Inborn stress reactivity shapes adult behavioral consequences of early-life maternal separation stress

Abstract

Early-life experience strongly impacts neurodevelopment and stress susceptibility in adulthood. Maternal separation (MS), an established model of early-life adversity, has been shown to negatively impact behavioral and endocrine responses to stress in adulthood. However, the impact of MS in rats with heightened inborn stress susceptibility has not been fully explored. To address this issue we conducted MS in Wistar-Kyoto (WKY) rats, an animal model of comorbid depression and anxiety, and Wistar rats, which share a similar genetic background with WKYs. WKY and Wistar pups experienced either 180-min daily MS or 15-min separation (neonatal handling) during the first two postnatal weeks, and were tested for depressive- and anxiety- like behaviors in adulthood. Exposure to early-life MS in WKY rats decreased anxiety- and depressive- like behaviors, leading to increased exploration on the open field test (OFT), enhanced social interaction, and diminished immobility on the forced swim test. MS had an opposite effect in Wistar offspring, leading to enhanced anxiety-like behaviors, such as reduced OFT exploration and decreased social interaction. These findings are consistent with the match/mismatch theory of disease and the predictive adaptive response, which suggest that early life stress exposure can confer adaptive value in later life within certain individuals. Our data supports this theory, showing that early-life MS has positive and perhaps adaptive effects within stress-vulnerable WKY offspring. Future studies will be required to elucidate the neurobiological underpinnings of contrasting behavioral effects of MS on WKY vs. Wistar offspring.

Paternal deprivation affects social behaviors and neurochemical systems in the offspring of socially monogamous prairie voles

“…Stress during early development can increase either anxiety-like behavior (Brunton, 2013; Maccari et al, 2014) or resilience to stressful stimuli (Faure et al, 2007; Zhang et al, 2014; Beery and Kaufer, 2015; Rana et al, 2015) in adulthood. Studies using maternal deprivation as an early life stressor have found both increased (Ishikawa et al, 2015) and decreased anxiety in adulthood in rats (Zhang et al, 2014).…”

Neonatal maternal separation stress elicits lasting DNA methylation changes in the hippocampus of stress‐reactive Wistar Kyoto rats

“…For the first phase of the experiment, male/female pairs were mated for 14 days, and at birth (postnatal day 0), litters were randomly assigned to one of two groups: (i) MS‐180 group or (ii) neonatal handling (NH) group ( n = 4 L/group/strain). Litters assigned to the MS‐180 and NH groups were separated from their dam daily for 180 and 15 min, respectively, between 8:30 and 12:00 h from postnatal day (P)1–P14 as previously described (Clinton et al ., ; Rana et al ., ). Dams remained in the home cages, while separated litters were transferred to a different room in a small cage placed on a heating pad (~37 °C).…”

“…This study exploited the WKY‐MS model to identify neurobiological and epigenetic mechanisms that mediate a PAR to convey adaptive behavioral and physiological changes in adult MS‐180‐exposed WKY offspring. We hypothesized that MS‐180 triggers DNA methylation changes in the brains of WKY offspring, which may contribute to their enhanced stress resilience in adulthood (Rana et al ., ). To test this, we first examined global DNA methylation (5‐methylcytosine) levels in multiple brain regions of adult WKY rats that were exposed to MS‐180 (or control condition).…”

“…Our final experiment tested the hypothesis that enhancing DNA methylation in adult WKYs (by increasing dietary methyl donor content) would elicit adaptive behavioral and cardiovascular changes akin to what occurred following MS‐180 exposure. Specifically, we predicted that feeding adult male WKYs a methyl donor fortified diet would: (i) have anxiolytic and antidepressant effects in tests of anxiety‐ and depression‐like behavior; and (ii) elicit positive cardiovascular changes, including reduced baseline HR and greater HR variability, similar to what we previously observed in MS‐180‐exposed WKY offspring (Rana et al ., , ).…”

“…We exposed Wistar Kyoto (WKY) offspring, a stress‐susceptible rat strain that exhibits behavioral abnormalities commonly associated with depression and anxiety disorders (Nam et al ., ), to daily 3‐h maternal separation (MS‐180) during the first 2 weeks of life. While MS‐180 has frequently been used to demonstrate deleterious effects on adult rodent emotional behavior [for review, see (Sanchez et al ., )], we found that MS‐180 elicits several adaptive effects in adult WKY offspring, including diminished behavioral despair, increased social exploration (Rana et al ., ) and improved cardiovascular measures, such as decreased baseline heart rate (HR) and increased HR variability (Rana et al ., ).…”