Synaptic regulation of affective behaviors

女性情感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（Brain-derived neurotrophic factor， BDNF）已被证明在情感行为中发挥两性二态效应。我们建议探索BDNF基因中常见的单核苷酸多态性、Val66Met多态性和性别之间潜在的相互作用对边缘下内侧前额叶皮层突触功能的影响。BDNF Val66Met多态性与认知功能障碍和包括焦虑和抑郁在内的几种神经精神疾病有关。此外，这种多态性以性别依赖的方式改变大脑功能。BDNFMet/Met小鼠是BDNF Val66Met敲入小鼠的一种变体，表现出类似焦虑的行为和恐惧消除的缺陷，这是一种抑制先前习得的恐惧的抑制性学习形式。BDNFMet/Met小鼠还显示出边缘下内侧前额叶皮层谷氨酸能神经传递的性别依赖性改变。已知BDNF Val66Met与雌二醇相互作用并改变脑功能。因此，我们假设Val66Met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（高雌二醇），发情后（低雌二醇）和去卵巢]BDNFMet/Met和野生型小鼠IL-mPFC V层锥体神经元中的谷氨酸能突触传递来验证这一假设。除了对突触功能的影响外，Val66Met还可能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Val66Met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。通过这项研究，我们希望了解IL-mPFC中BDNF Val66Met多态性与性别的相互作用及其在情感行为中性别二态性的参与。

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.