Sex differences in acute early life stress-enhanced fear learning in adult rats.

Patients diagnosed with posttraumatic stress disorder (PTSD) present with a spectrum of debilitating anxiety symptoms resulting from exposure to trauma. Women are twice as likely to be diagnosed with anxiety and PTSD compared to men; however, the reason for this vulnerability remains unknown. We conducted four experiments where we first demonstrated a female vulnerability to stress-enhanced fear learning (SEFL) with a moderate, acute early life stress (aELS) exposure (4 footshocks in a single session), compared to a more intense aELS exposure (15 footshocks in a single session) where males and females demonstrated comparable SEFL. Next, we demonstrated that this female vulnerability does not result from differences in footshock reactivity or contextual fear conditioning during the aELS exposure. Finally, using gonadectomy or sham surgeries in adult male and female rats, we showed that circulating levels of gonadal steroid hormones at the time of adult fear conditioning do not explain the female vulnerability to SEFL. Additional research is needed to determine whether this vulnerability can be explained by organizational effects of gonadal steroid hormones or differences in sex chromosome gene expression. Doing so is critical for a better understanding of increased female vulnerability to certain psychiatric diseases.

Social buffering of plasma corticosterone and amygdala responses of young rats following exposure to periorbital shock: Implications for eyeblink conditioning development.

The developmental onset of aversive learning processes depends on complex interactions between endocrine, neural, and social influences. Emergence of avoidance conditioning in rat pups is triggered by elevated plasma corticosterone activating the amygdala. Further, the mother's ability to buffer the corticosterone response delays the onset of avoidance in ˜2-week-old pups. Eyeblink conditioning (EBC) also develops during the pre-weaning period. In previous work, little or no conditioning was observed on Day 17 for pups housed in the home cage with mother and littermates between training sessions, whereas pups isolated between training sessions did show some conditioning. This suggests that social buffering may also delay the onset of this form of aversive learning. In the present study with Day-17 pups, one session of periorbital shock, the typical EBC unconditioned stimulus for young rat pups, resulted in lower plasma corticosterone levels and neural activity in the central nucleus of the amygdale (CeA) of pups returned to the mother and homecage following the session as compared to pups isolated following the shock session. These findings demonstrate social buffering of the physiological response to aversive stimulus exposure under conditions of EBC and support the hypothesis that social buffering of early adverse experience may adjust the timing of emergence of EBC in rat pups. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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

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.

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.

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.

Effect of delay interval on classical eyeblink conditioning in 5-month-old human infants.

Associative learning was evaluated in human infants with simple delay classical eyeblink conditioning. A tone conditioned stimulus (CS) was paired with an airpuff unconditioned stimulus (US) at three different delay intervals (250, 650, and 1,250 ms). Independent groups of healthy, full-term 5-month-old human infants were assigned to these three paired conditions and received two identical training sessions 1 week apart. The two longer delays resulted in associative conditioning, as confirmed by comparison with unpaired control groups. However, only at the 650-ms delay were associative eyeblinks adaptively timed to avoid the airpuff. The delay function at 5 months of age appears much sharper than is observed in adults. Together with the findings of A. H. Little, L. P. Lipsitt, and C. Rovee-Collier (1984), the present study suggests a downward shift in the optimal delay interval for associative eyeblink conditioning between 1 and 6 months of age. However, this delay remains longer than what is typically reported in adults.