Chronic stress, cognition, and hippocampal plasticity

慢性压力、认知和海马可塑性

• 批准号: RGPIN-2019-04168
• 负责人: Kalynchuk, Lisa
• 金额: $ 3.42万
• 依托单位: University of Victoria
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=714672
• 关键词: Chronic; stress; cognition; hippocampal; plasticity

Stress is ubiquitous. The focus of our research is to understand how repeated exposure to stress affects the brain to alter learning, memory, and emotional behavior. Much of our work focuses on the hippocampus, because this is the brain region where new neurons are continually born (i.e., neurogenesis) and where neuronal plasticity converges to regulate stress and key aspects of learning and memory. Corticosterone (CORT) is an adrenal hormone that is released in rodents during periods of stress. CORT is essential for survival, but at high levels it can negatively impact a number of brain regions, including the hippocampus. For example, CORT is known to decrease hippocampal neurogenesis and the complexity of dendritic branches in both new and mature neurons. These effects occur in a dose- and time-dependent manner such that administration of CORT at higher doses and for longer periods of time produces increasingly greater disruptions. CORT also disrupts specific aspects of learning and memory. It can alter the acquisition and retrieval of fear memories, and it also impairs memories for the location of objects in space (spatial memory). These cognitive changes are related to deficient hippocampal neurogenesis and deficient reelin expression. Reelin is a large protein located in the spaces between cells that is crucially important for cell migration, cellular connectivity, and cellular plasticity in the adult hippocampus. CORT lowers reelin levels selectively in the area of the hippocampus where new neurons are born. We have exciting preliminary data showing that infusions of reelin directly into the hippocampus can normalize spatial memory after an extended period of CORT administration. Therefore, the primary hypothesis driving the proposed research is that exposure to stress hormones alters cognitive behavior by decreasing hippocampal reelin levels and slowing the rate of neuronal birth and maturation. Our proposed research will examine this hypothesis in several important ways. First, we will systematically map the deleterious effects of CORT on object location memory in male and female rats. Second, we will investigate the cellular characteristics of neurons that are born and mature during the course of CORT administration. Third, we will identify the conditions under which intrahippocampal reelin infusions have beneficial effects on cognition after a period of CORT administration. Fourth, we will examine the consequences of decreasing expression of reelin in the absence of stress on cognition and hippocampal plasticity. Our experiments will shed new light on the functional consequences of chronic stress and they will also provide some of the first data about the relationship between sex, hippocampal reelin, and cognition, which is currently very poorly understood.

压力无处不在。我们研究的重点是了解反复暴露于压力如何影响大脑，从而改变学习，记忆和情绪行为。我们的大部分工作都集中在海马体上，因为这是新神经元不断诞生的大脑区域（即，神经发生）和神经元可塑性收敛，以调节压力和学习和记忆的关键方面。 皮质酮（CORT）是一种肾上腺激素，在啮齿动物的压力期间释放。CORT对生存至关重要，但在高水平下，它会对许多大脑区域产生负面影响，包括海马体。例如，已知CORT降低海马神经发生和新生和成熟神经元中树突分支的复杂性。这些作用以剂量和时间依赖性方式发生，使得以更高剂量和更长时间给予CORT产生越来越大的破坏。 CORT也会扰乱学习和记忆的特定方面。它可以改变恐惧记忆的获取和检索，也会损害物体在空间中的位置记忆（空间记忆）。这些认知变化与海马神经发生缺陷和reelin表达缺陷有关。Reelin是一种位于细胞之间的大蛋白质，对于成年海马中的细胞迁移、细胞连接和细胞可塑性至关重要。CORT选择性地降低新生神经元生长的海马区的reelin水平。我们有令人兴奋的初步数据表明，在长时间的CORT给药后，将reelin直接注入海马可以使空间记忆正常化。因此，推动这项研究的主要假设是，暴露于应激激素通过降低海马回素水平和减缓神经元出生和成熟的速度来改变认知行为。 我们提出的研究将从几个重要方面来检验这一假设。首先，我们将系统地绘制CORT对雄性和雌性大鼠物体位置记忆的有害影响。其次，我们将研究CORT给药过程中出生和成熟的神经元的细胞特征。第三，我们将确定在给予CORT一段时间后海马内输注reelin对认知产生有益影响的条件。第四，我们将研究在认知和海马可塑性的压力的情况下，减少reelin的表达的后果。 我们的实验将揭示慢性应激的功能后果，他们也将提供一些关于性别，海马回线和认知之间关系的第一批数据，目前还知之甚少。