Chronic Social Defeat Stress Shifts Peripheral Circadian Clocks in Male Mice in a Tissue-Specific and Time-of-Day Dependent Fashion

Uncontrollable stress is linked to the development of many diseases, some of which are associated with disrupted daily rhythms in physiology and behavior. While available data indicate that the master circadian pacemaker in the suprachiasmatic nucleus (SCN) is unaffected by stress, accumulating evidence suggest that circadian oscillators in peripheral tissues and organs can be shifted by a variety of stressors and stress hormones. In the present study, we examined effects of acute and chronic social defeat stress in mice and addressed the question of whether effects of uncontrollable stress on peripheral clocks are tissue specific and depend on time of day of stress exposure. We used mice that carry a luciferase reporter gene fused to the circadian clock gene Period2 (PER2::LUC) to examine daily rhythms of PER2 expression in various peripheral tissues. Mice were exposed to social defeat stress in the early (ZT13-14) or late (ZT21-22) dark phase, either once (acute stress) or repeatedly on 10 consecutive days (chronic stress). One hour after the last stressor, tissue samples from liver, lung, kidney, and white adipose tissue (WAT) were collected. Social defeat stress caused a phase delay of several hours in the rhythm of PER2 expression in lung and kidney, but this delay was stronger after chronic than after acute stress. Moreover, shifts only occurred after stress in the late dark phase, not in the early dark phase. PER2 rhythms in liver and WAT were not significantly shifted by social defeat, suggesting a different response of various peripheral clocks to stress. This study indicates that uncontrollable social defeat stress is capable of shifting peripheral clocks in a time of day dependent and tissue specific manner. These shifts in peripheral clocks were smaller or absent after a single stress exposure and may therefore be the consequence of a cumulative chronic stress effect.

Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice

Background Innate immune pre-stimulation can prevent the development of depression-like behaviors in chronically stressed mice; however, whether the same stimulation prevents the development of anxiety-like behaviors in animals remains unclear. We addressed this issue using monophosphoryl lipid A (MPL), a derivative of lipopolysaccharide (LPS) that lacks undesirable properties of LPS but still keeps immune-enhancing activities. Methods The experimental mice were pre-injected intraperitoneally with MPL before stress exposure. Depression was induced through chronic social defeat stress (CSDS). Behavioral tests were conducted to identify anxiety-like behaviors. Real-time polymerase chain reaction (PCR) and biochemical assays were employed to examine the gene and protein expression levels of pro-inflammatory markers. Results A single MPL injection at the dose of 400 and 800 μg/kg 1 day before stress exposure prevented CSDS-induced anxiety-like behaviors, and a single MPL injection (400 μg/kg) five but not 10 days before stress exposure produced similar effect. The preventive effect of MPL on anxiety-like behaviors was also observed in CSDS mice who received a second MPL injection 10 days after the first MPL injection or a 4 × MPL injection 10 days before stress exposure. MPL pre-injection also prevented the production of pro-inflammatory cytokines in the hippocampus and medial prefrontal cortex in CSDS mice, and inhibiting the central immune response by minocycline pretreatment abrogated the preventive effect of MPL on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine productions in the brain. Conclusions Pre-stimulation of the innate immune system by MPL can prevent chronic stress-induced anxiety-like behaviors and neuroinflammatory responses in the brain in mice.

Effects of Chronic Social Defeat Stress on Behavior and Dopamine Receptors in Adolescent Mice With 6-Hydroxydopamine Lesions of the Medial Prefrontal Cortex

Background: Social stress factors in schizophrenia have long-term effects, but will only induce symptoms in a portion of individuals, even if exposed to identical stress.Methods: In the current experiment, we examined mice with 6-hydroxydopamine (6-OHDA)-induced medial prefrontal cortical (mPFC) injury to select for members of a “stress-susceptible group,” and observed the changes in their behavior and the expression of D1 and D2 dopamine receptors in the amygdala and hippocampus.Results: We observed that after chronic social defeat stress, 72.6% of the 6-OHDA lesioned mice exhibited stress response to aggressors, compared to 52.3% of the blank control group. Both the 6-OHDA lesion + social defeat and social defeat groups exhibited anxiety and depression-like behavior. However, social cognitive impairment in the mice from the 6-OHDA lesion + social defeat group was more significant and the D1 expression levels in the amygdala were significantly decreased.Conclusion: These results suggest that the reason that adolescent mice with cortical injury were highly sensitive to defeat stress and had more prominent social cognitive impairment may be the decreased selectivity of D1 in the amygdala.

A novel mouse model of postpartum depression using emotional stress as evaluated by nesting behavior

Postpartum depression is an important mental health issue not only for the mother but also for the child’s development, other family members, and the society. An appropriate animal model is desired to elucidate the pathogenesis of postpartum depression. However, methods for stress loading during pregnancy have not been established. Behavioral experiments to investigate postpartum depression-like behaviors should be conducted without stress because behavioral tests affect rearing behaviors such as lactation. Therefore, we developed a new mouse model of postpartum depression using a psychological stress method. Mating partners were made to witness their partners experiencing social defeat stress and then listen to their cries. Emotional stress loading during pregnancy significantly increased postpartum depression-like behaviors. Postpartum depression also affected nurturing behaviors and caused disturbances in pup care. Furthermore, nesting behavior was impaired in the stressed group, suggesting that the observation of nesting behavior may be useful for assessing social dysfunction in postpartum depression. These results demonstrate the utility of this new mouse model of postpartum depression.