Peripubertal stress increases play fighting at adolescence and modulates nucleus accumbens CB1 receptor expression and mitochondrial function in the amygdala

Abstract

Play fighting is a highly rewarding behavior that helps individuals to develop social skills. Early-life stress has been shown to alter play fighting in rats and hamsters as well as to increase aggressive behaviors at adulthood. However, it is not known whether individual differences in stress-induced play fighting are related to differential developmental trajectories towards adult aggression. To address this question, we used a rat model of peripubertal stress (PPS)-induced psychopathology that involves increased aggression at adulthood. We report that, indeed, PPS leads to enhanced play fighting at adolescence. Using a stratification approach, we identify individuals with heightened levels of play fighting as the ones that show abnormal forms of aggression at adulthood. These animals showed as well a rapid habituation of their corticosterone responsiveness to repeated stressor exposure at peripuberty. They also showed a striking increase in mitochondrial function in the amygdala—but not nucleus accumbens—when tested ex vivo. Conversely, low, but not high players, displayed increased expression of the CB1 cannabinoid receptor in the nucleus accumbens shell. Our results highlight adolescence as a potential critical period in which aberrant play fighting is linked to the emergence of adult aggression. They also point at brain energy metabolism during adolescence as a possible target to prevent adult aggression.

Programming effects of peripubertal stress on spatial learning

“…While, as in previous studies (Cordero et al, 2016; Tzanoulinou et al, 2014a)), we observe here increased anxiety-like behavior when peripubertally stressed rats were tested at adulthood, decreased anxiety-like behaviors were reported when tested during late adolescence (Toledo-Rodriguez and Sandi, 2011). Furthermore, in the social domain, peripubertal stress leads to increased adult aggression (Marquez et al, 2013) in a protracted manner, as rats that showed aberrant play fighting during adolescence were those that developed a more aggressive phenotype at adulthood (Papilloud et al, 2018). In addition, and in line with its physiological contribution to deal with immediate challenges (de Kloet et al, 2008; Myers et al, 2014), it is the magnitude of adaptation of the peak corticosterone response to peripubertal stress that predicts alterations in emotional and social behaviors (Papilloud et al, 2018; Walker et al, 2018; 2017).…”

“…Importantly, the peripubertal period has been reported to set a change in HPA responsivity in both humans and rats, including changes not only in the peak but also in the recovery phases (McCormick et al, 2017). We have previously reported a strong link between the magnitude of adaptation of the peak corticosterone response to repeated stressors given during the peripubertal period in rats and subsequent changes in emotional and social behaviors (Papilloud et al, 2018; Walker et al, 2018; 2017). However, in the context of the current study on spatial learning, we hypothesize that it will be the adaptation of the recovery phase of corticosterone responsiveness that predicts spatial learning.…”

Neurobiological links between stress and anxiety

“…Interestingly, play-fighting is a peri-pubertal social behavior which has been linked to aggression in adulthood. Specifically, peri-puberal stress increases play-fighting and increases the chances to display abnormal aggressive behaviors later in adulthood (Papilloud et al, 2018). Importantly, this study also revealed a role of mitochondrial energy balance in regulating stress-induced behaviors, by showing that enhanced play-fighting behaviors following peri-pubertal stress was accompanied by enhanced mitochondrial function in the amygdala.…”

Anxiety and Brain Mitochondria: A Bidirectional Crosstalk

“…Proteomics-and metabolomics-based studies in mouse lines genetically-selected for differences in anxiety-like behaviors have been instrumental in pointing at a broad range of alterations in mitochondria and brain energy metabolism (for an account of energy production pathways and other mitochondrial functions, see Box 2) as a critical feature of anxiety. Importantly, they have consistently However, studies in other animal models and brain regions have not confirmed increased expression of oxidative phosphorylation complexes as a general characteristic of the anxious brain [35][36][37][38]. For example, in the nucleus accumbens from outbred Wistar rats, high anxious animals display, instead, lower mitochondrial complex I and II protein levels and respiratory capacity, as well as lower ATP levels, than low-anxious animals [36,38].…”