The relationship between ocus-coeruleus-norepinephrine network and neurovascular coupling in health and disease - The brain requires a continuous supply of nutrients and oxygen to fuel its normal functioning. Currently, there are two major processes that are known to control cerebral blood flow (CBF): autoregulation, the autonomous control of vascular diameter in response to blood pressure fluctuations, which largely reflects operation of the smooth muscle-intrinsic myogenic response, and neurovascular coupling (NVC), an activity-dependent process that increases blood flow to regions of high neuronal activity, presumably through release of vasodilatory or vasoconstrictive factors from neurons and astrocytes onto nearby vessels. Significant strides have been made in understanding these signaling pathways, which are presumed to operate independently of each other. However, whether these signaling pathways are integrated, and if so how, remains an unresolved question. Moreover, while a role for synaptic transmission via glutamate, GABA, and ATP has been implicated in NVC, the involvement of other signaling cascades, notably including the noradrenergic pathway, has received limited research attention. Norepinephrine (NE) is a robust vasoconstrictor in the peripheral system, but its role in the cerebral circulation remains uncertain. Data from Alzheimer’s disease (AD) patients and animal models of AD have shown profound degeneration of noradrenergic neurons in the locus coeruleus, the primary source of NE. The overall goal of this proposal is to identify the physiological and pathological roles of noradrenergic neurons in NVC. Specifically, we propose that noradrenergic signaling is integrated with glutamatergic signaling to modulate NVC and further that degeneration of noradrenergic neurons in AD alters NVC. Our preliminary data show that the state of wakefulness and engagement of the animal, which are often associated with the release of the long-range modulatory neurotransmitter, NE, as well as manipulations of noradrenergic signaling pathway modulate functional hyperemia and astrocyte Ca2+. To test the hypothesis that glutamatergic and noradrenergic signaling are integrated to control CBF, we will employ two-photon fluorescence imaging of the vasculature and Ca2+ dynamics in neurons and astrocytes in fully awake mice in conjunction with ex vivo preparations, knockout strategies, genetically encoded biosensors, and adeno-associated viruses. These integrated approaches are novel and powerful as they provide the ability to fully explore the integration of different signaling pathways under true physiological conditions in the absence of anesthetics. Aim 1 will elucidate the contribution of NE to sensory-induced increases in astrocyte Ca2+ and local CBF. Aim 2 will determine the mechanisms underlying central NE–induced vasomotor responses during whisker stimulation. Aim 3 will ascertain how degeneration of noradrenergic neurons affects astrocyte Ca2+ dynamics and CBF in AD and whether the condition can be rescued by manipulating NE transporters. Our investigation is expected to reveal the integrative nature of synaptic glutamatergic and long-range neuromodulatory noradrenergic signaling pathways in NVC and ultimately identify potential new diagnostic and/or therapeutic targets.
