Chronic stress, cognition, and hippocampal plasticity

压力无处不在。我们研究的重点是了解反复暴露在压力下是如何影响大脑改变学习、记忆和情绪行为的。我们的大部分工作都集中在海马体上，因为这是一个不断诞生新神经元(即神经发生)的大脑区域，神经元的可塑性在这里汇聚，以调节压力以及学习和记忆的关键方面。皮质酮(Cort)是一种肾上腺激素，在应激期间在啮齿动物体内释放。皮质醇对于生存是必不可少的，但在高水平时，它会对包括海马体在内的许多大脑区域产生负面影响。例如，已知皮质醇可以减少新生和成熟神经元中的海马神经发生和树突分支的复杂性。这些效应以剂量和时间依赖的方式发生，因此在较高剂量和较长时间内给予皮质醇会产生越来越大的干扰。皮质醇还扰乱了学习和记忆的特定方面。它可以改变恐惧记忆的获得和提取，还会损害对物体在空间中位置的记忆(空间记忆)。这些认知改变与海马神经发生缺陷和reelin表达缺陷有关。Reelin是一种位于细胞间隙中的大型蛋白质，对成年海马区的细胞迁移、细胞连通性和细胞可塑性至关重要。CORT选择性地降低海马区新生神经元的卷曲蛋白水平。我们有令人兴奋的初步数据表明，在较长时间的皮质醇注射后，将reelin直接注入海马体可以恢复正常的空间记忆。因此，推动这项研究的主要假设是，暴露在应激激素下会降低海马区的卷轴蛋白水平，减缓神经元的出生和成熟速度，从而改变认知行为。我们提出的研究将从几个重要方面检验这一假说。首先，我们将系统地描绘皮质醇对雄性和雌性大鼠物体位置记忆的有害影响。其次，我们将研究在皮质醇给药过程中出生和成熟的神经元的细胞特征。第三，我们将确定在给予皮质酮一段时间后，海马区内注射reelin对认知有有益影响的条件。第四，我们将研究在没有应激的情况下，reelin表达减少对认知和海马可塑性的影响。我们的实验将为慢性应激的功能后果提供新的线索，它们还将提供一些关于性别、海马体卷曲和认知之间关系的第一批数据，目前人们对此知之甚少。

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.