Perinatal Stress Programs Sex Differences in the Behavioral and Molecular Chronobiological Profile of Rats Maintained Under a 12-h Light-Dark Cycle

Abstract

Stress and the circadian systems play a major role in an organism’s adaptation to environmental changes. The adaptive value of the stress system is reactive while that of the circadian system is predictive. Dysfunctions in these two systems may account for many clinically relevant disorders. Despite the evidence that interindividual differences in stress sensitivity and in the functioning of the circadian system are related, there is limited integrated research on these topics. Moreover, sex differences in these systems are poorly investigated. We used the perinatal stress (PRS) rat model, a well-characterized model of maladaptive programming of reactive and predictive adaptation, to monitor the running wheel behavior in male and female adult PRS rats, under a normal light/dark cycle as well as in response to a chronobiological stressor (6-h phase advance/shift). We then analyzed across different time points the expression of genes involved in circadian clocks, stress response, signaling, and glucose metabolism regulation in the suprachiasmatic nucleus (SCN). In the unstressed control group, we found a sex-specific profile that was either enhanced or inverted by PRS. Also, PRS disrupted circadian wheel-running behavior by inducing a phase advance in the activity of males and hypoactivity in females and increased vulnerability to chronobiological stress in both sexes. We also observed oscillations of several genes in the SCN of the unstressed group in both sexes. PRS affected males to greater extent than females, with PRS males displaying a pattern similar to unstressed females. Altogether, our findings provide evidence for a specific profile of dysmasculinization induced by PRS at the behavioral and molecular level, thus advocating the necessity to include sex as a biological variable to study the set-up of circadian system in animal models.

Maternal stress programs a demasculinization of glutamatergic transmission in stress-related brain regions of aged rats

“…That is, it did not induce defeminization. These findings are consistent with previous data obtained in adult rats [ 42 ]. Thus, PRS demasculinizes rather than defeminizes, and indeed male PRS rats exhibited a profile similar to that of female PRS rats.…”

Early Life Stress Restricts Translational Reactivity in CA3 Neurons Associated With Altered Stress Responses in Adulthood

“…Glucocorticoid receptors play a key role in the programming of the ELS synapse as well as impaired response to AS (Weaver et al, 2004a,b; Meaney and Szyf, 2005; Mifsud and Reul, 2018). Moreover, transcriptional disruption of circadian rhythms is observed across diverse animal models of early life adversities (Baranger et al, 2016; Nätt et al, 2017; Yam et al, 2017; Morley-Fletcher et al, 2019). Neuropeptide Y (Npy) is implicated in the regulation of hippocampal synaptic plasticity and circuit structure in a model of predator scent stress (Li et al, 2017), while Nfkbia is involved in stress sensitization and recovery in a double-hit model of stress (Gray et al, 2014).…”

Sex-Dependent Effects of Piromelatine Treatment on Sleep-Wake Cycle and Sleep Structure of Prenatally Stressed Rats

“…Experimental studies on the model of prenatal stress (PNS), including our recent report, revealed that repeated stress procedures during pregnancy could cause long-term neurobiological alterations in offspring [ 3 , 4 , 5 , 6 ]. Prenatally stressed rats showed depressive-like responses with hyperactivity of the hypothalamus–pituitary–adrenal cortex axis (HPA) suggesting that this model resembles depression in humans [ 3 , 6 , 7 , 8 , 9 , 10 ]. Moreover, sex-dependent behavioral and biochemical differences were observed in the PNS model, with female rats exhibiting heavier concomitant disturbance than male offspring [ 3 , 6 , 7 , 8 , 9 ].…”

“…Prenatally stressed rats showed depressive-like responses with hyperactivity of the hypothalamus–pituitary–adrenal cortex axis (HPA) suggesting that this model resembles depression in humans [ 3 , 6 , 7 , 8 , 9 , 10 ]. Moreover, sex-dependent behavioral and biochemical differences were observed in the PNS model, with female rats exhibiting heavier concomitant disturbance than male offspring [ 3 , 6 , 7 , 8 , 9 ]. Offspring with a history of PNS have disturbed rhythms of motor activity and sleep/wake cycle [ 4 , 5 , 7 ].…”

“…Moreover, sex-dependent behavioral and biochemical differences were observed in the PNS model, with female rats exhibiting heavier concomitant disturbance than male offspring [ 3 , 6 , 7 , 8 , 9 ]. Offspring with a history of PNS have disturbed rhythms of motor activity and sleep/wake cycle [ 4 , 5 , 7 ]. Clinical studies demonstrated a positive correlation between impaired sleep architecture and depressive behavior [ 10 , 11 ].…”