Dragana Ivkovich Claflin

Infant Stress Exposure Produces Persistent Enhancement of Fear Learning Across Development

In recent years, it has become increasingly clear that early life stress experiences persistently impact subsequent physiological, cognitive, and emotional responses. In cases of trauma, these early experiences can result in anxiety disorders such as phobias and posttraumatic stress disorder. In the present paper, we examined the effects of infant footshock stress exposure at postnatal day (PND) 17 on subsequent contextual fear conditioning at postnatal days 18 (Experiment 1), 24 (Experiment 2), or 90 (Experiment 3). In each experiment, PND17 footshock stress exposure enhanced later fear conditioning, indicating that the stress enhancement of fear learning (SEFL) persists throughout development. Memory for the original stress exposure context was gradually forgotten, with significant fear expression evident at PND20, and a complete lack of fear expression in that same context at PND90. These data suggest that the stress-enhancing component of infant fear learning is dissociable from the infant contextual fear memory per se. In other words, early life stress produces persistent effects on subsequent cognition that are independent of the memory for that early life event.

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

The hippocampus is known to be especially sensitive to the deleterious effects of glucocorticoids. Previously, we administered exogenous corticosterone, the major stress-related glucocorticoid in rats, to young developing rats using subcutaneous pellets which produced high pharmacological levels of circulating corticosterone as well as a sex-specific learning deficit for males on a hippocampus-mediated associative learning task, trace eyeblink conditioning [1]. The present study evaluated the effects of corticosterone administered at a physiologically-relevant level by a more consistent release method, osmotic mini-pumps. Pumps were implanted subcutaneously in 15-day-old rats to deliver either corticosterone or the vehicle control (PEG) at a rate of 1 μl/h over 3 days. On Day 28, learning was assessed using trace eyeblink conditioning. The results of the present experiment revealed that a small elevation in corticosterone (11.77 μg/dl versus 6.02 μg/dl for controls) within the normal physiological range impaired learning as determined by a significantly lower percentage and amplitude of total conditioned responses (CRs) and lower amplitude of adaptive responses relative to the control group. There were no significant differences in response timing, although the corticosterone group tended to produce CRs which began and peaked a little later than controls. These findings indicate that even modest elevations of corticosterone for several days can produce later impairments on this hippocampally mediated learning task.

CS-US Preexposure Effects on Trace Eyeblink Conditioning in Young Rats: Potential Implications for Functional Brain Development

Recent studies of delay eyeblink conditioning (EBC) in young rats have demonstrated different effects of various conditioned and unconditioned stimulus (CS-US) preexposure conditions on learning at different ages. The present study extends this research to trace EBC. Subjects experienced 1 of 3 preexposure conditions (paired CS-US, unpaired CS-US, or no stimuli) at either 20 or 24 days of age. Four days later, they were conditioned using either trace (Experiment 1) or delay (Experiment 2) EBC parameters. Results were similar at both ages tested. Paired preexposure facilitated acquisition of delay but not trace relative to context preexposure. Unpaired preexposure impaired acquisition of both delay and trace. These behavioral findings provide a foundation for hypotheses about the functional maturation of cerebellar, hippocampal, and entorhinal learning circuits.

Short-term, high-dose administration of corticosterone by injection facilitates trace eyeblink conditioning in young male rats.

Glucocorticoids released as part of the physiological response to stress are known to affect cognitive function, presumably via effects on the hippocampus. Trace classical eyeblink conditioning is an associative learning task which depends on the hippocampus and has been used to examine the development of learning processes in young mammals. Previously, we demonstrated deficits in trace eyeblink conditioning associated with postnatal administration of the glucocorticoid corticosterone by creating a sustained elevation with methods such as subcutaneous timed-release pellets and osmotic mini-pumps which were active over several days. In the present study, we examined the effects of an oscillating pattern of corticosterone elevation on subsequent trace eyeblink conditioning. Twice daily corticosterone injections (high, low, or vehicle) were administered over a 3-day period, starting at postnatal day 15. Then, on postnatal day 28, animals underwent trace classical eyeblink conditioning to examine the possible influence of earlier corticosterone elevations on the development of learning and memory. Eyeblink conditioning was affected by corticosterone treatments, but only for males, and only very early in acquisition; Males receiving the high dose of corticosterone exhibited facilitation of learning relative to controls. These data demonstrate that oscillating corticosterone elevations produce opposite effects on this associative learning task than do sustained elevations.

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

HighlightsPreweaning glucocorticoids affect later eyeblink trace conditioning.Varying glucocorticoid elevation patterns differentially affect later cognition.Greater sensitivity of males to glucocorticoid effects on hippocampal tasks. 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.