Timing is everything: Developmental differences in the effect of chronic corticosterone exposure on extinction retention.

Abstract

Adolescence is noted as a time of “storm and stress.” In this developmental stage both rodents and humans exhibit an impairment in the extinction of learned fear; however, this impairment can be alleviated, at least in rodents, by increasing the amount of extinction training given or by administering the partial NMDA receptor agonist D-Cycloserine. In the present study we explored whether the benefits of these treatments would be reduced by chronic exogenous corticosterone (a commonly studied stress-related hormone). In 2 experiments, adolescent rats were given pairings of a white noise and shock (acquisition) and then given extinction training (white noise presented alone). In Experiment 1, adolescents exhibited impaired extinction retention even after 2 days of extinction training if they had been exposed to corticosterone in adolescence but not if the exposure occurred when they were juveniles. In Experiment 2, exposure to exogenous corticosterone in adolescence, but not during the juvenile period, reduced the efficacy of the pharmacological adjunct D-Cycloserine at enhancing extinction retention after 1 day of extinction training. Taken together, the results support the idea that adolescence is a time of particular susceptibility to elevated levels of the stress hormone corticosterone.

Maturational Changes in Prefrontal and Amygdala Circuits in Adolescence: Implications for Understanding Fear Inhibition during a Vulnerable Period of Development

“…In terms of effects on fear extinction in adolescence, chronic stressor exposure by restraint or social instability in adolescence impairs the acquisition or retention of extinction memories when tested in adolescence relative to non-stressed controls [100,101,102]. Adolescence appears to be a particularly stress-sensitive developmental period in terms of fear regulation because animals are more susceptible to extinction deficits when stress occurs during adolescence compared to when it occurs in the juvenile period [103] or adulthood [102,104]. Further, such deficits induced by adolescent stress are long-lasting, persisting into adulthood [104].…”

“…The consequences of adolescent stress on fear extinction are important clinically when considering strategies for chronically stressed youth presenting for treatment of anxiety disorders. This is because chronic exposure to the stress hormone corticosterone in adolescence reduces the benefit of two approaches that augment extinction retention in adolescent rats, namely extra extinction training [103,104] and pharmacological augmentation by DCS [103]. Such results suggest that a history of chronic stress could further reduce the efficacy of anxiety treatments in adolescents.…”

Pharmacological Enhancement of Extinction Retention in Non-stressed Adolescent Rats but Not Those Exposed to Chronic Corticosterone

“…Adolescent rats exposed to corticosterone displayed significantly higher CS-elicited freezing at the extinction retention test, as compared to rats exposed to vehicle or water, which did not differ from each other, following extended extinction training ( Den et al, 2014 ). In another set of experiments, Stylianakis et al (2019) replicated those effects and further reported that pharmacological enhancement of extinction retention by DCS in adolescent rats was abolished when animals had been exposed to chronic corticosterone in their drinking water. These findings suggest that two methods that have been shown to ameliorate the extinction retention deficit in non-stressed adolescent rats, extended extinction training and DCS, do not facilitate extinction retention in adolescents exposed to chronic stress.…”

“…Placebo pellets, purchased from the same supplier, were the same size and consisted of the same matrix without the corticosterone. Dose and duration of hormone administration were chosen based on the average daily dose consumed by rats across 7 days of corticosterone administration in drinking water in our previous studies on extinction in stressed adolescent rats (i.e., Den et al, 2014 ; Stylianakis et al, 2019 ). Before implantation of pellets, animals received a pre-emptive subcutaneous (s.c.) injection of the non-steroidal anti-inflammatory analgesic Carprofen (5 mg/kg; 1 ml/kg).…”

“…An important consideration in the use of behavioral or pharmacological interventions to enhance extinction is that exposure to chronic stress can affect their efficacy in adolescent rats ( Stylianakis et al, 2019 ). Specifically, exposure to chronic stress during adolescence impairs extinction retention even after extended extinction training.…”