Neuroscience Blog

Written by Brett Weiss

October 2019

            Biological rhythms play a significant role in individual and interpersonal well-being.  Among biological rhythms, the circadian rhythm plays perhaps the greatest in health with abnormalities in circadian rhythm linked to psychopathologies, including mood disorders.  Circadian rhythm entails the body going through sleep/wake cycles of approximately 24 hours, which corresponds to the Earth’s light/dark cycle.  In humans, the circadian rhythm in healthy adults is 24 hours and 11 minutes plus or minus 16 minutes (Charrier et al., 2017).  The mechanism through which the circadian rhythm adjusts each day to remain on a 24-hour schedule based on lighting conditions and/or alarm clocks (among other signals or ‘zeitgebers’) is termed entrainment.  Entrainment does not always work for some as circadian rhythms often go awry in patients with mood disorders.  One might ask, “What characteristics underly circadian rhythm abnormalities?”  Research has linked genetic and molecular abnormalities in psychopathologies which often coincide with circadian rhythm abnormalities.  The following will explore the research and offer genetic explanations of mechanisms involved with dysfunctional sleep cycles.

            The area of the brain considered to constitute the ‘central clock,’ the suprachiasmatic nucleus, lies in a region above the eyes, above the optic chiasm more specifically.  The suprachiasmatic nucleus receives light cues (photic cues) and non-photic cues that entrain this region to the external environment (Vadnie & McClung, 2017).  Intriguingly, entrainment not only occurs in the ‘central clock region,’ the suprachiasmatic nucleus, but also occurs in peripheral cells of organs.  Hence, most cells in the body have a circadian rhythm.  The suprachiasmatic nucleus plays a central role in synchronizing circadian rhythms in regions of the brain outside of the suprachiasmatic nucleus and in peripheral tissues.  This region achieves the synchronization through synaptic connections and hormonal mechanisms (Vadnie & McClung, 2017).

            At the cellular level, a genetic mechanism plays a role in generating the circadian rhythm.  Researchers first discovered the ‘clock’ genes in fruit flies (Drosophila melanogaster) and then found analogous genes in mice and humans.  The mechanism entails transcription and translation; transcription involves generating an RNA read-out from DNA, while translation involves generating protein from the aforementioned RNA.  Hence, DNA gets transcribed to RNA which gets translated to protein.  Transcription and translation occur with the help of molecules.  Transcription occurs through the action of an enzyme, RNA polymerase, acting upon DNA; and translation occurs through the action of cellular proteins, ribosomes, translating the RNA to amino acids that comprise proteins.  In the self-regulating (autoregulatory) cellular loop, proteins CLOCK and BMAL1 bind to one another (heterodimerize) to drive the expression of genes Period and Cryptochrome.  Through transcription and translation of Period and Cryptochrome, proteins PERIOD and CRYPTOCHROME result which constitute the negative arm of the self-regulatory loop.  In turn, PERIOD and CRYPTOCHROME bind to one another (heterodimerize) and enter the nucleus where DNA is present to inhibit their own transcription (Vadnie & McClung, 2017).  When PERIOD and CRYPTOCHROME protein levels become low, the CLOCK and BMAL1 proteins act with one another to reinitiate transcription of the genes, Period and Cryptochrome (Charrier et al., 2017; Vadnie & McClung, 2017).  A secondary feedback loop exists in concert to this core transcription/translation feedback loop involving proteins REV-ERBα and RORα.  The CLOCK/BMAL1 protein complex drives expression of the genes Rev-erbα and Rorα which then regulate rhythmic expression of the Bmal1 gene (Vadnie & McClung, 2017).  Nearly all cells in the body possess these circadian genes; however, the suprachiasmatic nucleus has properties that allow it to synchronize rhythms of the various tissues (Vadnie & McClung, 2017).

            The suprachiasmatic nucleus has self-sustaining oscillators and when isolated will display robust molecular and electrical rhythms (Vadnie & McClung, 2017).  Some cells of the suprachiasmatic nucleus respond directly to external cues (zeitgebers), the most powerful of which is light.  Light information travels to the suprachiasmatic nucleus from projections that originate in the intrinsically photosensitive retinal ganglion cells of the eye’s retina (Vadnie & McClung, 2017).  Light acts via glutamate (a neurotransmitter involved in learning and excitation) signaling to activate NMDA and AMPA receptors (receptors for glutamate) in suprachiasmatic nucleus cells to increase neural activity and cellular signaling (Vadnie & McClung, 2017).  As mentioned, external signals (zeitgebers) such as light are important for entrainment.  For instance, when subjective night arrives and PERIOD proteins levels start to decrease, light hitting the retina increases PERIOD protein expression, which induces a phase delay in the circadian rhythm (Vadnie & McClung, 2017).  Abnormal circadian rhythms and disruption of the molecular mechanisms thereof often associate with psychopathology, and scientists still work to uncover why this relation exists.

            Scientists have formulated some hypotheses regarding the relationship between psychiatric disorders and circadian rhythm.  The first presented here states that sleep problems may facilitate cognitive impairments from the effects of fatigue and sleep deprivation on learning and attention capabilities, long-term memory, language development, and emotions (Charrier et al., 2017).  Another hypothesis says that motor, emotional, and interpersonal rhythmicity and synchrony in early development of social communication result from abnormal circadian rhythm; this situation may lead to impairments and vulnerability to psychiatric disorders such as autism spectrum disorder or schizophrenia (Charrier et al., 2017).  A third hypothesis says that circadian rhythm genes control critical periods of development and that abnormal expression of these ‘clock’ genes may facilitate neurodevelopmental disorders such as psychiatric disorders (Charrier et al., 2017).  Last, another hypothesis states that circadian rhythm impairments may disrupt adaptation to the environment, inhibiting homeostasis; this would result in a loss of synchronization between external and internal rhythms leading to disruption of adaptation and appearance of psychiatric disorders (Charrier et al., 2017).  Other hypotheses relating circadian dysfunction to psychiatric disorder onset exist; however, these four hypotheses give ideas of the ways that circadian rhythm disruptions may lead to psychopathologies.

            Among mood disorders, bipolar disorder entails periods of mania, hypomania, and depression.  In bipolar disorder, the most common sign or symptom (prodrome) of mania is sleep disorder (Charrier et al., 2017; Jackson et al., 2003).  Between mood episodes in this disorder, sleep-wake cycles remain disrupted as well with difficulty falling asleep and frequent awakenings during the night (Charrier et al., 2017).  From a genetic standpoint, research has implicated ‘clock’ genes of the cellular mechanism regulating circadian rhythm in bipolar disorder.  An example of a study in humans with bipolar disorder found that a Cryptochrome gene, Cryptochrome2, has abnormal expression in the disorder compared to healthy controls (Lavebratt et al., 2010).  This study found lower mRNA levels (resulting from transcription) of Cryptochrome2 in depressed individuals with bipolar disorder, and these subjects were unresponsive to sleep deprivation (Charrier et al., 2017; Lavebratt et al., 2010).  This makes sense in that build-up of CRYPTOCHROME protein throughout the day correlates with wakefulness along with tapering levels at night in diurnal animals including humans.  Another study of the same gene showed an association between Cryptochrome2 gene markers (small nucleotide polymorphisms) and rapid cycling or higher frequency of mania and depression episodes in a year in bipolar disorder (Charrier et al., 2017; Sjoholm et al., 2010).  Hence, evidence from studies point to gene markers (small nucleotide polymorphisms) found more frequently in bipolar disorder patients than healthy volunteers that affect the genetic and molecular mechanisms involved in circadian rhythm.  Other studies point to genotype (genetic constitution of an individual) association with ‘clock’ gene abnormalities in anxiety disorder, major depressive disorder, seasonal affective disorder, attention hyperactivity disorder, schizophrenia, and autism spectrum disorder (Charrier et al., 2017).

            The ‘clock’ genes that play pivotal roles in the cellular mechanism that controls circadian rhythm have gene compositions that differ between patients with mood disorders and healthy neurotypicals (statistically speaking).  How this affects the ability of the ‘central clock’ of the body, the suprachiasmatic nucleus in the brain, to synchronize circadian rhythms of all tissues remains unclear.  Also, the degree to which and how these genotypes in patients with mood disorders affect disease onset remain unclear.  The next step in research should entail reproducing these findings to validate them and then conducting further research on these ‘clock’ genes and their molecular pathways to find out the importance of their roles in brain pathology.  As stated previously, sleep issues constitute a very common sign or symptom (a prodrome) in mood disorders such as bipolar disorder.  Hence, one must ask the following: do sleep issues occur in mood-related illness as a result of disease, or do genetically-determined sleep problems contribute to the causation of the disease?  Perhaps the answer lies somewhere between these two possibilities.  Only future investigation can reveal the details.

References

Charrier A, Olliac B, Roubertoux P, & Tordjman S (2017).  “Clock Genes and Altered Sleep-Wake Rhythms: Their Role in the Development of Psychiatric Disorders.”  Int J Mol Sci.  18(5).

Jackson A, Cavanagh J, & Scott J (2003).  “A systematic review of manic and depressive prodromes.”  J Affect Disord.  74: 209-217.

Lavebratt C, Sjoholm LK, Soronen P, Paunio T, Vawter MP, Bunney WE, Adolfsson R, Forsell Y, Wu JC, Kelsoe JR et al. (2010).  “CRY2 Is Associated with Depression.”  PLoS ONE.  5: e9407.

Sjoholm L, Backlund L, Cheteh EH, Ek IR,, Frisen L, Schalling M, Osby U, Lavebratt C, & Nikamo P (2010).  “CRY2 is associated with rapid cycling in bipolar disorder patients.”  PLoS ONE.  5: e12632.

Vadnie CA & McClung CA (2017).  “Circadian Rhythm Disturbances in Mood Disorders: Insights into the Role of the Suprachiasmatic Nucleus.”  Neural Plast.