。在已知的能量平衡中心中，脑源性神经营养因子在VMH中含量最丰富，在那里它扮演着必需的饱腹感角色。支持的证据包括：1)能量状态对VMH中BDNF及其受体TrkB表达的强烈影响；2)选择性删除成年小鼠VMH中BDNF引起的过度吞噬和肥胖；3)BDNF2L/2LCk-cre小鼠VMH中兴奋性突触密度降低，兴奋性突触后电流频率降低。BDNF影响VMH神经元兴奋性的细胞和分子机制仍未完全阐明。脑源性神经营养因子是神经元可塑性的动态调节因子，可改变星形胶质细胞的形态并介导钙信号转导。这些都是重要的影响，因为胶质细胞形态的变化与突触接触重塑有关。此外，突触周围星形胶质细胞对谷氨酸的清除在维持谷氨酸稳态和形成突触电流方面也很重要。脑源性神经营养因子对星形胶质细胞的这些影响已经在几个大脑区域被发现，但在喂养回路中却没有。事实上，星形胶质细胞-神经元相互作用在下丘脑喂养回路和能量平衡调节中的作用仍然是一个巨大的研究领域。这是值得研究的，因为下丘脑回路突触连接的动态变化，包括涉及VMH的回路，被认为有助于食欲控制。作为了解VMH中的星形胶质细胞如何影响馈入回路的第一步，我们建议检查能量状态和BDNF对该细胞群体的影响。研究包括利用前沿的解剖学、电生理学和分子学方法检测能量状态和BDNF对VMH星形胶质细胞结构可塑性、谷氨酸摄取动力学和翻译mRNAs的动态变化的影响。计划中的研究将阐明涉及VMH中神经胶质细胞通讯的新机制，这些机制调节喂养回路和饱腹感的活动，从而确定治疗肥胖症的新靶点。

 DESCRIPTION (provided by applicant): Obesity is a risk factor for the development of type 2 diabetes, cardiovascular disease and other afflictions. Our previous studies identified a novel and critical role for brain-derived neurotrophic factor (BDNF) in central neural circuits controllig food intake and body weight. In agreement, mice with global central (BDNF2L/2LCk-cre) or selective BDNF depletion in the adult ventromedial hypothalamus (VMH) exhibit excessive feeding, obesity and metabolic disturbances. Diminished BDNF function has also been associated with hyperphagic behavior and severe obesity in humans. These findings have significant clinical implications as the BdnfVal66Met variant, which interferes with BDNF signaling, is highly prevalent among Americans. Here, we propose investigating whether BDNF regulates astrocyte structural plasticity and function to increase the excitatory drive of anorexigenic neurons in the VMH, a satiety center. Among known energy balance centers, BDNF is most abundant in the VMH, where it plays a required satiety role. Supportive evidence includes: i) robust effects of energy status on expression of BDNF and its receptor, TrkB, in the VMH, ii) the hyperphagia and obesity elicited by selectively deleting Bdnf in the VMH of adult mice iii) reduced density of excitatory synapses and decreased frequency of excitatory post synaptic currents in the VMH inBDNF2L/2LCk-cre mice. The cellular and molecular mechanisms underlying the effects of BDNF on neuronal excitability in the VMH remain to be fully elucidated. BDNF is a dynamic regulator of neuronal plasticity and alters morphology and mediates calcium signaling in astrocytes. These are significant effects as changes in glial morphology are associated with synaptic contact remodeling. Moreover, glutamate clearance by perisynaptic astrocytes is important in maintaining glutamate homeostasis and shaping synaptic currents. These effects of BDNF on astrocytes have been identified in several brain regions, but not in feeding circuits. Indeed, the role of astrocyte-neuron interactions in hypothalamic feeding circuits and the regulation of energy balance remains a vastly under studied research area. It warrants examination as dynamic changes in synaptic connectivity of hypothalamic circuits, including those involving the VMH, are thought to contribute to appetite control. As a first step t understand how astrocytes in the VMH influence feeding circuits, we propose examining the effect of energy status and BDNF on this cell population. Studies comprise examination of effects of energy status and BDNF on structural plasticity, glutamate uptake kinetics and dynamic changes in translating mRNAs in VMH astrocytes using cutting edge anatomical, electrophysiological and molecular approaches. The planned studies will elucidate novel mechanisms involving glial-neuron communication in the VMH that regulate activity of feeding circuits and satiety and thereby identify new targets for therapeutic strategies to treat obesity.