Sex differences in the entorhinal cortex

描述（由申请人提供）：女性和男性在大脑、行为和疾病方面存在许多差异。其中一个是在啮齿类动物和人类身上建立起来的：空间记忆。潜在的基础是什么？在这个项目中，我们测试了啮齿动物内侧内嗅皮层存在强大的性别差异的假设，这可以解释空间记忆的性别差异。考虑到内嗅皮层对大鼠的空间表征至关重要，它似乎是一个合乎逻辑的候选者，并且由于它位于海马体和皮层之间，因此处于理想的解剖位置。我们使用内嗅皮层切片的初步数据显示，内嗅皮层对传入输入的诱发反应存在性别差异：在雌性的切片中，相对于雄性，反应是重复的或延长的，这种性别差异被NMDA受体拮抗剂D-APV阻断。当雌激素水平高时，这些事件最强烈，当雌激素水平低时，或对青春期前的动物进行评估时，它们相对较少。我们假设雌性大鼠的内嗅神经元对传入输入的反应相对于雄性大鼠增加，这破坏了信息处理和突触可塑性，即长期增强（LTP）。由于差异似乎局限于浅层，因此投射到海马体的穿孔路径可能会受到选择性影响，这一点很重要，因为穿孔路径是从内嗅皮层到海马体的主要传入系统。本课题将在雌性和雄性大鼠的内嗅皮层切片上建立细胞生理学，测试内嗅皮层和海马LTP的性别差异，并探讨青春期和雌激素是否是关键因素。总之，这些结果将揭示大脑中性别差异相对未被探索的区域，并可能对理解认知功能以及治疗学习障碍具有重要意义。该项目将评估性别差异是否存在于先前未被认识到的大脑内嗅皮层部分，并解决其影响。我们假设女性内嗅皮层的神经元活动增加，这破坏了对新信息的处理，特别是空间信息。根据初步研究结果，雌激素似乎通过促进NMDA受体介导的内嗅神经元激活发挥关键作用。这一发现意义重大，因为它有助于解决认知功能的性别差异，并为学习障碍的治疗带来新的思路。

DESCRIPTION (provided by applicant): There are many differences between females and males in the brain, behavior, and disease. One of these is established in rodents as well as man: spatial memory. What could be the underlying basis? In this project we test the hypothesis that there are robust sex differences in the rodent medial entorhinal cortex that could explain sex differences in spatial memory. The medial entorhinal cortex seems a logical candidate given it is critical to spatial representation in the rat, and lies in an ideal anatomical position because it is situated between hippocampus and cortex. Our preliminary data, using slices of entorhinal cortex, shows a sex difference in evoked responses to afferent input in entorhinal cortex: in slices from females, responses are repetitive or prolonged relative to males, a sex difference that is blocked by the NMDA receptor antagonist D-APV. When estrogen levels are high, these events are most robust, and when estrogen is low, or a prepubertal animal is evaluated, they are relatively rare. We hypothesize that the responses of entorhinal neurons to afferent input are increased in the female rat relative to males, and this disrupts information processing and synaptic plasticity, i.e., long-term potentiation (LTP). Because the difference appears to be localized to superficial layers, the perforant path projection to hippocampus may be selectively influenced, and this is important because the perforant path is the major afferent system to hippocampus from entorhinal cortex. In this proposal, we will establish the cellular physiology in slices of entorhinal cortex of female and male rats, test sex differences in LTP in the entorhinal cortex and hippocampus, and address whether puberty and estrogen are key factors, as Preliminary data suggest. Together the results will shed light on an area of the brain where sex differences are relatively unexplored, and could have important implications for understanding cognitive function, as well as treating learning disorders. PUBLIC HEALTH RELEVANCE This project will evaluate whether sex differences exist in a part of the brain where they have not previously been recognized, the entorhinal cortex, and address their implications. We hypothesize that there is increased neuronal activity in the female medial entorhinal cortex and this disrupts processing of new information, particularly spatial information. Based on Preliminary findings, estrogen appears to play a key role by facilitating NMDA receptor mediated activation of entorhinal neurons. The implications are important because they could help address sex differences in cognitive function, and lead to new considerations for treatment of learning disorders.