This web page was produced as an assignment for Genetics 564, an undergraduate course at UW-Madison.
Our Circadian Rhythm and Depression
The image at right exhibits a simplistic explanation of our circadian rhythm. Our circadian rhythm cycles over a period of twenty-four hours and governs many of our physiological, metabolic, and behavioral functions [1]. In humans, the master biological clock, the suprachiasmatic nucleus (SCN), resides in the hypothalamus of the brain [1]. Our "clock" controls gene transcription via cyclic positive and negative feedback loops. The daily light/dark cycle is the most powerful synchronizer of mammalian circadian clocks [1]. Studies show that disruptions in the circadian rhythm are associated with major depressive disorder (MDD). An aspect of MDD is deficits in reward processing and motivation, both of which are regulated by the circadian clock [1]. Antidepressant drugs may help depressive symptoms because they entrain the circadian clock [1].
Per2's Role
As you can see from the above figure, Per2 is involved with maintaining the circadian clock in mammals. Per2 transcription is regulated by the CLOCK/BMAL1 protein complex. Per2 inhibits CLOCK/BMAL1, and thus its own transcription. The Clock gene is a major regulator of the circadian clock (hence its name) [1]. Data on Clock gene mutations suggest that defects in the clock system affect dopamine synthesis and thus may contribute to depressive symptoms. A polymorphism in the PER2 protein is responsible for the availability of dopamine receptors in the brain's striatum [1].
Expression of Per2 in the circadian rhythm has been investigated in mice. The SCN contained the most intense hybridization signal with antisense probes, indicating that mPer2 expression is concentrated in this section of the brain (see image at left--the arrow indicates the SCN) [2].
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mPer2 RNA levels were highest during day circadian times (CT) of 3, 6, and 9, as well as nighttime CT 15 [2]. High levels were also observed in the retina of mice, but at CT 9, 15, 18, and 21 (see the northern blot at right that indicates hybridization of Per2 at multiple circadian times. The horizontal bar below represents the lighting cycle. The shaded half is subjective day.) [2]. It was determined that mPer2 genes are expressed in the developing SCN, three days before the birth of mice. Addtionally, this study showed that Per2 is secondarily affected by light pulses. A light pulse will delay the induction of mPer2 mRNA levels, altering gene expression in the SCN and shifting the phase of SCN-controlled behavioral rhythms [2].
A study in postmortem human brains indicates a similar cycle of PER2 expression in humans. As depicted in the image above left, PER2 peaks in the afternoon at CT 9 [3]. However, as you can see from the images above right, patients with major depressive disorder (MDD) are less synchronized with the solar day than control groups [3].
Additionally, this study showed that normal patterns of gene-gene correlations are disrupted in patients with MDD (see image below [3]). The gene pairing of BHLHE40-PER2 exhibited a large out-of-phase correlation in patients with MDD. Gene pairs with a strong normal correlation are seen in red (in-phase=positive correlation) while out-of-phase gene pairs have a negative correlation (seen in blue). The asterisk marks gene pairs with significant differences between controls and MDD patients . The results from this study suggest that shifted circadian timing and disrupted regulatory relationships between gene pairs may both play a role in depression [3].
References
[1] Golombek, D., Bussi, I., and Agostino, P. (2014). Minutes, days, and years: molecular interactions among different scales of biological timing. Philosophical Transactions of the Royal Society. B 369. doi: 20120465
[2] Shearman, L., et al. (1997). Two period Homologs: Circadian Expression and Photic Regulation in the Suprachiasmatic Nuclei. Neuron, Vol. 19.
[3] Li, J., et al. (2013). Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. PNAS. 110(24). doi:10.1073/pnas.1305814110
[1] Golombek, D., Bussi, I., and Agostino, P. (2014). Minutes, days, and years: molecular interactions among different scales of biological timing. Philosophical Transactions of the Royal Society. B 369. doi: 20120465
[2] Shearman, L., et al. (1997). Two period Homologs: Circadian Expression and Photic Regulation in the Suprachiasmatic Nuclei. Neuron, Vol. 19.
[3] Li, J., et al. (2013). Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. PNAS. 110(24). doi:10.1073/pnas.1305814110