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Thesis advisor: Gorica D. Petrovich / Thesis advisor: Michael McDannald / Cues existing in the surrounding environment repeatedly paired with biologically relevant events can exert a powerful drive over behavior. When learned cues recurrently signal consumption, this can lead to eating in the absence of hunger or physiological need. The difficulties associated with resisting palatable foods and maintaining healthy habits may be related to the neurobiological underpinnings of pervasive responding to food cues. Behavioral flexibility through updating information about formed reward associations is vital to appropriately adapt to the surrounding environment and physiological need. Studying the renewal of responding of extinguished food-seeking behaviors can help us better understand the mechanisms mediating behavioral control over responding to learned reward cues. This dissertation aimed to explore behavioral sex differences and the neural substrates of renewal of responding to food cues after extinction by utilizing a context-mediated renewal of responding paradigm. The first chapter in this dissertation explored the effects of context habituation on context-induced renewal of responding to food cues in males and females. We investigated if increased familiarity with the behavioral contexts, and if presentation of food reward or not during these habituation sessions, would impact the strength of cue-food learning and renewal of responding after extinction differently in males and females. We discovered that when males received context habituation paired with food prior to training they exhibited elevated food-seeking behaviors throughout conditioning, as well as strengthened renewal. This suggests that for males the context habituation with food had a lasting, amplifying effect on cue-food learning. For females, however, increased context familiarity did not improve renewal of responding and, moreover, these experiments revealed evidence for resistance to extinguishing food-seeking behaviors in females. Then, in Chapter 2, we found neural evidence for potential plasticity mechanisms in the prelimbic (PL) and infralimbic (ILA) subregions, which were both recruited during context-mediated renewal of responding to food cues. Our findings are in line with evidence demonstrating that the PL and ILA are both recruited during appetitive learning and possibly provide overlapping contributions to encoding and responding in context-based reward learning. Taken together, the experiments outlined in this dissertation add to existing evidence of sex differences in appetitive motivated behaviors and the intricacies of the roles of the PL and ILA in cue-food learning and contextual processing. The findings from these studies advance our understanding of persistent food-seeking behaviors and highlight the importance of elucidating the neural substrates mediating behavioral responding to learned reward cues. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

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<p dir="ltr">Compulsive alcohol drinking is a defining feature of alcohol use disorder and is characterized as drinking alcohol despite knowledge of negative consequences. This behavior is hypothesized to be due to a disruption in the decision-making process. Decision making relies on a balance between goal-directedness and habit systems to efficiently execute behavior. An important distinction between compulsive and non-compulsive individuals is the ability to withhold drinking in the face of a negative consequence. The dorsomedial striatum (DMS) and dorsomedial prefrontal cortex (dmPFC) are brain regions necessary for goal directed behavior where the dmPFC is important for cognitive control and behavioral inhibition while the DMS is important for action selection. Importantly, the dmPFC sends a glutamatergic input to the DMS. We hypothesize this input is a behavioral control which is necessary to withhold action selection. Thus, in order to maintain non-compulsive alcohol use, the dmPFC and DMS need to work together to orchestrate inhibition of action selection in the face of negative consequences. Previous research shows a causal role for both the dmPFC and DMS in preventing compulsive alcohol drinking and a role for the projections from the dmPFC to DMS in behavioral inhibition. However, no research has demonstrated a role for this circuit’s activity in prevention of compulsive alcohol use. The current experiment tested the hypothesis that inhibiting the glutamatergic projection from the dmPFC to the DMS will cause non-compulsive Wistar rats to drink alcohol compulsively.</p>

Dysregulation of glutamatergic signaling mechanisms is a component of many psychiatric diseases. A number of these diseases exhibit a bias toward one sex, yet the ways in which glutamate is affected by or modulates this bias is poorly understood. In cocaine addiction, women progress from initial use of the drug to substance use disorder faster than men, and have more difficulty remaining abstinent. The same is true in female rodents. We used a mouse model of cocaine self-administration to study the role of glutamate receptor trafficking proteins in cocaine addiction-like behavior in males and females. In the first set of experiments, mice received a conditional knockout of glutamate receptor interacting protein 1 (GRIP1) in the medial prefrontal cortex (mPFC). This led to an increase in motivation for cocaine as well as enhanced likelihood of relapse behavior, as measured by a progressive ratio schedule and cue-induced reinstatement, respectively. No sex differences were seen after prefrontal deletion of GRIP1. The next set of experiments used the same behavioral paradigm, but mice received a conditional knockout of protein interacting with C kinase 1 (PICK1) in the mPFC. PICK1 and GRIP1 are both involved in the activity dependent trafficking of the GluA2-containing AMPA receptor, but while GRIP1 maintains these receptors in the synapse, PICK1 internalizes them in response to a stimulus such as drug experience. The prefrontal deletion of PICK1 was predicted to decrease cue-reinstatement responding, and this was observed in the male mice. The female mice displayed an increase in cue-induced reinstatement responding, similar to the effects seen by prefrontal GRIP1 deletion. Sex differences in PICK1 have not previously been described in the literature. Our results suggest that PICK1 is involved in different baseline processes in females, and merit further study. The final set of experiments considered the interaction of gonadal hormones and PICK1 in males. Bilateral gonadectomy or sham surgery was combined with prefrontal PICK1 knockout to determine if circulating gonadal hormones could explain the results in males. After gonadectomy or sham surgery, there was no significant effect of prefrontal PICK1 deletion on cue-induced reinstatement. These results do not fully explain the sex difference observed in intact mice. Together, these studies suggest that baseline sex differences exist in PICK1-mediated mechanisms of cocaine reinstatement and that these differences are not due to the influence of gonadal hormones alone. / Psychology