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Hadfield, Heather
Roesch, Matthew R
For decisions both great and small, the brain utilizes an extensive network that integrates value assessment, reward prediction, and motivation to quickly and efficiently select the most beneficial option while minimizing aversive consequences for ourselves. Numerous psychiatric conditions, in particular drug addiction, can disrupt this network and impair decision-making behavior. It is therefore important to understand the neural underpinnings of decision-making and how neural activity and its associated behavior are disrupted by drugs of abuse. My dissertation will expand on current studies of this circuitry by examining epigenetic and neurophysiological mechanisms of value-based decision-making within two regions of the brain. In my final aim, I explore a new behavioral assay that may be used to study these and other regions relevant for value-based decision-making in the context of another complex behavior.In my first aim, I have recorded from single neurons in the rat dorsal lateral striatum (DLS) after overexpressing histone deacetylase 5 (HDAC5), an epigenetic enzyme implicated in incubation of craving, in the dorsal striatum (DS). In my second aim I used pharmacological lesion and single-neuron recording combined with cocaine self-administration techniques to study anterior insula, a region well-known for combining internal and external experience but largely under-studied in the context of higher cognitive processes. These studies were conducted while rats performed an odor-guided decision-making task in which the value of rewards were manipulated by either the delay to or the size of the reward across a series of trial blocks. I have found overexpression of HDAC5 in DS promoted inflexible, faster, and automatic behavior in the decision-making task while increasing DLS’s response to reward cues- similar to previous studies examining DLS activity and behavior after cocaine self-administration. In my studies of insula, I found recording from this region novel, global signals of reward value that seemed to reflect the overall structure of the behavioral task. Following cocaine-exposure, these signals were diminished while immediate rewards were over-represented on a trial-by-trial basis, leading to steeper discounting of delayed rewards. Additional studies lesioning this region promoted faster reaction times and increased goal-directed behavior. Together, these results provide insights into how drugs of abuse may impair behavioral flexibility and the tracking of long-term changes in reward from multiple mechanisms. However, it is still unknown how these changes in value assessment give rise to complex impairments of behavior. As a first step to addressing this issue, I used a new task to examine how chronic drug use- which disrupts both neural signals in the corticostriatal circuit and epigenetic enzymes- also impairs the complex ability to delay gratification. This final study replicated well-established findings of drug-induced reversal-learning impairment, but surprisingly did not alter decision-making. This collection of work demonstrates the complexity with which drug exposure alters neural circuitry and value-based decision-making, and additionally shows the importance of utilizing complex behavioral assays to explore the relationship between brain and behavior.