Overexpressing Histone Deacetylase 5 in Rat Dorsal Striatum Alters Reward-Guided Decision-Making and Associated Neural Encoding.

Accumulating evidence in the past decade implicates histone-modifying enzymes, such as class I histone deacetylases (HDACs), in learning and memory and, recently, habit formation. However, it is unclear whether HDACs play roles in complex cognitive function. To address this issue, we examined the role of dorsal striatal HDAC5, a class II HDAC, in reward-guided decision-making and associated neural encoding in rats. We first injected adeno-associated virus to overexpress a nuclear-localized HDAC5 in dorsal striatum (DS). We then recorded neural correlates from dorsolateral striatum (DLS) as rats performed two reward-guided choice tasks, in which we manipulated either the size of or delay to reward. During these tasks, rats first learned which of two options led to the better reward and then reversed those contingencies in a second block of trials. We found that rats with HDAC5 overexpression in DS responded faster and chose higher value reward more often during the first block of trials but were less able to reverse those contingencies in the second block of trials. At the neural level, HDAC5 overexpression in DS elevated and reduced the number of cells in DLS that increased firing to stimuli and reward, respectively, and shifted encoding toward cues that predicted more immediate reward. These results suggest that the HDAC5 overexpression in DS contributes to inflexible decision-making, demonstrating a role of histone-modifying enzymes in complex cognitive function.SIGNIFICANCE STATEMENT HDACs are important for learning and habit formation. Here, we expanded on these functions and found that overexpression of HDAC5 produced faster and more automatic behavior, and related changes in dorsolateral striatal neural firing in rats performing a value-based decision-making task. These results implicate HDAC5 as a potential therapeutic target for psychiatric conditions that impair decision-making and executive function.

Prior Cocaine Exposure Increases Firing to Immediate Reward While Attenuating Cue and Context Signals Related to Reward Value in the Insula.

The insula contributes to behavioral control and is disrupted by substance abuse, yet we know little about the neural signals underlying these functions or how they are disrupted after chronic drug self-administration. Here, male and female rats self-administered either cocaine (experimental group) or sucrose (control) for 12 consecutive days. After a 1 month withdrawal period, we recorded from insula while rats performed a previously learned reward-guided decision-making task. Cocaine-exposed rats were more sensitive to value manipulations and were faster to respond. These behavioral changes were accompanied by elevated counts of neurons in the insula that increased firing to reward. These neurons also fired more strongly at the start of long-delay trials, when a more immediate reward would be expected, and fired less strongly in anticipation of the actual delivery of delayed rewards. Although reward-related firing to immediate reward was enhanced after cocaine self-administration, reward-predicting cue and context signals were attenuated. In addition to revealing novel firing patterns unique to insula, our data suggest changes in such neural activity likely contribute to impaired decision making observed after drug use.SIGNIFICANCE STATEMENT The insula plays a clear role in drug addiction and drug-induced impairments of decision making, yet there is little understanding of its underlying neural signals. We found that chronic cocaine self-administration reduces cue and context encoding in insula while enhancing signals related to immediate reward. These changes in neural activity likely contribute to impaired decision making and impulsivity observed after drug use.