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

Abstract

Recent interest in the lasting effects of early-life stress has expanded to include effects on cognitive performance. An increase in circulating glucocorticoids is induced by stress exposure and glucocorticoid effects on the hippocampus likely underlie many of the cognitive consequences. Here we review studies showing that corticosterone administered to young rats at the conclusion of the stress-hyporesponsiveness period affects later performance in hippocampally-mediated trace eyeblink conditioning. The nature and even direction of these effects varies with the elevation patterns (level, duration, temporal fluctuation) achieved by different administration methods. We present new time course data indicating that constant glucocorticoid elevations generally corresponded with hippocampus-mediated learning deficits, whereas acute, cyclical elevations corresponded with improved initial acquisition. Sensitivity was greater for males than for females. Further, changes in hippocampal neurogenesis paralleled some but not all effects. The findings demonstrate that specific patterns of glucocorticoid elevation produced by different drug administration procedures can have markedly different, sex-specific consequences on basic cognitive performance and underlying hippocampal physiology. Implications of these findings for glucocorticoid medications prescribed in childhood are discussed.

Keywords: Development; Eyeblink conditioning; Glucocorticoids; Hippocampus; Neurogenesis; Sex differences; Trace conditioning.

Figure 1

Schematic diagram of Trace versus Delay classical conditioning as used in the studies described here. A tone conditioned stimulus is paired with a periorbital shock unconditioned stimulus separated in time for trace conditioning, but overlapping in delay conditioning. Trace conditioning engages forebrain structures, including the hippocampus, in addition to the brainstem structures necessary for simpler delay conditioning.

Figure 2

Percentage conditioned responses for delay (left) and trace (right) conditioning on PND 28-29, two weeks after corticosterone or placebo pellets were implanted on PND 15. Effects of corticosterone were not significant for delay conditioning but a significant impairment in acquisition of trace was observed for males only. (Adapted from Claflin et al., 2005)

Figure 3

Percentage and amplitude of adaptive conditioned responses for trace conditioning on PND 28-29, two weeks after corticosterone or vehicle mini-pumps were implanted on PND 15. Impairment in CR amplitude was statistically significant. (Adapted from Claflin et al., 2014)

Figure 4

Percentage of CRs plotted separately for males and females. Impairment following corticosterone delivery was not significant, though males administered corticosterone exhibited numerically lower percentages of responses throughout training than did corticosterone-treated females.

Figure 5

Percentage of adaptive conditioned responses for males only during trace conditioning on PND 28-29. Facilitation in CR percentage was statistically significant in the first session (left). Right panel shows Session 1 data only, across blocks of 9 trials. Facilitation of initial acquisition during Session 1 was statistically significant the high dose corticosterone-treated males relative to the control males. (Adapted from Wentworth-Eidsaune et al., 2016)

Figure 6

Circulating corticosterone levels over time (hours and days, all starting at PND 15) for the three administration methods, pellets (A), mini-pumps (B), and injection (C). Commercially available pellets contained 35 mg of corticosterone intended to release slowly over 21 days. Osmotic mini-pumps were loaded with 100 μl of 50 mg/ml of corticosterone and designed to release at a steady rate of 1μl/hr over 3 days. Injections were dosed at 20 mg/kg and administered at 9 a.m. and 5 p.m. for 3 days.

Figure 7

Confocal images of dorsal dentate gyrus showing all fluorescent co-labelling (left). Immunohistochemical staining (right) allowed us to identify newly generated neurons: a) combined fluorochromes, b) BrdU labeled cells (any dividing cells), c) NeuN labeled mature neurons, and d) GFAP/Sox-10 labeled glia. The yellow perimeter tracing was used for calculating the cross-sectional area/volume of the dorsal dentate gyrus.

Figure 8

Total number of newly generated neurons (includes both mature and immature neurons) on PND 28, two weeks after corticosterone treatments began by pellet, injection, and mini-pump methods. Statistically significant effects of corticosterone treatment were found within the pellet groups only. Untreated control data are provided for comparison.