Synaptic regulation of affective behaviors

女性情感性精神障碍高患病率的神经生物学基础尚不清楚。情感行为的性别依赖性改变的一个潜在机制是与遗传风险因素的相互作用。脑源性神经营养因子（BDNF）在情感行为中具有性别差异。我们建议探讨一个共同的单核苷酸多态性的BDNF基因，Val 66 Met多态性，和性别之间的潜在相互作用的影响下边缘内侧前额叶皮层的突触功能。BDNF Val 66 Met多态性与认知功能障碍和几种神经精神疾病（包括焦虑和抑郁）有关。此外，已知这种多态性以性别依赖的方式改变大脑功能。BDNFMet/Met小鼠，一种变体BDNF Val 66 Met基因敲入小鼠，表现出焦虑样行为和恐惧消退缺陷，这是一种抑制性学习，抑制了先前学习的恐惧。BDNFMet/Met小鼠也表现出性别依赖性的修改，下边缘内侧前额叶皮层的多巴胺能神经传递。已知BDNF Val 66 Met与雌二醇相互作用并改变脑功能。因此，我们假设Val 66 Met多态性通过与雌二醇的相互作用加剧了IL-mPFC突触功能的缺陷。我们将通过分析雄性和雌性[发情前期（高雌二醇），间情期（低雌二醇）和卵巢切除] BDNF Met/Met和野生型小鼠IL-mPFC V层锥体神经元中的多巴胺能突触传递来验证这一假设。除了对突触功能的影响外，Val 66 Met还可以以性别特异性的方式影响IL-mPFC神经元的内在特性。因此，我们还将研究Val 66 Met和雌二醇之间的相互作用是否会改变IL-mPFC V层锥体神经元的内在特性。通过本研究，我们希望了解IL-mPFC中BDNF Val 66 Met多态性与性别的相互作用及其在情感行为中的性二态性。

The neurobiological basis of the high prevalence of affective disorders in women is not well understood. One potential mechanism for sex-dependent modification of affective behaviors is an interaction with genetic risk factors. Brain-derived neurotrophic factor (BDNF) has been shown to exert sexually dimorphic effect on affective behaviors. We propose to explore the effect of a potential interaction between a common single nucleotide polymorphism in the BDNF gene, the Val66Met polymorphism, and sex on synaptic function in the infralimbic medial prefrontal cortex. The BDNF Val66Met polymorphism has been implicated in cognitive dysfunctions and several neuropsychiatric disorders including anxiety and depression. Also, this polymorphism is known to modify brain functions in a sex-dependent manner. BDNFMet/Met mice, a variant BDNF Val66Met knock-in mouse, showed anxiety-like behavior and deficit in fear extinction, a form of inhibitory learning that suppresses a previously learned fear. BDNFMet/Met mice also showed a sex-dependent modification of glutamatergic neurotransmission in the infralimbic medial prefrontal cortex. The BDNF Val66Met is known to interact with estradiol and alter brain function. Therefore, we hypothesize that the Val66Met polymorphism exacerbates deficits in IL-mPFC synaptic function by its interaction with estradiol. We will test this hypothesis by analyzing glutamatergic synaptic transmission in the IL-mPFC layer V pyramidal neurons from male and female [proestrus (high-estradiol), diestrus (low-estradiol) and ovariectomized] BDNFMet/Met and wild-type mice. In addition to the effect on synaptic function, the Val66Met could affect intrinsic properties of IL-mPFC neurons in a sex-specific fashion. Therefore, we will also study whether an interaction between Val66Met and estradiol modifies intrinsic properties of the IL-mPFC layer V pyramidal neurons. By undertaking this study, we expect to understand the interaction of BDNF Val66Met polymorphism and sex in the IL-mPFC and its involvement in sexual dimorphism in affective behaviors.