Influencing the number of receptors in a key brain region alters the daily patterns of rest and wakefulness in mice.
In both humans and other animals, signals from a central circadian clock in the brain dictate the seasonal and daily rhythms of life. These signals help the body anticipate environmental changes and optimize activities such as sleep, eating, and other daily routines.
Researchers at Washington University in St. Louis are delving into the intricacies of how our internal biological clocks function. Their recent study, published on July 24 in the Proceedings of the National Academy of Sciences, sheds light on how circadian rhythms are established and maintained.
In all mammals, circadian rhythm signals originate from a small brain region known as the suprachiasmatic nucleus (SCN). Previous studies from WashU and other institutions aimed to understand the role of the neurotransmitter GABA in synchronizing circadian rhythms among individual SCN neurons. However, the specific contribution of GABA in the SCN had been unclear.
Lead author of the study, Daniel Granados-Fuentes, explained, “Previous data from our research on the pharmacological inhibition of the GABA system resulted in only modest improvements in synchrony among SCN cells.”
Given that chemical interventions did not significantly alter SCN neuron firing patterns or affect circadian behavior in mice, Granados-Fuentes and his team opted for a different strategy. They tested whether adjusting the expression of two types of GABA receptors would impact synchrony or behavior.
Granados-Fuentes noted, “Although tuning receptor numbers is known to regulate processes like learning and memory, its effect on circadian rhythms is not well-established.” Surprisingly, altering the density of γ2 or δ GABA receptors had a profound effect in this case.
In mice, reducing or mutating these receptors in the SCN reduced the amplitude of circadian rhythms by a third. These mice exhibited increased daytime activity and reduced nocturnal running.
The researchers observed that decreasing or mutating γ2 or δ GABA receptors halved the synchrony and amplitude of circadian SCN cells, as indicated by firing rate or protein expression in vitro.
Moreover, overexpression of either GABA receptor type compensated for the loss of the other, suggesting a similar functional role in the SCN, despite their distinct physiological functions, Granados-Fuentes highlighted.
Understanding circadian rhythms is crucial as disruptions can lead to various negative consequences such as daytime fatigue, hormonal imbalances, digestive issues, mood swings, and more.
Granados-Fuentes proposed, “These findings raise the possibility of exploring the significance of GABA receptor density changes in regulating seasonal responses, such as how animals adapt to long summer days or short winter days.”
Granados-Fuentes collaborates with biologist Erik Herzog, the Viktor Hamburger Distinguished Professor in Arts & Sciences and a co-author of the study. Steven Mennerick, the John P. Feighner Professor of Neuropsychopharmacology at Washington University School of Medicine and a professor of psychiatry and neuroscience, also contributed to the research.
This study contributed to securing a new grant from the National Institute of Neurological Disorders and Stroke, which is part of the National Institutes of Health (NIH), for the Herzog laboratory in partnership with collaborators from WashU’s McKelvey School of Engineering and Saint Louis University.
Funding for this research was provided by a grant from the NINDS (RO1NS121161), with additional support from the Taylor Family Institute for Innovative Psychiatric Research.
