Histone deacetylase and acetyltransferase inhibitors modulate behavioral responses to social stress

Abstract

Histone acetylation has emerged as a critical factor regulating learning and memory both during and after exposure to stressful stimuli. There are drugs that we now know affect histone acetylation that are already in use in clinical populations. The current study uses these drugs to examine the consequences of acutely increasing or decreasing histone acetylation during exposure to social stress. Using an acute model of social defeat in Syrian hamsters, we systemically and site-specifically administered drugs that alter histone acetylation and measured subsequent behavior and immediate-early gene activity. We found that systemic administration of a histone deacetylase inhibitor enhances social stress-induced behavioral responses in males and females. We also found that systemic administration completely blocks defeat-induced neuronal activation, as measured by Fos-immunoreactivity, in the infralimbic cortex, but not in the amygdala, after a mild social defeat stressor. Lastly, we demonstrated that site-specific administration of histone deacetylase inhibitors in the infralimbic region of the prefrontal cortex, but not in the basolateral amygdala, mimics the systemic effect. Conversely, decreasing acetylation by inhibiting histone acetyltransferases in the infralimbic cortex reduces behavioral responses to defeat. This is the first demonstration that acute pharmacological manipulation of histone acetylation during social defeat alters subsequent behavioral responses in both males and females. These results reveal that even systemic administration of drugs that alter histone acetylation can significantly alter behavioral responses to social stress and highlight the importance of the infralimbic cortex in mediating this effect.

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

“…These drugs also reverse social avoidance when administered to the amygdala and PFC (Covington, Maze, Vialou, & Nestler, ; Covington et al., ). Inhibition of HDAC with valproic acid not only increases the effects induced by SD (McCann et al., ), but also the conditioning rewarding effects of cocaine because HDAC inhibitors increase associative learning (Montagud‐Romero, Montesinos et al., ; Ploense et al., ). On the contrary, inhibition of HAT activity with the HAT inhibitor curcuma longa, or through viral‐mediated transfer and overexpression of specific HDACs in the NAc, markedly inhibits the increase in cocaine‐induced CPP in defeated animals (Hui, Wang, & Li, ; Renthal et al., ).…”

“…For example, there are cases in which female rodents exhibit territorial and maternal aggression, which constitutes an avenue for examining sex differences in physiology and behavior in response to stress (Solomon, ). Female rodents are capable of displaying threat and attack behavior, and in some species are more aggressive than males during agonistic encounters (Huhman et al., ; McCann et al., ). Defeated females respond to a caged opponent with similar social avoidance to that observed in males, but research some decades ago showed that female rats do not become “permanently” submissive after losing an aggressive encounter (Brain et al., ; Scholtens, Van Haaren, & Van De Poll, ; Swanson, ).…”

Brain-derived neurotrophic factor signaling mitigates the impact of acute social stress

“…These data also demonstrate that measuring conditioned defeat in hamsters that are tested with a freely moving, non-aggressive intruder produces comparable data to that generated in mice using social avoidance of a caged opponent as the dependent measure. Although we have shown that hamsters, like mice, display social avoidance to caged opponents 68,[85][86][87] , conditioned defeat testing in hamsters adds complementary data in that it is possible to measure not only submission and social avoidance, but also to determine if treatments have any effect on aggression. Importantly, we observed no changes in aggressive behavior following any of the treatments used in this study.…”

Oxytocin Manipulation Alters Neural Activity in Response to Social Stimuli in Eusocial Naked Mole-Rats

“…Interestingly, the IL (in addition to the PrL) is also activated in a shifting social environment in which social ascent is possible, as in the case of removing an alpha male in a mouse hierarchy ( Williamson et al, 2018 ). Administration of a histone deacetylase inhibitor to the IL increases stress behaviors in a Syrian hamster model of social defeat ( McCann et al, 2017 ), further implicating the IL in social interactions involving dominance.…”