Circadian rhythms are physical, mental and behavioral changes that follow a 24-hour cycle. Research from Washington University in St. Louis will test how these daily patterns are set and maintained through the coordinated activity of certain neurons and hormones.
The five-year $1.98 million project relies on new high-throughput machine learning techniques to determine the roles of cortical neurons and glial cells in distinct, daily activities of mice.
Erik Herzog, the Viktor Hamburger Distinguished Professor in the Department of Biology in Arts & Sciences, will lead this research with funding from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH).
“Daily rhythms in rest-activity are well known, but we don’t know how they arise or synchronize to local time,” Herzog said.
“We recently found that cells within the motor cortex can be synchronized to daily cycles of glucocorticoids,” Herzog said. “We will test the roles of specific cells and molecules in producing daily rhythms in cortical neurons and astrocytes and in a variety of behaviors.”
While much previous research on circadian rhythms has focused on a small part of the hypothalamus called the suprachiasmatic nucleus (SCN), this project looks at how the SCN interacts within a framework that includes the larger cortical brain areas — and specifically the motor cortex.
The new work takes advantage of biological and mathematical tools to improve understanding of how the brain is organized as a network of synchronized circadian cells.
“Surprisingly little is known about the mechanisms that generate and entrain daily rhythms in the brain outside the SCN,” Herzog said. “Despite a growing literature on clock gene expression in neocortex and its disruption under shifting light schedules and in disorders such as schizophrenia and Alzheimer’s disease, we lack a causal link between circadian biology and cortical function.”
Herzog’s team will conduct experiments to investigate the roles of daily rhythms in gene expression and excitability in astrocytes and pyramidal neurons in the primary motor cortex to drive daily rhythms of diverse motor behaviors in mice — like grooming, eating, exploring and nesting — and their regulation by circulating corticosterone.
The Washington University group is one of a few in the world that is able to collect long-term, real-time recordings of gene expression and calcium with ultrasensitive, non-invasive imaging.
“We are equipped to simultaneously monitor daily rhythms in the brain, glucocorticoid secretion and, with our recent addition of DeepEthogram, diverse behaviors with unprecedented precision and throughput,” Herzog said. “Ultimately we are aiming to understand normal and pathological regulation of daily activity in the brain and behavior.”