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的例子。班加瑟博士的实验室感兴趣的是，压力能够损害某些类型的记忆。以前的研究人员通过探索压力激素是否直接影响陈述性的关键区域（例如，自传体）和空间记忆，称为海马体。然而，海马体是记忆回路的一部分，它接收来自另一个称为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，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，该项目的目标是确定原因。实验将评估如何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-降低促肾上腺皮质激素释放因子的功效-促进女性对内侧隔中促肾上腺皮质激素释放因子引起的记忆缺陷的恢复力。此外，海马中的化学变化，导致在内侧隔促肾上腺皮质激素释放因子将进行调查，以更好地了解电路的压力可以影响记忆。这些结果最终可用于开发改善经历压力的健康受试者以及患有以压力失调和记忆障碍为特征的疾病（例如，精神分裂症和抑郁症患者）。压力会损害海马体（HPC）依赖的记忆，因此许多研究人员研究压力激素如何直接影响HPC功能。然而，HPC并不孤立地工作，而是由传入结构调节，例如来自内侧隔（MS）的胆碱能投射。Bangasser博士的实验室发现，给予MS的应激神经肽，促肾上腺皮质激素释放因子（CRF）会损害HPC依赖的空间记忆，男性对这种效应更敏感。女性在MS中对CRF的弹性不是由于卵巢激素，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。本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对MS中由CRF引起的空间记忆缺陷的脆弱性。目的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，将在女性中阻断CRF-BP功能，以观察其是否增加MS中对低剂量CRF的敏感性，模仿男性效应。目的3将使用安培记录来证实MS中的CRF改变HPC中的ACh释放。然后将恢复适当的ACh水平，以评估这是否可以挽救多发性硬化症中由慢性肾功能衰竭引起的记忆缺陷。总的来说，这些研究将确定生物性别和慢性肾功能衰竭如何相互作用，以推动对压力引起的认知变化的脆弱性与恢复力。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.