Chronic Stress Induces Brain Region-Specific Alterations of Molecular Rhythms that Correlate with Depression-like Behavior in Mice

Abstract

Background Emerging evidence implicates circadian abnormalities as a component of the pathophysiology of major depressive disorder (MDD). The suprachiasmatic nucleus (SCN) of the hypothalamus coordinates rhythms throughout the brain and body. On a cellular level, rhythms are generated by transcriptional, translational, and post-translational feedback loops of core circadian genes and proteins. In patients with MDD, recent evidence suggests reduced amplitude of molecular rhythms in extra-SCN brain regions. We investigated whether unpredictable chronic mild stress (UCMS), an animal model that induces a depression-like physiological and behavioral phenotype, induces circadian disruptions similar to those seen with MDD. Methods Activity and temperature rhythms were recorded in C57BL/6J mice before, during, and after exposure to UCMS, and brain tissue explants were collected from Period2 luciferase (Per2::luc) mice following UCMS to assess cellular rhythmicity. Results UCMS significantly decreased circadian amplitude of activity and body temperature in mice, similar to findings in MDD patients and these changes directly correlate with depression-related behavior. While amplitude of molecular rhythms in the SCN was decreased following UCMS, surprisingly, rhythms in the nucleus accumbens were amplified with no changes seen in the prefrontal cortex or amygdala. These molecular rhythm changes in the SCN and the nucleus accumbens (NAc) also directly correlated with mood-related behavior. Conclusions These studies find that circadian rhythm abnormalities directly correlate with depression-related behavior following UCMS and suggest a desynchronization of rhythms in the brain with an independent enhancement of rhythms in the NAc.

Gene and stress history interplay in emergence of PTSD-like features

“…We used p < 0.05 as the significance threshold for all the calculations. M a n u s c r i p t M a n u s c r i p t We measured the bodyweights ( Figure 1A and Figure S2A) and temperatures of the Agg-E mice ( Figure S2B-C) before (pre-stress) and after (post-stress) the 6h 'cage-within-cage' confinement, and the urine markings ( Figure 1B Unlike the bodyweight profile, the body temperature was found to be unrelated to the Agg-E stress ( Figure S2B-C) although other studies have reported the alteration of core body temperature as a consequence of emotional disturbances (41,42). Nevertheless, a significant strain-to-strain difference was registered in the longitudinal alteration of pre-stress temperature of Agg-E mice.…”

Circadian Rhythms and Psychopathology: From Models of Depression to Rhythms in Clock Gene Expression and Back Again

“…There are also some important contrasts between the in vivo and in vitro observations made by Logan et al (1). When brain areas were studied in vitro ( Figure 5 in Logan et al [1]), the daily oscillations of PER2 luciferase activity were similar in phase and period but exhibited different amplitude oscillations in the SCN and NAc in response to UCMS.…”

“…To gain insight into the role of local clock function in UCMS-induced behavioral changes, it will also be important to disrupt the circadian feedback loop in a region-specific manner with Cre-Lox recombination or RNA-interference strategies. Whatever the approach, now that Logan et al (1) have clearly identified behavioral correlates of specific rhythms of clock gene expression in the NAc and SCN, this finding will help to direct future research toward the elucidation of this more general link between circadian rhythms and psychopathology.…”

“…One critical difference between these methods is that the in vitro rhythms of luciferase expression represent a stronger demonstration that rhythms within a particular brain area are autonomous and independent from cyclical environmental and biological cues. Logan et al (1) are among the first to report robust oscillations in PER2 expression in the explanted prefrontal cortex and basolateral amygdala and, to a lesser/noisier extent, the central nucleus of the amygdala and ventral tegmental area for at least 3-4 days after explantation ( Figure S5 in Logan et al [1]). However, compared with the nearly indefinite rhythms of the explanted SCN that are sustained for weeks to months, it is unclear how long these extra-SCN rhythms would continue unabated.…”

“…When brain areas were studied in vitro ( Figure 5 in Logan et al [1]), the daily oscillations of PER2 luciferase activity were similar in phase and period but exhibited different amplitude oscillations in the SCN and NAc in response to UCMS. However, when messenger RNA expression was studied in vivo ( Figure 6 in Logan et al [1]), there appeared to be changes in the amplitude and the phase of several clock gene rhythms (Figure 7 in Logan et al [1]) in response to UCMS. These differences could stem from the fact that the PER2: Luciferase fusion protein undoubtedly captures some posttranscriptional and post-translational modifications, which are important (9) but are missing from raw measures of relative mRNA expression.…”