Neuroendocrine dysfunction and hypertension

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Project summary: Hypertension affects two-thirds of elders older than 60 years and significantly increases the risk of dementia and exacerbates the pathogenesis of Alzheimer’s Disease (AD). AD is a chronic neurodegenerative disorder that represents the most common form of dementia among the elderly, manifesting the loss of cognitive function. AD is confirmed by the accumulation of the extracellular amyloid-β (Aβ) containing plaques and intracellular neurofibrillary tangles formed by the aggregated tau protein. Although extensive studies have been carried out, the pathogenesis of AD is mainly undefined, and effective treatments are still unavailable. Hypertension is associated with an increased density of cerebral amyloid, neurofibrillary tangles, and angiopathy tangles in postmortem brains from hypertension patients. However, the pathophysiological mechanisms underlying the increased risk of AD in hypertension remain unclear. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is common in AD and hypertension patients. The corticotropin-releasing hormone (CRH) synthesizing neurons in the paraventricular nucleus (PVN) of the hypothalamus (CRHPVN neurons) are importantly regulate HPA axis activity. CRHPVN neuron activity is increased in spontaneously hypertensive rats (SHRs). Thus, SHRs will be used to determine the role of CRHPVN neurons in cognitive deficits in hypertension. The scope of the parent R01 project is to determine the role of CRHPVN neurons in hypertension. This supplemental application is to determine the role of CRHPVN neurons in cognitive deficits in hypertension. Thus, the scope of this supplemental application is within the scope of its parent grant. The preliminary study found that SHRs display cognitive deficits in the Barnes maze task and novel objective recognition test. Hippocampal long-term potentiation (LTP) was significantly decreased in SHRs. The expression levels of CRH and CRHR1 in the hippocampus were increased. We will use a recently developed chemo-genetic approach to selectively manipulate CRH neurons activity and test our central hypothesis that hyperactivity of CRHPVN neurons is critically involved in cognitive deficits in hypertension by pursuing the following specific Aims: Aim 1 is to determine if cognitive deficits and impaired LTPs in hypertension are attributed to hyperactivity of CRHPVN neurons. Aim 2 is to determine if enhanced CRH-CRHR signals are involved in cognitive deficits and impaired LTPs in hypertension. The proposed studies will greatly improve the understanding of the cellular mechanisms involved in cognitive deficits in primary hypertension. Successful completion of the proposed studies will yield novel mechanisms responsible for cognitive deficits in hypertension and an essential rationale for targeting CRHPVN neurons and CRHR1 to treat cognitive deficits in hypertension. After successfully completing the proposed studies, we will develop a new project to study AD pathologies, such as neurodegeneration, synaptic dysfunction, tauopathy, by targeting the CRH-CRHR signal and HPA axis.