The Role of Astrocytes in Circadian Control of Blood Pressure in the Nucleus of the Solitary Tract - PROJECT SUMMARY/ABSTRACT Our 24-hour society requires an increasing number of individuals to work rotating shifts to adapt to schedules on a global scale. In the United States, 15 million people participate in some form of shift work. Shift work is associated with the risk of cardiovascular health problems including increased blood pressure (BP), decreased heart rate variability (HRV), ischemic stroke, and cardiovascular disease (CVD). Previous research revealed that shift work induces a misalignment between the endogenous circadian system and the sleep/wake cycle, a phenomenon known as circadian misalignment. Despite the relationship between circadian misalignment and reduced cardiovascular health, there are limited studies on the biological mechanisms responsible for the development of these problems. The nucleus of the solitary tract (nTS) is the first central integration site of peripheral afferents and reflexes. Alterations of the balance within the nTS, of synaptic and/or neuronal excitation, results in elevations in blood pressure. Astrocytes are closely associated with nTS synapses and together with the presynaptic terminal and nTS neuron, form the “tripartite synapse”. In the nTS, astrocytes contribute to synaptic and neuronal activity and their plasticity, as well as pH regulation. The extracellular concentration of glutamate, the primary excitatory neurotransmitter in the nTS, is maintained by astrocytic excitatory amino acid transporters (EAATs). These transporters are critical in maintaining the balance of inhibition and excitation in the nTS via uptake of their respective neurotransmitters. In our preliminary work, we demonstrated that the animal model of circadian misalignment leads to elevated BP and HRV and that these changes were accompanied by decreases in nTS glutamatergic activity. Therefore, in this project, we ask: what is the role of nTS astrocytes in glutamate modulation in the nTS following circadian misalignment and does this pathway contribute to increased BP? Answering this question would address a critical need in our understanding of neural control of blood pressure in response to circadian misalignment. Based on our preliminary data and previous work, we hypothesize that circadian misalignment perturbs the balance of the glutamatergic system in the nTS through disruption of EAATs on astrocytes, leading to an increase in blood pressure. This hypothesis will be tested using an established rodent model of circadian misalignment, which has already been set up in our laboratory. We propose the following aims: Aim 1: Determine astrocytic morphology and expression of EAATs in circadian control of blood pressure. Does circadian misalignment alter this astrocytic morphology and/or EAAT expression? Aim 2. Define the extent to which nTS astrocyte function, specifically EAATs, contribute to nTS circadian regulation of blood pressure and how circadian misalignment alters their activity.
