Chronic stress, cognition, and hippocampal plasticity

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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.