Neonatal corticosterone administration impairs adult eyeblink conditioning and decreases glucocorticoid receptor expression in the cerebellar interpositus nucleus

Abstract

Neonatal maternal separation alters adult learning and memory. Previously, we showed that neonatal separation impaired eyeblink conditioning in adult rats and increased glucocorticoid receptor (GR) expression in the cerebellar interpositus nucleus, a critical site of learning-related plasticity. Daily neonatal separation (1h/day on postnatal days 2-14) increases neonatal plasma corticosterone levels. Therefore, effects of separation on GR expression in the interpositus and consequently adult eyeblink conditioning may be mediated by neonatal increases in corticosterone. As a first step in exploring a potential role for corticosterone in the neonatal separation effects we observed, we assessed whether systemic daily (postnatal days 2-14) corticosterone injections mimic neonatal separation effects on adult eyeblink conditioning and GR expression in the interpositus. Control uninjected animals were compared to animals receiving either daily corticosterone injections or daily injections of an equal volume of vehicle. Plasma corticosterone values were measured in a separate group of control, neonatally separated, vehicle injected, or corticosterone injected pups. In adulthood, rats underwent surgery for implantation of recording and stimulating electrodes. After recovery from surgery, rats underwent 10 daily sessions of eyeblink conditioning. Then, brains were processed for GR immunohistochemistry and GR expression in the interpositus nucleus was assessed. Vehicle and corticosterone injections both produced much larger increases in neonatal plasma corticosterone than did daily maternal separation, with the largest increases occurring in the corticosterone-injected group. Neonatal corticosterone injections impaired adult eyeblink conditioning and decreased GR expression in the interpositus nucleus, while the effects of vehicle injections were intermediate. Thus, while neonatal injections and maternal separation both produce adult impairments in learning and memory, these manipulations produce opposite changes in GR expression. This suggests an inverted U-shaped relationship may exist between both neonatal corticosterone levels and adult GR expression in the interpositus nucleus, and adult GR expression in the interpositus and eyeblink conditioning.

Modest elevation of corticosterone in preweanling rats impairs subsequent trace eyeblink conditioning during the juvenile period

“…Species such as the guinea pig and human that are born more mature experience significant brain and neuroendorcrine development in utero, resulting in greater vulnerability to glucocorticoid exposure and stress during the prenatal period. Furthermore, studies in the rat and guinea pig have revealed that moderate glucocorticoid exposure during a period of significant brain growth results in modified corticosteroid receptor expression in the adult brain [58-59]. The present study is consistent with these and similar studies indicating that even short duration and modest glucocorticoid exposure at a time of continued brain growth and neuroendocrine development produces effects that last beyond the time of the exposure.…”

Influence of postnatal glucocorticoids on hippocampal-dependent learning varies with elevation patterns and administration methods

“…Certainly Wilber et al, (2007, 2010, 2011) demonstrated that early postnatal maternal separation and corticosterone administration during the SHRP resulted in impaired delay eyeblink conditioning for males in adulthood, but not females, and that the deficits corresponded with enhanced GR expression in the interpositus nucleus of the cerebellum, an area critical for this form of associative learning. However, our results obtained by manipulating corticosterone after the SHRP are consistent with adult human studies suggesting that hippocampus-mediated trace, but not delay conditioning, is more sensitive to these later variations in glucocorticoid levels.…”

The Cerebellum, Sensitive Periods, and Autism

“…Experimentally, brain development in rodent pups, which closely resembles brain development in humans during the second and third semester (Workman et al, 2013), is influenced by stress due to variation in maternal care, leading to epigenetic variation (Gudsnuk and Champagne, 2011) and long-term changes in behavior (Moriceau et al, 2010). Stress in rodent pups alters the excitable properties of CNS neurons (Schneider et al, 2013), decreases hypothalamic-pituitary-gonadal axis reactivity (McEwen, 2007), and impairs cerebellar learning in adulthood (Wilber et al, 2011). Speculatively, in the case of ASD such mechanisms might underlie the effects of premature birth (Moster et al, 2008), elective cesarean section (Glasson et al, 2004), being born to mothers caught in a hurricane strike zone (Kinney et al, 2008a), maternal emigration (Magnusson et al, 2012), and maternal post-traumatic stress disorder (Roberts, 2014), all of which have been shown to be positively correlated with risk for autism in the offspring.…”