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: 1929829
• 负责人: Debra Bangasser
• 金额: $ 100万
• 依托单位: Temple University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1929829&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，很容易想到生活压力事件如何损害认知的例子。 Bangasser博士实验室感兴趣的是压力损害某些类型的记忆力的能力。以前的研究人员通过探索压力恐怖是否直接影响宣言性（例如自传）和空间记忆（称为海马）的区域来研究这个问题。但是，海马是内存电路的一部分，它从另一个名为介质隔膜的区域接收输入。该项目中的研究将调查压力马，皮质激素释放因子如何影响雄性和雌性大鼠的培养基，以破坏记忆。初步数据表明，女性对皮质激素释放因子定义的记忆更具弹性，并且该项目的目标是确定原因。实验将评估皮质激素释放因子结合蛋白的性腺恐怖和性别差异（降低皮质激素释放因子的效率）如何促进女性对培养基中皮质激素释放因子引起的记忆缺陷的抗原能力。此外，将研究由培养基膜中皮质激素释放因子引起的海马的化学变化，以更好地理解压力会影响记忆的电路。结果最终可能用于开发能够改善健康受试者认知的化合物，以及以压力失调和助记符障碍（例如，精神分裂症和抑郁症患者）的特征性疾病患者。压力会损害海马（HPC）依赖性记忆，因此许多研究人员研究了应力激素如何直接影响HPC功能。但是，HPC不孤立地工作，而是受传入结构的调节，例如内侧隔膜（MS）的胆碱能项目。 Bangasser博士的实验室发现，对MS的压力神经肽，皮质激素释放因子（CRF）会损害HPC依赖性的空间记忆，而男性对这种效果更敏感。女性对CRF在MS中的适应能力不是由于卵巢恐怖剂，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。该项目将确定如何建立性别差异以及MS中的CRF如何调节HPC。 AIM 1将测试睾丸激素是否介导男性对MS中CRF引起的空间记忆防御的脆弱性。 AIM 2将通过首先确定表达CRF-BP并确定其性别差异的MS细胞类型来表征MS中CRF-BP中的性别差异。接下来，CRF-BP功能将在女性中被阻止，以查看其是否增加了其对MS中CRF低​​剂量的敏感性，从而模仿了男性效应。 AIM 3将使用安培记录来确认MS在HPC中ACH释放中的CRF。然后，将恢复适当的ACH水平，以评估这是否响应MS中CRF导致的助记符缺陷。总的来说，这些研究将决定生物学性别和CRF如何相互作用，以推动对压力引起的认知变化的脆弱性与韧性。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子和更广泛影响的评估来审查标准的评估值得支持的。

项目成果

Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes

早年逆境促进雄性大鼠对阿片类药物成瘾相关表型的恢复能力和性别特异性转录变化

• DOI: 10.1073/pnas.2020173118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Ordoñes Sanchez, Evelyn;Bavley, Charlotte C.;Deutschmann, Andre U.;Carpenter, Rachel;Peterson, Drew R.;Karbalaei, Reza;Flowers, II, James;Rogers, Charleanne M.;Langrehr, Miranda G.;Ardekani, Cory S.
• 通讯作者: Ardekani, Cory S.

Corticotropin releasing factor in the nucleus basalis of Meynert impairs attentional performance and reduces levels of glutamate and taurine in male and female rats

• DOI: 10.1016/j.neuropharm.2022.109280
• 发表时间: 2022-10-12
• 期刊: NEUROPHARMACOLOGY
• 影响因子: 4.7
• 作者: Eck, Samantha R.;Kokras, Nikolaos;Bangasser, Debra A.
• 通讯作者: Bangasser, Debra A.

Stress Regulation of Sustained Attention and the Cholinergic Attention System

• DOI: 10.1016/j.biopsych.2020.04.013
• 发表时间: 2020-10-01
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Eck, Samantha R.;Xu, Song-Jun;Bangasser, Debra A.
• 通讯作者: Bangasser, Debra A.

Effects of early life adversity on male reproductive behavior and the medial preoptic area transcriptome

• DOI: 10.1038/s41386-022-01282-9
• 发表时间: 2022-01-31
• 期刊: NEUROPSYCHOPHARMACOLOGY
• 影响因子: 7.6
• 作者: Eck, Samantha R.;Palmer, Jamie L.;Bangasser, Debra A.
• 通讯作者: Bangasser, Debra A.

Sex differences in anxiety and depression: circuits and mechanisms

• DOI: 10.1038/s41583-021-00513-0
• 发表时间: 2021-09-20
• 期刊: NATURE REVIEWS NEUROSCIENCE
• 影响因子: 34.7
• 作者: Bangasser, Debra A.;Cuarenta, Amelia
• 通讯作者: Cuarenta, Amelia