Sex differences in corticotropin releasing factor regulation of the septohippocampal memory circuit

趣闻轶事很容易让人想到生活中的压力事件如何损害认知能力的例子。班加瑟博士的实验室感兴趣的是，压力会损害某些类型的记忆。以前的研究人员通过探索压力荷尔蒙是否直接影响对陈述性(例如自传性)和空间记忆至关重要的海马体区域来研究这个问题。然而，海马体是记忆回路的一部分，它接受来自另一个称为内侧隔区的区域的输入。这个项目的研究将调查一种应激激素--促肾上腺皮质激素释放因子--如何影响雄性和雌性大鼠的内侧隔，从而破坏记忆。初步数据表明，女性对促肾上腺皮质激素释放因子引起的记忆缺陷更具弹性，该项目的一个目标是确定原因。实验将评估性腺激素和促肾上腺皮质激素释放因子结合蛋白的性别差异如何提高女性对内侧隔促肾上腺皮质激素释放因子引起的记忆缺陷的韧性。促肾上腺皮质激素释放因子结合蛋白会降低促肾上腺皮质激素释放因子的疗效。此外，还将研究由内侧隔区促肾上腺皮质激素释放因子导致的海马体化学变化，以更好地了解压力影响记忆的回路。这些结果最终可能被用来开发化合物，改善承受压力的健康受试者的认知，以及以压力调节失调和助记障碍为特征的患者(例如，精神分裂症和抑郁症患者)。应激损伤海马区(HPC)依赖记忆，因此许多研究人员研究应激激素如何直接影响HPC功能。然而，HPC并不是单独工作的，而是受到传入结构的调节，例如来自内侧隔(MS)的胆碱能投射。班加瑟博士的实验室发现，给MS注射应激神经肽促肾上腺皮质激素释放因子(CRF)会损害依赖HPC的空间记忆，男性对这种影响更敏感。多发性硬化症中女性对CRF的恢复能力不是由于卵巢激素，而是与CRF结合蛋白(CRF-BP)的增加有关，这降低了CRF的生物利用度。这个项目将确定这种性别差异是如何建立的，以及MS中的CRF如何调节HPC。目的1将测试睾酮是否介导男性在MS中对CRF引起的空间记忆缺陷的易感性。Aim 2将通过首先确定表达CRF-BP的MS细胞类型并鉴定其中的性别差异来表征MS中CRF-BP的性别差异。接下来，女性的CRF-BP功能将被阻断，看看它是否会增加她们对MS中低剂量CRF的敏感性，模仿男性的效应。AIM 3将使用安培记录来确认MS中的CRF改变了HPC中的ACh释放。然后，适当的ACh水平将被恢复，以评估这是否挽救了由于CRF在MS中造成的助记缺陷。总的来说，这些研究将确定生物性和CRF如何相互作用，以驱动对压力诱导的认知变化的脆弱性和弹性。这一奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

Anecdotally it is easy to think of examples of how stressful life events can impair cognition. Of interest to Dr. Bangasser’s laboratory, is the ability of stress to impair certain types of memory. Previous researchers have studied this question by exploring whether stress hormones directly impact a region critical for declarative (e.g., autobiographical) and spatial memory, called the hippocampus. However, the hippocampus is part of a memory circuit and it receives input from another region called the medial septum. The studies in this project will investigate how a stress hormone, corticotropin releasing factor, impacts the medial septum of male and female rats to disrupt memory. Preliminary data indicate that females are more resilient to the memory deficits caused by corticotropin releasing factor and a goal of the project is to determine why. Experiments will evaluate how gonadal hormones and sex differences in corticotropin releasing factor binding protein — which reduces the efficacy of corticotropin releasing factor — promote female resilience to the memory defects caused by corticotropin releasing factor in the medial septum. Additionally, chemical changes in the hippocampus that result from corticotropin releasing factor in the medial septum will be investigated to better understand circuits by which stress can affect memory. The results may eventually be utilized to develop compounds that improve cognition in healthy subjects experiencing stress, as well as in patients with disorders characterized by stress dysregulation and mnemonic impairments (e.g., patients with schizophrenia and depression). Stress impairs hippocampus (HPC)-dependent memory, so many researchers investigate how stress hormones directly impact HPC function. Yet, the HPC does not work in isolation, but is regulated by afferent structures, such as cholinergic projections from the medial septum (MS). Dr. Bangasser’s laboratory discovered that the stress neuropeptide, corticotropin releasing factor (CRF), administered to the MS impairs HPC-dependent spatial memory, and males are more sensitive to this effect. Female resilience to CRF in the MS was not due to ovarian hormones but was associated with an increase in CRF binding protein (CRF-BP), which reduces the bioavailability of CRF. This project will determine how this sex difference is established and how CRF in the MS regulates the HPC. Aim 1 will test whether testosterone mediates male vulnerability to the spatial memory deficit caused by CRF in the MS. Aim 2 will characterize the sex difference in CRF-BP in the MS by first determining the MS cell-type that expresses CRF-BP and identifying sex differences therein. Next, CRF-BP function will be blocked in females to see if it increases their sensitivity to the low dose of CRF in the MS, mimicking the male effect. Aim 3 will use amperometric recordings to confirm that CRF in the MS alters ACh release in the HPC. Then proper ACh levels will be restored to assess if this rescues the mnemonic deficit resulting from CRF in the MS. Collectively, these studies will determine how biological sex and CRF interact to drive vulnerability vs. resilience to stress-induced cognitive changes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.