Synaptic regulation of affective behaviors

女性情感性精神障碍发病率高的神经生物学基础还不是很清楚。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)已被证明在情感行为中具有性别二态效应。我们建议探索BDNF基因中常见的单核苷酸多态Val66Met多态与性别之间潜在的相互作用对下缘内侧前额叶皮质突触功能的影响。BDNF Val66Met基因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，众所周知，这种多态以一种性别依赖的方式改变大脑功能。BDNFMet/Met小鼠，一种变异的BDNF Val66Met敲入小鼠，表现出焦虑样的行为和恐惧消退方面的缺陷，恐惧消退是一种抑制学习的形式，可以抑制先前习得的恐惧。BDNFMet/Met小鼠的下缘内侧前额叶皮质中的谷氨酸能神经传递也显示出性别依赖性的改变。众所周知，BDNF Val66Met可以与雌二醇相互作用，改变大脑功能。因此，我们推测Val66Met多态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BDNFMet/Met和野生型小鼠[发情前期(高雌二醇)、发情间期(低雌二醇)和去卵巢]BDNFMet/Met和野生型小鼠的IL-mPFC Layer V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还可以以性别特异性的方式影响IL-mPFC神经元的固有特性。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 Layer V锥体神经元的固有特性。通过开展这项研究，我们希望了解BDNF Val66Met基因多态性与IL-mPFC中的性别之间的相互作用，以及它在情感行为中性二型性的作用。

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.