Ventromedial hypothalamic expression of Bdnf is required to establish normal patterns of afferent GABAergic connectivity and responses to hypoglycemia.
Ventromedial hypothalamic expression of Bdnf is required to establish normal patterns of afferent GABAergic connectivity and responses to hypoglycemia.
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DOI：
10.1016/j.molmet.2015.11.007
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发表时间：
2016-02
影响因子：
8.1
通讯作者：
Simerly R
中科院分区：
文献类型：
--
作者：
Kamitakahara A;Xu B;Simerly R
下丘脑腹内侧核 (VMH) 通过直接连接到下丘脑、中脑和后脑的分布式核网络来控制能量和葡萄糖稳态。 VMH 回路形态的结构变化有可能改变整个生命周期的 VMH 功能，然而，负责指定其神经连接的分子信号尚未完全定义。 VMH 含有高密度的神经元，表达脑源性神经营养因子 (BDNF)，这是一种有效的神经发育效应因子，已知可调节许多神经系统中的神经元存活、生长、分化和连接。在当前的研究中，我们检查了 BDNF 是否影响 VMH 的传入和传出连接以及能量稳态功能。为了确定 VMH 回路形成是否需要 BDNF，在与其他区域建立神经连接之前，使用转基因小鼠模型有条件地从表达类固醇生成因子 1 (SF1) 的 VMH 神经元中删除 Bdnf。使用基因靶向荧光标记使表达 SF1 的神经元的投影可视化，并使用免疫荧光来测量在缺乏 BDNF 的情况下传入 SF1 神经元的密度。还评估了突变小鼠体重和循环血糖的生理变化。我们的研究结果表明，需要 BDNF 才能在位于 VMH 腹外侧部分的 SF1 神经元上建立正常的 GABA 能传入神经密度。此外，VMH SF1 神经元 BDNF 的缺失会导致对胰岛素引起的低血糖的生理反应受损。这项研究的结果表明，BDNF 是形成和/或维持 SF1 神经元抑制性输入所必需的，对血糖控制具有持久影响。 BDNF 在神经发育过程中在 VMH 中高度表达。 BDNF 的缺失会导致 SF1 神经元上的抑制性突触数量增加。 SF1 神经元的轴突生长不需要 BDNF。 SF1 神经元中缺乏 BDNF 的动物对低血糖的反应受损。
The ventromedial nucleus of the hypothalamus (VMH) controls energy and glucose homeostasis through direct connections to a distributed network of nuclei in the hypothalamus, midbrain, and hindbrain. Structural changes in VMH circuit morphology have the potential to alter VMH function throughout life, however, molecular signals responsible for specifying its neural connections are not fully defined. The VMH contains a high density of neurons that express brain-derived neurotrophic factor (BDNF), a potent neurodevelopmental effector known to regulate neuronal survival, growth, differentiation, and connectivity in a number of neural systems. In the current study, we examined whether BDNF impacts the afferent and efferent connections of the VMH, as well as energy homeostatic function. To determine if BDNF is required for VMH circuit formation, a transgenic mouse model was used to conditionally delete Bdnf from steroidogenic factor 1 (SF1) expressing neurons of the VMH prior to the onset of establishing neural connections with other regions. Projections of SF1 expressing neurons were visualized with a genetically targeted fluorescent label and immunofluorescence was used to measure the density of afferents to SF1 neurons in the absence of BDNF. Physiological changes in body weight and circulating blood glucose were also evaluated in the mutant mice. Our findings suggest that BDNF is required to establish normal densities of GABAergic afferents onto SF1 neurons located in the ventrolateral part of the VMH. Furthermore, loss of BDNF from VMH SF1 neurons results in impaired physiological responses to insulin-induced hypoglycemia. The results of this study indicate that BDNF is required for formation and/or maintenance of inhibitory inputs to SF1 neurons, with enduring effects on glycemic control. BDNF is highly expressed in the VMH during neural development. Loss of BDNF results in increased inhibitory synapse number onto SF1 neurons. BDNF is not required for axonal outgrowth from SF1 neurons. Animals lacking BDNF in SF1 neurons have impaired responses to hypoglycemia.