Adolescent Alcohol Exposure Results in Sex-specific Alterations in Conditioned Fear Learning and Memory in Adulthood

Abstract

The present study used auditory fear conditioning to assess the impact of repeated binge-like episodes of alcohol exposure during adolescence on conditioned fear in adulthood. Male and female Long-Evans rats were subjected to adolescent intermittent ethanol (AIE) exposure by vapor inhalation between post-natal day 28 and 44. After aging into adulthood, rats then underwent fear conditioning by exposure to a series of tone-shock pairings. This was followed by cued-tone extinction training, and then testing of fear recovery. In male rats, AIE exposure enhanced conditioned freezing but did not alter the time-course of extinction of cued-tone freezing. During subsequent assessment of fear recovery, AIE exposed rats exhibited less freezing during contextual fear renewal, but greater freezing during extinction recall and spontaneous recovery. Compared to males, female rats exhibited significantly lower levels of freezing during fear conditioning, more rapid extinction of freezing behavior, and significantly lower levels of freezing during the tests of fear recovery. Unlike males that were all classified as high conditioners; female rats could be parsed into either a high or low conditioning group. However, irrespective of their level of conditioned freezing, both the high and low conditioning groups of female rats exhibited rapid extinction of conditioned freezing behavior and comparatively low levels of freezing in tests of fear recovery. Regardless of group classification, AIE had no effect on freezing behavior in female rats during acquisition, extinction, or fear recovery. Lastly, exposure of male rats to the mGlu5 positive allosteric modulator CDPPB prevented AIE-induced alterations in freezing. Taken together, these observations demonstrate sex-specific changes in conditioned fear behaviors that are reversible by pharmacological interventions that target mGlu5 receptor activation.

Adolescent alcohol exposure alters threat avoidance in adulthood

“…While the limited number of studies involving traditional fear-conditioning and extinction paradigms have yielded some conflicting conservations (Velasco et al, 2019 ), they tend to suggest that female rats display a reduction in the acquisition of contextual fear conditioning compared to males (Maren et al, 1994 ; Pryce et al, 1999 ; Wiltgen et al, 2001 ; Kosten et al, 2005 ; Gresack et al, 2009 ; Ribeiro et al, 2010 ). In agreement with this, we recently reported that female Long-Evans rats exhibited lower levels of freezing during fear conditioning, more rapid extinction of freezing behavior, and lower levels of freezing during fear recovery compared to male rats (Chandler et al, 2022 ). With active avoidance paradigms, some studies suggest that females rats may adopt more active coping strategies compared to male rats and that female rats exhibit an increase in risk-aversive behavior, which may promote increases in active avoidance compared to male rats (Beatty and Beatty, 1970 ; Steenbergen et al, 1990 ; Lalanza et al, 2015 ; Orsini et al, 2016 , 2021 ; Shanazz et al, 2022 ).…”

“…Preclinical studies investigating the long-term effects of adolescent alcohol exposure indicate that adult rats that had been subjected to repeated episodes of binge-like alcohol intoxication during adolescence display signs of increased anxiety-like behaviors and deficits in decision-making (Nasrallah et al, 2009 ; Clark et al, 2012 ; Gass et al, 2014 ; Schindler et al, 2014 ; Pandey et al, 2015 ; Crews et al, 2016 ; Barker et al, 2017 ; Chandler et al, 2022 ). There is also evidence that certain types of experiences during critical periods of adolescence can alter brain development and circuit maturation and lead to permanent changes in adult behavior, including the expression of threat responding (Dow-Edwards et al, 2019 ; Gerhard et al, 2021 ).…”

Adolescent Intermittent Ethanol Exposure Alters Adult Exploratory and Affective Behaviors, and CerebellarGrin2BExpression in C57BL/6J Mice

“…Sex differences in the acute and long-term effects of adolescent ethanol exposure are increasingly found in clinical and preclinical research. In rats, AIE exposure sex-specifically alters cognitive flexibility (Macht et al, 2020), affective behaviors (Healey et al, 2022; Varlinskaya et al, 2020), fear conditioning (Chandler et al, 2022), and social drinking (Towner et al, 2022) in adulthood. We recently showed that male and female AIE-exposed mice showed sex-specific patterns of subsequent ethanol drinking and withdrawal period-dependent differences in affective behaviors.…”

“…Sex differences in the acute and long-term effects of adolescent ethanol exposure are increasingly found in clinical and preclinical research. In rats, AIE exposure sex-specifically alters cognitive flexibility (Macht et al, 2020), affective behaviors (Healey et al, 2022;Varlinskaya et al, 2020), fear conditioning (Chandler et al, 2022), and social drinking (Towner et al, 2022) in adulthood.…”

Comparative gene pathway analysis during adolescent binge-EtOH exposure, withdrawal, and following abstinence

“…Parallels are beginning to emerge between human findings and rat models of binge drinking that are consistent across laboratories (Spear and Swartzwelder, 2014, Crews et al, 2019). Hippocampal-dependent tasks, which change the goal location, include the administration of acute ethanol (EtOH) challenge, or have a higher cognitive load, reveal significant deficits in learning processes that persist into adulthood (Risher et al, 2013, Acheson et al, 2013, Coleman et al, 2014, Vetreno and Crews, 2015, Chandler et al, 2022). These behavioral deficits coincide with long-term changes in hippocampal neuronal structure and function (Fujii et al, 2008, Risher et al, 2015a, Sabeti and Gruol, 2008, Swartzwelder et al, 2016), indicative of neuronal remodeling.…”