Early life stress increases anxiety-like behavior in Balbc mice despite a compensatory increase in levels of postnatal maternal care

Abstract

A better understanding of the molecular and cellular mechanisms by which early life stress (ELS) modifies brain development and adult behavior is necessary for diagnosing and treating psychopathology associated with exposure to ELS. For historical reasons most of the work in rodents has been done in rats and attempts to establish robust and reproducible paradigms in the mouse have proven to be challenging. Here we show that under normal rearing conditions, increased levels of postnatal maternal care are associated with a decrease in anxiety-like behavior in BALB/cByj offspring. Brief daily pup-dam separation (BDS) during the postnatal period was associated with increased postnatal maternal care but was surprisingly associated with increased anxiety-like behavior in adult offspring, providing the first example in which offspring receiving higher levels of postnatal maternal care are more anxious in adulthood. Plasma corticosterone levels were elevated in BDS pups even three hours after the pups were reunited with the dam, suggesting that this paradigm represents a form of early life stress. We also show that levels of total RNA and DNA in the hippocampus reach a peak at postnatal day 14 and that exposure to BDS seems to inhibit this developmental growth spurt. We propose that exposure to stress during the postnatal period overrides the ability of high levels of postnatal maternal care to program anxiety-like behavior by inhibiting the normal growth spurt that characterizes this period.

The impact of early postnatal environmental enrichment on maternal care and offspring behaviour following weaning

“…However, self-grooming can be seen as a de-arousing activity which is increased in anxious rats (Spruijt et al 1992;Kalueff and Tuohimaa 2005;Voigt et al 2005). Although the present design did not allow for analysing anxiety-related behaviour in dams, earlier studies demonstrated that offspring from dams previously exposed to a stress-inducing environment will show stronger responses to anxiogenic stimuli (Plotsky and Meaney 1993;Ladd et al 2000;Wei et al 2010;Maccari et al 2014;Barzegar et al 2015). Alternatively, grooming could also be associated with the significantly increased feeding as observed in the dams in the present study.…”

“…Instead, an U-shaped inverse relationship between environmental adversity and maternal care has been suggested. Above a certain level of adversity, environmental stress could affect the pups independently of maternal care (Macri and Wurbel 2006;Wei et al 2010). For example, it remains unclear from the present study, if, and to what extent, the enrichment procedure has a direct effect on the offspring.…”

Early Life Stress Inhibits Expression of a Novel Innate Immune Pathway in the Developing Hippocampus

“…Mating, BDS exposure, and observation of maternal behavior were done as described previously (Wei et al, 2010). In brief, animals were mated using a 2 : 1 female to male ratio with visibly pregnant dams placed individually in maternity cages with no nesting material.…”

“…However, the establishment of early life stress paradigms that are associated with robust and reproducible behavioral outcomes in the mouse has proven to be a challenging task (Millstein and Holmes, 2007;Priebe et al, 2005), explaining the paucity of studies that have used unbiased genomic tools and transgenic animals to study this issue. We spent a significant effort to develop a robust early life stress paradigm in the mouse and recently showed that brief daily separation (BDS), in the highly stress-reactive mouse strain BALB/cByj, is associated with prolonged elevation of corticosterone during the postnatal period, abnormal hippocampal development, and robust behavioral changes in adulthood that occur despite a compensatory increase in maternal care (Wei et al, 2010).…”

Molecular Mechanisms of Neurodevelopmental Alterations in Prenatal and Neonatal Periods

“…Важно, что даже после возвращения потомства к матери в экспери-менте на животных, уровень глюкокортикоидов в крови детенышей остается высоким, что результирует в нару-шении синтеза белков и пролиферации клеток в течение длительного периода [47], а также может обусловливать нарушение когнитивных функций.…”