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

有趣的是，我们很容易想到生活中的压力事件如何损害认知能力的例子。班加塞博士的实验室感兴趣的是压力损害某些类型记忆的能力。之前的研究人员通过探索应激激素是否直接影响对陈述性（如自传体）和空间记忆至关重要的区域——海马体，来研究这个问题。然而，海马体是记忆回路的一部分，它接收来自另一个叫做内侧隔的区域的输入。本项目的研究将探讨应激激素，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膜，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有弹性，该项目的目标是确定原因。实验将评估性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促进女性对中隔促肾上腺皮质激素释放因子引起的记忆缺陷的恢复能力。促肾上腺皮质激素释放因子结合蛋白降低了促肾上腺皮质激素释放因子的作用。此外，为了更好地理解压力影响记忆的回路，将研究由内侧隔膜促肾上腺皮质激素释放因子引起的海马体化学变化。这些结果可能最终用于开发化合物，以改善承受压力的健康受试者以及以压力失调和记忆障碍为特征的疾病患者（例如精神分裂症和抑郁症患者）的认知能力。应激损害海马（HPC）依赖性记忆，因此许多研究者研究应激激素如何直接影响HPC功能。然而，HPC并不是孤立地起作用，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。班加塞博士的实验室发现，给多发性硬化症患者服用应激神经肽，促肾上腺皮质激素释放因子（CRF），会损害hpc依赖的空间记忆，而且男性对这种影响更敏感。在MS中，女性对CRF的恢复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。该项目将确定这种性别差异是如何建立的，以及MS中的CRF是如何调节HPC的。Aim 1将测试睾酮是否介导男性对MS中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细胞类型并识别其中的性别差异来表征MS中CRF- bp的性别差异。接下来，研究人员将阻断女性体内的CRF- bp功能，以观察这是否会增加她们对MS中低剂量CRF的敏感性，模仿男性的效果。目的3将使用电流记录来确认质谱中的CRF改变HPC中的ACh释放。然后恢复适当的乙酰胆碱水平，以评估这是否挽救了ms中由CRF引起的记忆缺陷。总的来说，这些研究将确定生物性别和CRF如何相互作用，以驱动压力诱导的认知变化的脆弱性和复原性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识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.