Picture yourself in a room stripped of windows and light sources with no alarm clocks, cell phones, or television. Under complete darkness and in the absence of external cues, how would you be able to tell time? How would you know when to sleep or wake-up? Would it affect your mood? It turns out, your body would maintain rhythms of behavior and physiological processes that last around 24-hours, because of your internal circadian clocks.
The word circadian comes from the Latin circa and dies, meaning “around a day” and it is commonly used to describe our regular daily rhythms . Circadian clocks are present in every living organism including plants, animals, bacteria, and humans. In mammals, these biological clocks can be found in every cell of the body to ensure that we do the right things at the right time of day. A master, or “grandfather”, clock orchestrates the function of all the cell-level clocks found in the body. This master clock is located in the brain in a region known as the Suprachiasmatic Nucleus (SCN) of the hypothalamus . Proper function of the master clock is necessary to keep you alert in the morning and allow you to sleep in the evening.
Sunlight keeps our internal rhythms in sync with the world around us due to its control over melatonin release . In darkness, the clock triggers the production of large amounts of melatonin, making us sleepy and ready for bed. However, when the clock receives a signal that light is present, as it does during the day, melatonin production drops which in turn keeps us alert. A disruption to this process has been shown to contribute to the onset of many diseases. One common clock disruption is the exposure to artificial light at night. Consider the experience of shift workers, like nightshift nurses. Artificial hospital lighting at night trick nurses’ master clock (and by extension their bodies) into thinking it is still daytime, making it harder for them to fall asleep.
A misalignment between the biological clock and the external environment has been linked to a number of mood disorders, such as anxiety and depression, for which altered sleep-wake patterns are frequently experienced . Due to their inherently altered sleep-wake schedule, shift workers are 33% more likely to develop depression than individuals working a nine-to-five job [5,6]. Further, research examining the post-mortem brains of people with Major Depressive Disorder (MDD) has revealed abnormalities in genes that control the function of biological clocks . However, rather than being in the SCN, the abnormal gene expression was located in the nucleus accubens (NAc); a key structure in mediating mood, especially in relation to the experience of reward. Unsurprisingly, the NAc has also been implicated in depression, anxiety, and substance use disorders . Studies in rodents have corroborated these findings. For example, mice that exhibit depressive-like or anxiety-like behavior lack circadian rhythmicity and its related gene expression in the NAc [9,10]. Furthermore, abnormal clock gene expression has been associated with an increase in alcohol consumption in mice .
What exactly do researchers mean by abnormal gene expression? Much like the inner workings of an analog watch that require synchronous work of cogs and gears to give time, our biological clocks require specific genes to work together for optimal function. The clock begins to “tick” with light entering the eye that ultimately triggers clock genes to “turn on” and synthesize proteins. Gene expression refers to these proteins. The proteins then act as a feedback signal to turn off further synthesis. When one component of the process is missing, the entire clock loop unravels. Importantly, clock genes are found widespread across the brain.
For my thesis project, conducted under the supervision of Dr. Amir at Concordia University, I investigated the role of one specific clock gene, Per2, in the NAc. Preliminary research from a fellow colleague, Dr. De-Zavaila, suggests that mice lacking Per2 in the striatum, a brain region known to mediate processes like mood and motor control, showed a tendency towards increased ethanol consumption. Based on these findings, my own research examines the role of Per2 in the NAc, a subregion of the striatum. Thirteen male mice were surgically treated to knockout out the Per2 gene from all of the neurons in the NAc. Next, these mice were tested for depressive-, anxiety-, and addiction- like behaviors and compared to aged matched controls. Genetically removing Per2 from the NAc of mice did not affect tests of depressive- or anxiety- like behavior. However, mice lacking Per2 tended to consume more ethanol than controls. That is, the mice demonstrated a similar pattern of drinking behavior from the global Per2 knockouts raising the possibility that the NAc plays a central role in mediating this effect. To look into this possibility, future studies should examine the role of Per2 at a cell-specific level and comparing Per2 in opposing NAc neurons such as those that excite versus inhibit the firing of other neurons.
Overall, evidence from human and rodent studies have shown that altered circadian rhythms contribute to the epidemiology of depression and anxiety as well as substance use disorders. Understanding how our biological clock functions and how it influences diseases, can help researchers develop innovative and effective therapies that would help millions of people. Next time you glimpse at your wrist-watch, remember the molecular clock in your brain that ticks to keep you happy and healthy.
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