Chronic circadian phase advance in male mice induces depressive-like responses and suppresses neuroimmune activation

Abstract

Altered working and sleeping schedules during the COVID-19 pandemic likely impact our circadian systems. At the molecular level, clock genes form feedback inhibition loops that control 24-hr oscillations throughout the body. Importantly, core clock genes also regulate microglia, the brain resident immune cell, suggesting circadian regulation of neuroimmune function. To assess whether circadian disruption induces neuroimmune and associated behavioral changes, we mimicked chronic jetlag with a chronic phase advance (CPA) model. 32 adult male C57BL/6J mice underwent 6-hr light phase advance shifts every 3 light/dark cycles (CPA) 14 times or were maintained in standard light/dark cycles (control). CPA mice showed higher behavioral despair but not anhedonia in forced swim and sucrose preferences tests, respectively. Changes in behavior were accompanied by altered hippocampal circadian genes in CPA mice. Further, CPA suppressed expression of brain-derived neurotrophic factor (BDNF) and pro-inflammatory cytokine interleukin-1 beta in the hippocampus. Plasma corticosterone concentrations were elevated by CPA, suggesting that CPA may suppress neuroimmune pathways via glucocorticoids. These results demonstrate that chronic circadian disruption alters mood and neuroimmune function, which may have implications for shift working populations such as frontline health workers.

Exposure to Circadian Disruption During Adolescence Interacts With a Genetic Risk Factor to Modify Schizophrenia-relevant Behaviors in a Sex-dependent Manner

“…An interesting follow-up study would be to subject adult Sdy mice to CJL to see whether these changes in behaviors are still seen or whether they are restricted to disruption during adolescence. In a previous study using a similar CJL procedure, male mice showed an increased depression-like behavior but no changes found in anxiety-like behavior in the elevated plus maze (Chen et al, 2021). This is in contrast to our mice exposed to CJL during adolescence, which show alterations of anxiety-like behavior.…”

Brain-derived neurotrophic factor Val66Met polymorphism modulates the effects of circadian desynchronization on activity and sleep in male mice

“…At this stage, it is too early to know which (or all) of these outcomes contribute to the observed effects. However, a chronic phase advance circadian disruption model seems to reduce BDNF levels in the hippocampus ( Chen et al, 2021 ), suggesting that links between chronic circadian rhythm desynchronization and BDNF certainly extend beyond the SCN.…”

Circadian Clock, Glucocorticoids and NF-κB Signaling in Neuroinflammation- Implicating Glucocorticoid Induced Leucine Zipper as a Molecular Link

“…GCs regulate the expressions of clock genes in many regions of the brain (Bonaconsa et al, 2013;Chen et al, 2021;Leliavski et al, 2014;Spencer et al, 2018). Using a microdialysis probe inserted in both the jugular vein and the hippocampus in adult rats, Qian et al found that the free corticosterone in both compartments exhibited very similar rhythms (Qian et al, 2012).…”

“…However, since mouse and human tissues exhibit opposing patterns of expression of BMAL1 with respect to GC rhythm, extrapolating data from mouse models to human AD should be done with caution. Evaluating the role of GILZ in modulating inflammatory mediators in chronic jetlag represents another strategy to study the interrelationship between circadian rhythm, GILZ, and neuroinflammation (Chen et al, 2021;Shen et al, 2019). During health, release of GC is rhythmically in phase with CLOCK-BMAL1 transcripts with higher expression in the active phase (morning) and gradually decreasing reaching a nadir in the middle of the resting phase followed by gradual increase.…”

“…While the GC induced transcripts of CLOCK, BMAL1 and PER1 involved binding ofe GRE in rodent tissues, expression of PER2 mRNA was mediated by the overlapping GRE and E-box (GE2) elements in a BMAL1 dependent manner. Glucocorticoid-mediated PER2 induction delayed the phase of the circadian rhythm ( Cheon et al, 2013 ). Further, corticosterone treatment decreased the expression of the accessory clock genes REV-ERBα and RORα in a GR-dependent manner, supporting a direct trans-repressive effect ( Gibbs et al, 2012 ; Griffin et al, 2019 ).…”