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.
