Vascular Effects on Astrocyte Functions in Young and Aging Brains

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The brain is an incredibly energy-demanding organ, consuming ~20% of the total blood supply despite constituting only approximately 2% of body weight. Thus, the brain requires a continuous supply of oxygen and glucose to fuel its normal functioning. Aging has been shown to impair the cerebral blood flow (CBF), an effect attributable to endothelial dysfunction, and defects in neurovascular coupling (NVC) and autoregulation. Since the pioneering work of Roy and Sherrington over 100 years ago, it has been known that the brain possesses an intrinsic ability to increase blood flow to localized regions to meet the energy demands imposed by increased brain activity. This neuronal activity-dependent increase in blood flow, known as functional hyperemia, is regulated by NVC mechanisms. Studies have highlighted the essential role of neurons and astrocytes in the brain in releasing vasoactivators such as prostaglandins and nitric oxide onto nearby vessels and triggering changes in arteriole diameter and thus controlling CBF. Work performed to date has predominantly focused on the uni-directional nature of this regulation going from the brain to vessels. In contrast, very little is known about the communication in the reversed direction—vessel-to-brain communication—and virtually nothing is known about how aging might affect this cell-to-cell communication. Our previous studies showed that changes in arteriole diameter can alter astrocytic Ca2+. The goal of this project is to establish the role of arteriole-to-brain communication and elucidate how this process, and consequently CBF control, is altered in aging. The overarching hypothesis is that arteriole-to-astrocyte communication during functional hyperemia modifies Ca2+- dependent neural activity, and this process is altered in aging. To test our hypothesis, we will employ two-photon fluorescence imaging of the vasculature and Ca2+ dynamics in neurons and astrocytes in fully awake animals in conjunction with ex vivo preparations, knockout strategies, genetically encoded biosensors, pharmacogenetics and optogenetics. These integrated approaches are novel and powerful as they enable us to fully explore the integration of different signaling pathways under true physiological conditions without the confounding effects of anesthetics. Aim 1 will determine how arteriole-to-astrocyte communication can be initiated. To understand the critical initiating stimuli that cause the arteriole-to-astrocyte signaling, we will selectively manipulate the brain microvasculature using several physiological and experimental (optogenetics and DREADD) strategies. Aim 2 will explore the downstream cellular signaling pathways utilized to relay information from arterioles to astrocytes. These studies will assess contributions of the nitric oxide cascade and mechanosensitive channels to arteriole- to-astrocyte communication. Aim 3 will examine potential impacts of aging on the way information is relayed from arterioles to astrocytes. Our investigations into this novel model may establish a previously unappreciated physiological cell-to-cell communication in which blood vessels modulate brain cells, defining a new process that is essential for CBF regulation and ultimately providing insights that may help maintain brain health.