Epigenetic manipulation of anterior insular cortex alters neural signals and cognitive control.

The balance between impulsive prepotent behavior and inhibition is a crucial aspect of self-control, and disruptions to this balance are observed in aging and various neuropsychiatric conditions, such as addiction. Both the insula and histone deacetylases (HDACs), a family of epigenetic enzymes, are implicated in these disruptions, with HDAC inhibitors showing therapeutic potential. However, the role of single neuron activity in the insula in relation to cognitive control and how this activity is affected by HDAC modulation in behaving animals remains unclear. In this study, we focus on HDAC5, a class II HDAC that regulates gene transcription and shuttles between the nucleus and cytoplasm in response to neuronal activity. We investigate how overexpression of nuclear-localized HDAC5 in the anterior insula influences cognitive control and associated neural processes in rats performing a STOP-change task. This task contrasts frequent prepotent responding (GO trials) with infrequent response inhibition and behavioral redirection (STOP-change trials). Our results show that HDAC5 overexpression altered neural activity linked to executive control signals in the anterior insula, leading to faster prepotent responses and a reduced capacity for behavioral inhibition (i.e., increased motor impulsivity). Additionally, while insula firing was influenced by trial history (i.e., previous trial rewarded or not), HDAC5 overexpression did not affect this feature. These findings suggest that increased HDAC5 activity impair cognitive control, and targeting HDAC5 in this region may offer a promising therapeutic approach for enhancing executive control and mitigating impulsivity-related cognitive, emotional, and social impairments.