Abstract
The period homolog genes Per1, Per2 and Per3 are important components of the circadian clock system. In addition to their role in maintaining circadian rhythm, these genes have been linked to mood disorders, stress response and vulnerability to addiction and alcoholism. In this study, we combined high-resolution sequence analysis and quantitative trait locus (QTL) mapping of gene expression and behavioral traits to identify Per3 as a compelling candidate for the interaction between circadian rhythm, alcohol and stress response. In the BXD family of mouse strains, sequence variants in Per3 have marked effects on steady-state mRNA and protein levels. As a result, the transcript maps as a cis-acting expression QTL (eQTL). We found that an insertion/deletion (indel) variant in a putative stress response element in the promoter region of Per3 causes local control of transcript abundance. This indel results in differences in protein binding affinities between the two alleles through the Nrf2 transcriptional activator. Variation in Per3 is also associated with downstream differences in the expression of genes involved in circadian rhythm, alcohol, stress response and schizophrenia. We found that the Per3 locus is linked to stress/anxiety traits, and that the basal expression of Per3 is also correlated with several anxiety and addiction-related phenotypes. Treatment with alcohol results in increased expression of Per3 in the hippocampus, and this effect interacts with acute restraint stress. Our data provide strong evidence that variation in the Per3 transcript is causally associated with and also responsive to stress and alcohol.
Highlights
Numerous physiological processes and behaviors in mammals exhibit an inherent circadian oscillation that is vital for normal function
We have recently shown that prolonged restraint stress significantly upregulates expression of Dbp, Per[1], Per[2] and Per[3] in multiple brain regions of C57BL/6J (B6) and DBA/ 2J (D2) inbred mouse strains.[13]
The stress response core element (STRE) motif is known to regulate gene expression in response to cellular stress, possibly by affecting the binding of transcription factors such as NRF2 and ATF3.48,49 We examined whether NRF2 or ATF3 binds to the STRE site by performing a super-shift assay using antibodies against these two transcription factors
Summary
Numerous physiological processes and behaviors in mammals exhibit an inherent circadian oscillation that is vital for normal function. Disruption in the diurnal cycle is a common feature of different types of psychiatric illnesses including stress and anxiety disorders, bipolar disorder and depression.[1] The circadian rhythm is under the coordinated regulation of clock genes such as Arntl, Dbp and Csnk1d, and the period homologs Per[1], Per[2] and Per3.2,3 There is growing evidence that implicates allelic variants in these genes in the development of neuropsychiatric diseases.[4,5] clock genes have been linked to responses to neuropharmacological agents in model organisms, as well as alcoholism and addiction in humans.[2,6] In mice, inactivation of Per[1] and Per[2] leads to changes in sensitivity to cocaine and ethanol,[7] and in humans, gene variants in PER2 have been linked to alcoholism.[8]. An important question is whether or not natural variation in the expression of these genes has a causal impact on stress and ethanol response in these mice?
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