The hippocampus has been implicated in the biology of stress as both a stress sensor and a regulator of the stress response. It exhibits the brain's highest concentration of glucocorticoid and mineralocorticoid receptors, as well as extensive structural and physiological plasticity in response to chronic stress exposure7. The hippocampus is also involved in encoding context, learning and memory, and has been repeatedly implicated in performance on depression and anxiety-related tasks in rodents and humans. Hence, it is no surprise that hippocampal pathology has been attributed to a wide range of psychiatric diseases like Schizophrenia, depression, anxiety, and Alzheimer's disease. Within the hippocampus, a postnatal neural stem cell system is exquisitely sensitive to environmental changes including stressful and enriching experiences. Exposure to chronic stress decreases neurogenesis and increases the proliferation of stem cells, while exposure to environmental enrichment, exercise, and antidepressants increases neurogenesis without impacting stem cells. While hippocampal neurogenesis is highly sensitive to environmental manipulations, the resulting neurons are thought to contribute to all of the hippocampal functions described above including stress regulation. Thus, neurons that support diverse functions are born continuously throughout postnatal development and this process of neurogenesis is sensitive to stress and to other environmental changes. We are interested in unraveling the cellular logic supporting the functional repertoire of the hippocampal dentate gyrus. Studies outlined in this proposal aim to identify cells within the dentate gyrus of the hippocampus that are important for each of the hippocampal functions. We will use a series of state of the art genetic approaches for targeting discrete populations of dentate gyrus neurons as they would be by stress during development and then examine how each population of cells contributes to normal hippocampal functioning and circuitry. Completing the proposed studies will help decipher which hippocampal neurons contribute to encoding stress responses and determine whether the same or different cells support other hippocampal functions.

Public Health Relevance

Millions of Americans suffer from depression, anxiety, and other disorders related to stress exposure. Hippocampal function is compromised in these and many other psychiatric conditions. Exposure to stress and other environmental insults, especially during sensitive periods in development, can have life-long consequences for hippocampal function and for mental health, yet the mechanisms are still poorly understood. Here the investigators propose to identify hippocampal cells that encode stress and govern other hippocampal functions. The studies are designed to explore how neurons born during developmental periods of stress sensitivity participate in normal brain functions and in disease. By completing these studies we hope to identify targets to counter the detrimental effects of stress on mental health and confer resilience.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Nadler, Laurie S
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New York State Psychiatric Institute
New York
United States
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