Sex differences in the entorhinal cortex

描述(申请人提供)：女性和男性在大脑、行为和疾病方面有许多不同之处。其中之一是在啮齿动物和人类身上建立的：空间记忆。潜在的基础可能是什么？在这个项目中，我们测试了啮齿动物内侧嗅觉皮质中存在强大的性别差异的假设，这可以解释空间记忆中的性别差异。内侧嗅觉皮质似乎是一个合乎逻辑的候选者，因为它对大鼠的空间表征至关重要，并且位于理想的解剖位置，因为它位于海马体和皮质之间。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：在女性的切片中，反应相对于男性是重复的或延长的，这种性别差异被NMDA受体拮抗剂D-APV阻断。当雌激素水平较高时，这些事件最强烈，而当雌激素水平较低时，或对青春期前动物进行评估时，它们相对较少。我们假设雌性大鼠内嗅神经元对传入输入的反应比雄性大鼠增加，这扰乱了信息处理和突触可塑性，即长时程增强(LTP)。由于这种差异似乎局限于浅层，向海马体的穿支路径可能受到选择性的影响，这一点很重要，因为穿支路径是从内嗅觉皮质到海马体的主要传入系统。在这个方案中，我们将建立雌性和雄性大鼠内嗅皮层切片的细胞生理学，测试内嗅皮层和海马区LTP的性别差异，并解决青春期和雌激素是否为关键因素，正如初步数据所显示的那样。总而言之，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。公共卫生相关性这个项目将评估性别差异是否存在于大脑的一个以前没有被认识到的部分，即内嗅皮层，并解决它们的影响。我们假设女性内侧嗅觉皮质的神经元活动增加，这扰乱了新信息的处理，特别是空间信息。根据初步发现，雌激素似乎通过促进NMDA受体介导的内嗅神经元激活而发挥关键作用。这项研究意义重大，因为它们可以帮助解决认知功能的性别差异，并为学习障碍的治疗带来新的考虑。

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.