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

促肾上腺皮质激素释放因子调节隔膜海马记忆回路的性别差异

• 批准号: 2313253
• 负责人: Debra Bangasser
• 金额: $ 100万
• 依托单位: Georgia State University Research Foundation, Inc.
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2313253&HistoricalAwards=false
• 关键词: Sex; differences; corticotropin; releasing; factor

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.

有趣的是，我们很容易想到生活压力事件如何损害认知的例子。 Bangasser 博士的实验室感兴趣的是压力会损害某些类型的记忆。之前的研究人员通过探索压力激素是否直接影响对陈述性（例如自传体）和空间记忆至关重要的区域（称为海马体）来研究这个问题。然而，海马体是记忆回路的一部分，它接收来自另一个称为内侧隔膜的区域的输入。该项目的研究将调查应激激素、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，从而扰乱记忆。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）如何促进女性对内侧隔膜中促肾上腺皮质激素释放因子引起的记忆缺陷的恢复能力。此外，还将研究由内侧隔膜中促肾上腺皮质激素释放因子引起的海马化学变化，以更好地了解压力影响记忆的回路。研究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以及患有压力失调和记忆障碍疾病的患者（例如精神分裂症和抑郁症患者）的认知能力。压力会损害海马体 (HPC) 依赖性记忆，因此许多研究人员研究压力激素如何直接影响海马体功能。然而，HPC 并不是孤立工作的，而是受到传入结构的调节，例如来自内侧隔膜 (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 依赖性空间记忆，而男性对这种效应更为敏感。 MS 中女性对 CRF 的抵抗力不是由于卵巢激素，而是与 CRF 结合蛋白 (CRF-BP) 的增加有关，从而降低了 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 如何调节 HPC。目标 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脆弱性。目标 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，看看它是否会增加她们对 MS 中低剂量 CRF 的敏感性，模仿男性效应。目标 3 将使用电流记录来确认 MS 中的 CRF 改变 HPC 中的 ACh 释放。然后恢复适当的 ACh 水平，以评估这是否可以挽救 MS 中 CRF 造成的记忆缺陷。总的来说，这些研究将确定生物性别和 CRF 如何相互作用，以驱动对压力引起的认知变化的脆弱性与弹性。该奖项反映了 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。