Hippocampal neurogenesis mediates sex-specific effects of social isolation and exercise on fear extinction in adolescence.

Impaired extinction of conditioned fear is associated with anxiety disorders. Common lifestyle factors, like isolation stress and exercise, may alter the ability to extinguish fear. However, the effect of and interplay between these factors on adolescent fear extinction, and the relevant underlying neural mechanisms are unknown. Here we examined the effects of periadolescent social isolation and physical activity on adolescent fear extinction in rats and explored neurogenesis as a potential mechanism. Isolation stress impaired extinction recall in male adolescents, an effect prevented by exercise. Extinction recall in female adolescents was unaffected by isolation stress. However, exercise disrupted extinction recall in isolated females. Extinction recall in isolated females was positively correlated to the number of immature neurons in the ventral hippocampus, suggesting that exercise affected extinction recall via neurogenesis in females. Pharmacologically suppressing cellular proliferation in isolated adolescents using temozolomide blocked the effect of exercise on extinction recall in both sexes. Together, these findings highlight sex-specific outcomes of isolation stress and exercise on adolescent brain and behavior, and highlights neurogenesis as a potential mechanism underlying lifestyle effects on adolescent fear extinction.

Assessing methamphetamine-related cue reactivity in people with methamphetamine use disorder relative to controls.

Methamphetamine use disorder involves methamphetamine-related cues invoking intense craving leading to relapse. Such cue reactivity is thought to arise from Pavlovian conditioning that occurs during the drug-taking experience. Cue reactivity then should be selective to methamphetamine cues (and not other cues), and not observed in people who have never experienced methamphetamine. However, these premises have never been tested and reported using objective measures such as skin conductance response (SCR). The primary aim of this study was to test these premises using a cue reactivity paradigm we developed using control cues. The secondary aim was to explore the relationship between cue reactivity, drug use characteristics, and cognition. Thirty people with a current diagnosis of methamphetamine use disorder and 30 matched controls with no history of substance use disorder were recruited. We observed higher overall subjective reactivity (F = 62.810; p < 0.001) and cue-selective physiological reactivity (F = 5.160; p = 0.026) in people with methamphetamine use disorder but not in controls. Co-morbid sedative use was associated with higher subjective craving (r = 0.521; p = 0.003). People who use methamphetamine intravenously had higher cue-selective SCR than smokers (t = 3.750; p < 0.001). Low inhibitory control measured by the Stroop task was associated with increased craving across the cue paradigm (r = -0.494; p = 0.006). Overall, these results support that cue reactivity in people with methamphetamine use disorder is due to Pavlovian conditioning. Its association with drug use and cognition highlights cue reactivity paradigm's utility in understanding methamphetamine use disorder to develop new treatments targeting cue-induced craving.

Extinction and drug-induced reinstatement of cocaine seeking following self-administration or conditioned place preference in adolescent and adult rats.

Adolescence marks a particularly vulnerable period to developing substance use disorders, and people who start using drugs in adolescence are more likely to relapse. A limited number of studies have investigated age difference in relapse following re-exposure to the drug after a period of abstinence. Using a cocaine self-administration paradigm, we showed no age difference in acquisition or extinction of self-administration. Interestingly, adolescent rats displayed impaired cocaine-primed reinstatement of cocaine seeking. Using the same dose as that self-administered in the first experiment, we then investigated age differences in acquisition and extinction of conditioned place preference, as well as locomotor sensitization. While there were no differences in locomotor activity or acquisition of preference, adolescents failed to extinguish their preference, even when the number of extinction sessions was doubled from what adults received. Taken together, these results suggest that while cocaine has similar rewarding and reinforcing effects regardless of age, adolescents may attribute stronger salience to the drug-associated context. In addition, re-exposure to cocaine itself may not be a strong relapse trigger in adolescence. Overall, these findings suggest that we should focus more on alleviating drug-context salience compared to re-exposure to substance in order to reduce relapse of drug seeking in adolescents.

Sex differences in the neurochemistry of frontal cortex: Impact of early life stress.

Traumatic events during early life have been linked with later life psychopathology. To understand this risk factor, researchers have studied the effects of prenatal and postnatal early life stress on neurochemical changes. Here we review the rodent literature on sex differences and sex-specific impact of early life stress on frontal cortex neurochemistry. This region is implicated in regulating motivation and emotion, which are often disrupted in psychological disorders. The prefrontal cortex (PFC) in particular is one of the last brain regions to develop, and there are sex differences in the rate of this development. To draw direct comparisons between sexes, our review of the literature was restricted to studies where the effects of prenatal or postnatal stress had been described in male and female littermates. This literature included research describing glutamate, γ-amino butyric acid (GABA), corticosteroids, monoamines, and cannabinoids. We found that sex-dependent effects of stress are mediated by the age at which stress is experienced, age at test, and type of stress endured. More research is required, particularly into the effects of adolescent stress on male and female littermates. We hope that a greater understanding of sex-specific susceptibilities in response to stress across development will help to uncover risk factors for psychological disorders in vulnerable populations.

Assessment of conditioned fear extinction in male and female adolescent rats.

Pavlovian fear conditioning and extinction have been widely studied across many species to understand emotional learning and memory. Importantly, it is becoming clear that these processes are affected by sex and age. In adult rodents and humans, sex differences are evident in extinction, with estradiol playing a significant role. In adolescence, an extinction deficit has been reported in rodents and humans. However, the influence of sex on extinction during adolescence is unknown. This is surprising, since adolescence coincides with the onset of hormone cycling, and therefore it might be expected that hormones fluctuations exert a more profound effect at this time. Therefore, we examined Pavlovian fear conditioning and extinction in adolescent male and female rats. In experiment 1, 35-day-old male and female rats were exposed to 6 pairings of a conditioned stimulus (CS, a tone) with an aversive unconditioned stimulus (US, a footshock). The next day they were extinguished in a contextually distinct chamber, via 60 presentations of the CS without the US. Extinction recall was tested 24 hours later in the extinction context. Estrous phase was monitored by cytology on vaginal smears taken 1 hour after each behavioral session. In experiment 2, male and female rats were given sham surgery or gonadectomy at 21 days of age. They were then trained and tested as for experiment 1. We observed that females in proestrus or met/diestrus during extinction showed delayed extinction and impaired extinction recall the next day compared to males. Ovariectomy enhanced extinction for female rats, but orchidectomy delayed extinction for males. Plasma analyses showed that met/di/proestrus phases were associated with high estradiol levels. These findings suggest that high plasma estradiol levels impair extinction for adolescent females. These results contradict what is reported in adult animals, suggesting that hormonal influences on extinction are dependent on age. Given that impaired extinction is widely used as a model to understand resistance to exposure-based therapies, our findings have important implications for understanding mental health treatments in adolescents.

Extinction of Conditioned Fear in Adolescents and Adults: A Human fMRI Study.

Little is known about the neural correlates of fear learning in adolescents, a population at increased risk for anxiety disorders. Healthy adolescents (mean age 16.26) and adults (mean age 29.85) completed a fear learning paradigm across two stages during functional magnetic resonance imaging (fMRI). Stage 1 involved conditioning and extinction, and stage 2 involved extinction recall, re-conditioning, followed by re-extinction. During extinction recall, we observed a higher skin conductance response to the CS+ relative to CS- in adolescents compared to adults, which was accompanied by a reduction in dorsolateral prefrontal cortex (dlPFC) activity. Relative to adults, adolescents also had significantly reduced activation in the ventromedial PFC, dlPFC, posterior cingulate cortex (PCC), and temporoparietal junction (TPJ) during extinction recall compared to late extinction. Age differences in PCC activation between late extinction and late conditioning were also observed. These results show for the first time that healthy adolescent humans show different behavioral responses, and dampened PFC activity during short-term extinction recall compared to healthy adults. We also identify the PCC and TPJ as novel regions that may be associated with impaired extinction in adolescents. Also, while adults showed significant correlations between differential SCR and BOLD activity in some brain regions during late extinction and recall, adolescents did not show any significant correlations. This study highlights adolescent-specific neural correlates of extinction, which may explain the peak in prevalence of anxiety disorders during adolescence.