Histone deacetylase and acetyltransferase inhibitors modulate behavioral responses to social stress.
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.
Neuroscience Institute, Georgia State University, 161 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA. Electronic address: kmccann3@gsu.edu.
Katharine E
KE
McCann
Neuroscience Institute, Georgia State University, 161 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA. Electronic address: arosenhauer1@student.gsu.edu.
Anna M
AM
Rosenhauer
Neuroscience Institute, Georgia State University, 161 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA. Electronic address: gjones26@student.gsu.edu.
Genna M F
GMF
Jones
Neuroscience Institute, Georgia State University, 161 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA. Electronic address: anorvelle@gsu.edu.
Alisa
A
Norvelle
Neuroscience Institute, Georgia State University, 161 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA. Electronic address: dchoi15@gsu.edu.
Dennis C
DC
Choi
Neuroscience Institute, Georgia State University, 161 Jesse Hill Jr. Drive, Atlanta, GA 30303, USA. Electronic address: khuhman@gsu.edu.
Kim L
KL
Huhman
D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D006224:Cricetinae; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D017397:Prefrontal Cortex / Q000187:drug effects*; D012919:Social Behavior; D013315:Stress, Psychological / Q000503:physiopathology*
D056572:Histone Deacetylase Inhibitors; D000123:Acetyltransferases
Epigenetics; Medial prefrontal cortex; Social defeat; Valproic acid