On the clock: Circadian genes may regulate brain plasticity

brain circadian rhythmsFirst in a two-part series on circadian biology and disease. Read part 2.

It’s long been known that a master clock in the hypothalamus, deep in the center of our brain, governs our bodily functions on a 24-hour cycle. It keeps time through the oscillatory activity of timekeeper molecules, much of which is controlled by a gene fittingly named Clock.

It’s also been known that the timekeeper molecules and their regulators live outside this master clock, but what exactly they do there remains mysterious. A new study reveals one surprising function: they appear to regulate the timing of brain plasticity—the ability of the brain to learn from and change in response to experiences.

“We found that a cell-intrinsic Clock may control the normal trajectory of brain development,” says Takao Hensch, PhD, a professor in the Departments of Molecular and Cellular Biology and Neurology at Harvard University and a member of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

In the April 8 issue of Neuron, researchers from Hensch’s lab report that mice deficient for the Clock gene had significantly delayed plasticity in the visual system, a system often used as a model for studying plasticity.

Shifting critical periods

In humans and many other animals, experiences and sensory inputs have their most potent impact on brain circuits during developmental windows of plasticity known as “critical periods.” Critical periods are the reason why it’s easier for us to learn languages or master musical instruments when we’re young and our brains are still maturing.

In the visual system, unbalanced inputs early in life—as in children who are cross-eyed—usually bias vision in favor of the less visually deprived eye. Typically, such visual deprivation has no effect in adulthood.

Intriguingly, however, in mice lacking the Clock gene, this scenario was reversed: visual deprivation of one eye had no effect on vision in young mice but did have a clear effect in adult mice, suggesting that the critical period had shifted. This abnormal pattern could be avoided when the mice were given diazepam, a drug known to boost the activity of inhibitory neurons that communicate via the neurotransmitter GABA, notes postdoctoral fellow and lead author Yohei Kobayashi, PhD.

L-R: Zhanlei Ye, Yohei Kobayashi, Takao Hensch (courtesy Harvard Dept. of Molecular and Cellular Biology)
L-R: Zhanlei Ye, Yohei Kobayashi, Takao Hensch (courtesy Harvard Dept. of Molecular and Cellular Biology)

Kobayashi wondered whether the loss of Clock was disrupting specific subsets of neurons in the visual cortex. After investigating a broad range of neuron types, he zeroed in on a subtype of GABA neurons called parvalbumin cells (PV-cells), known to be key players in the timing of critical periods. A battery of tests revealed that PV-cell maturation was significantly delayed when Clock was deficient.

Was delayed maturation of PV circuits causing the delay in visual plasticity in the mutant mice? To begin poking at this question, the researchers designed mice in which Clock (or an associated circadian rhythm protein, Bmal1) was deleted only in PV-cells. That was enough to cause the PV-cell maturation problems as well as abnormal visual plasticity—directly implicating the Clock machinery of PV-cells in both phenomena.

Circadian rhythms, neurodevelopment and mental illness

This new research might unite neurobiologists studying circadian rhythms with those studying developmental brain plasticity, Kobayashi notes. It could open inquiries into the role of circadian rhythm genes beyond the visual system, including brain regions that control cognition and social behaviors.

Specifically, the findings may have implications for disorders such as autism and schizophrenia. A number of genes associated with mental illness were expressed differently in the PV-cells of Clock-deficient versus control mice. The Hensch group and others have long proposed a link between neurodevelopmental disorders and timing defects in critical periods of brain plasticity. And finally, factors that influence circadian rhythms—sleep deprivation, seasonal changes limiting sunlight exposure, night shift work, etc.—have been linked to mood disorders.

By implicating circadian rhythm genes in the control of developmental brain plasticity, the new study may help bridge these ideas and suggests that further exploring the Clock machinery of PV-cells might have clinical value, helping unravel the pathology of some brain disorders.

Hensch, who also directs the NIMH Silvio Conte Center for Mental Health research at Harvard, says, “Such breakthroughs in basic neuroscience are needed to drive deeper insight into the etiology of mental illness and novel strategies for correcting them—ideally, before they arise.”

This blog post is adapted from a news release posted on the Harvard Department of Molecular and Cellular Biology and Conte Center websites.