Dr. Zielinski's research is focused on understanding mechanisms of how inflammation regulates sleep and is activated by sleep loss and disease. Currently, Dr. Zielinski is a postdoctoral fellow under the mentorship of Dr. Radhika Basheer at the Veteran Affairs Boston Healthcare System. Compared to the general population, veterans have an increased prevalence of sleep disorders and sleep disturbances including those that induce sleep loss. Sleep loss causes lost productivity, sleepiness, fatigue, and increased health and memory problems. Sleep loss increases inflammatory substances in the brain. Enhancements in these inflammatory molecules in the brain are associated with sleepiness, impaired cognition, and sleep disorders including insomnia. However, the exact mechanisms governing these inflammatory processes in relation to sleep loss remain poorly understood. My current research has provided strong preliminary evidence that the nucleotide leucine-rich protein-3 inflammasome protein complex, which forms in response to increased extracellular adenosine tri-phosphate levels to activate caspase-1 and cleave the pro-form of interleukin-1 beta into its mature active form is activated by sleep loss and enhances sleep and electroencephalogram delta power (0.5- 4 Hz range; an indicator of sleep need). Interestingly, cerebral blood flow is associated with changes in sleep state and electroencephalogram delta power and interleukin-1 beta is a potent vasodilative substance enhancing cerebral blood flow suggesting a common mechanistic link. The neurovascular unit is comprised of different cell types including microglia, brain macrophages, astrocytes, and neurons that sense neuronal activity and function to alter cerebral blood flow to maintain homeostasis from pathogenic and normal physiologic activities. The neurovascular unit does this, in part, through releasing inflammatory substances including interleukin-1 beta-a molecule that enhances cerebral blood flow and sleep. The goal of this proposal is to determine how energy-related mechanisms induced by sleep loss activate a mechanism of inflammation, the inflammasome, to alter sleep and cerebral blood flow.
Aim 1 tests the hypothesis that sleep loss enhances energy substrates to activate the inflammasome to enhance sleep.
Aim 2 investigates the hypothesis that sleep loss activates the inflammasome in cells of the neurovascular unit.
Aim 3 examines the hypothesis that sleep loss enhances interleukin-1 beta to alter cerebral blood flow during sleep states. Findings from this proposal will allow for an understanding of inflammatory mechanism induced by sleep loss so that novel pharmaceutical and treatments can be identified for veterans who experience debilitating disturbed sleep including those with insomnia, post-traumatic stress disorder, traumatic brain injury and schizophrenia. The team of mentors and collaborators assembled for this proposal at the Veteran Affairs Boston Healthcare System are world class leaders in sleep, brain immune function, and cerebral blood flow research that will provide exceptional training and guidance to ensure successful completion of this proposal. Further, this Veteran Affairs Career Development Award will provide important training in immunological, cellular, and neuroscience techniques that will enable Dr. Zielinski to achieve his long-term goal of becoming an independent scientist within the Veteran Affairs research community making significant contributions to the field of sleep research aiding veterans.

Public Health Relevance

Veterans often experience debilitating sleep disturbances and undergo sleep loss, which is associated with detriments that affect their quality of life including sleepiness, impaired memory and health, fatigue, and reduced productivity. Sleep loss increases brain inflammation, although the exact mechanisms remain unknown. Brain cells of the neurovascular unit are located around the vasculature, sense changes in energy demands of the brain, and produce inflammatory substances that regulate local blood flow and homeostasis. We propose experiments to determine the role of sleep loss on inflammation in cells of the neurovascular unit, which will have practical application to understand mechanisms that will allow for future pharmaceutical treatments and strategies for veterans and individuals with dysregulated sleep and brain damage.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IK2)
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Neurobiology R (NURR)
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VA Boston Health Care System
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Gerashchenko, Dmitry; Schmidt, Michelle A; Zielinski, Mark R et al. (2018) Sleep State Dependence of Optogenetically evoked Responses in Neuronal Nitric Oxide Synthase-positive Cells of the Cerebral Cortex. Neuroscience 379:189-201
Zielinski, Mark R; Gerashchenko, Dmitry (2017) Sleep-inducing effect of substance P-cholera toxin A subunit in mice. Neurosci Lett 659:44-47
Zielinski, Mark R; Gerashchenko, Dmitry; Karpova, Svetlana A et al. (2017) The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide. Brain Behav Immun 62:137-150