Aberrant Early in Life Stimulation of the Stress-Response System Affects Emotional Contagion and Oxytocin Regulation in Adult Male Mice

Abstract

Results over the last decades have provided evidence suggesting that HPA axis dysfunction is a major risk factor predisposing to the development of psychopathological behaviour. This susceptibility can be programmed during developmental windows of marked neuroplasticity, allowing early-life adversity to convey vulnerability to mental illness later in life. Besides genetic predisposition, also environmental factors play a pivotal role in this process, through embodiment of the mother’s emotions, or via nutrients and hormones transferred through the placenta and the maternal milk. The aim of the current translational study was to mimic a severe stress condition by exposing female CD-1 mouse dams to abnormal levels of corticosterone (80 µg/mL) in the drinking water either during the last week of pregnancy (PreCORT) or the first one of lactation (PostCORT), compared to an Animal Facility Rearing (AFR) control group. When tested as adults, male mice from PostCORT offspring and somewhat less the PreCORT mice exhibited a markedly increased corticosterone response to acute restraint stress, compared to perinatal AFR controls. Aberrant persistence of adolescence-typical increased interest towards novel social stimuli and somewhat deficient emotional contagion also characterised profiles in both perinatal-CORT groups. Intranasal oxytocin (0 or 20.0 µg/kg) generally managed to reduce the stress response and restore a regular behavioural phenotype. Alterations in density of glucocorticoid and mineralocorticoid receptors, oxytocin and µ- and κ-opioid receptors were found. Changes differed as a function of brain areas and the specific age window of perinatal aberrant stimulation of the HPA axis. Present results provided experimental evidence in a translational mouse model that precocious adversity represents a risk factor predisposing to the development of psychopathological behaviour.

Callous unemotional trait-like mice and their stressed dams

“…In parallel with clinical evidence, preclinical investigations (Panksepp and Panksepp, 2013) describe a neuro-endocrine network, which includes oxytocin and vasopressin and the hypothalamic-pituitary-adrenal (HPA) axis, at the basis of a plethora of behaviors including empathy, sociability and emotional memory. According to recent reports from our lab (Laviola et al, 2017;Zoratto et al, 2018Zoratto et al, , 2019, we originally hypothesised that dampened physiological reactivity to external stressors may represent a proxy for callous-unemotional trait-like and tested this hypothesis through the evaluation of concurrent phenotypes in an experimental model (Macrì et al, 2016; see also Laviola et al, 2021).…”

“…The effects of stress on emotional contagion appear to be mediated by both high-affinity MRs, known to mediate the effects of basal glucocorticoids, and the lower-affinity GRs, which predominantly mediate signaling by stress-induced increases in glucocorticoid levels (Martin et al, 2015). The establishment of the physiological set up of the HPA, and its functional response to external stressors goes under strict regulation of genes and environmental variables during development (Marceau et al, 2013;Laviola et al, 2021). In most mammalian species, the mother does play a major role in this process due to nutrients, hormones and direct active care she provides to the immature offspring, particularly early in development (Macrì et al, 2011;Cirulli et al, 2003).…”

“…An increasing number of evidences also suggests the involvement in the onset of conduct disorder and other psychiatric conditions of changes of the oxytocinergic system. Indeed, the oxytonergic system along with the opioid ones belong to a neuronal network essential for social behavior and, specially, they are involved in alterations of sociability and aggressive behavior (Zoratto et al, 2018;Laviola et al, 2021). We also aimed to investigate the effects of exogenous intranasal oxytocin administrations in our mouse model (Hiraoka and Nomura, 2019;Zoratto et al, 2018).…”

“…Indeed, the interest to investigate on the use of oxytocin as a treatment for behavioral and physiological symptoms is actually great in the literature. Our study finds its rationale in the framework of the mixed literature, actually available on both preclinical and clinical studies, with the use of oxytocin, and the highly potential associated with its use for psychiatric disorders (Laviola et al, 2021).…”

“…A further aim was to analyze whether the differential milieu of early plasma corticosterone concentration and received maternal care, could modulate in the offspring the gene brain expression of neural pathways regulating stress-related behaviors (namely, the nuclear gluco/mineralcorticoid receptors) and social responses (namely, the oxytocin receptor, and the opioid receptors M1 and K1) (Reeta et al, 2006;Laviola et al, 2021).…”