A Master Gear in The Circadian Clock – Newswise

Newswise DALLAS Aug. 19, 2021 A gene calledNpas4, already known to play a key role in balancing excitatory and inhibitory inputs in brain cells, appears to also be a master timekeeper for the brains circadian clock, new research led by UT Southwestern scientists suggests. Thefinding, published online today inNeuron, broadens understanding of the circadian clocks molecular mechanisms, which could eventually lead to new treatments for managing challenges such as jet lag, shift work, and sleep disorders.

To reset the circadian clock, you ultimately need to reset its molecular gears, said study leaderJoseph S. Takahashi, Ph.D.,Professor and Chair of Neuroscience at UTSW and a Howard Hughes Medical Institute Investigator. This study suggests thatNpas4might be one of the most important components for resetting the clock to light.

For decades, researchers have known that a brain region called the suprachiasmatic nucleus (SCN) is responsible for controlling circadian rhythms, the various cycles of activity that typically run on a 24-hour basis. These rhythms are entrained by light, Dr. Takahashi explained; cells in the SCN respond to signals relayed by the retina, the eyes light-sensitive tissue. However, the molecular basis of this phenomenon is not well understood.

To better understand how the SCN sets circadian rhythms, the researchers used a technique called single-nucleus sequencing to look at gene activity in individual cells in mice after the animals were exposed to light. Dr. Takahashi and his colleagues found that three different subpopulations of SCN neurons respond to light stimulation. A common thread tying these subtypes together was increased activity in genes that respond to neuronal PAS domain protein 4 (NPAS4), the protein made by theNpas4gene.

When Dr. Takahashi and his colleagues exposed mice engineered to lackNpas4to light, it dampened the response of hundreds of circadian clock genes. In addition, the animals circadian period lengthened about an extra hour, to nearly 25 hours instead of the normal 24. Together, these results suggest thatNpas4is a master regulator of many light-induced genes, a key piece in the puzzle of how the circadian system works, Dr. Takahashi said.

The more researchers learn about the molecular underpinnings of the circadian clock, Dr. Takahashi added, the more they may be able to manipulate it to improve health and well-being for example, to ease jet lag or help shift workers stay awake or asleep to match their work cycles. It could also lead to new treatments for disorders marked by abnormal sleep/wake cycles.

Other researchers who contributed to this research include Pin Xu, Stefano Berto, Ashwinikumar Kulkarni, Byeongha Jeong, Chryshanthi Joseph, Kimberly H. Cox, Tae-Kyung Kim, all of UT Southwestern; and Michael E. Greenberg of Harvard Medical School.

Dr. Takahashi holds the Loyd B. Sands Distinguished Chair in Neuroscience at UTSW. This work was a collaboration with thelaboratoryofGenevieve Konopka, Ph.D., Associate Professor of Neuroscience, the Jon Heighten Scholar in Autism Research, and Director of the UTSW Neurogenomics Core.Drs. Takahashi and Konopka are members of the Peter ODonnell Jr. Brain Institute.Dr. Kim, a Distinguished Scholar in Neuroscience, is also a member of the ODonnell Brain Institute.

This research was supported by grants from the National Institutes of Health (NS106657, DC014702, MH102603, NS028829), the Howard Hughes Medical Institute, the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition Scholar Award (220020467), and the Chan Zuckerberg Initiative, an advised fund of Silicon Valley Community Foundation (HCA-A-1704-01747).

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to Southwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.

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A Master Gear in The Circadian Clock - Newswise