Prefrontal Cortex Circuitry in Sex Differences of Context-Mediated Renewal of Appetitive Pavlovian Conditioned Responding

Abstract

Learned associations are formed when cues from the environment are paired with biologically important events and can later drive appetitive and aversive behaviors. These behaviors can persist and reappear after extinction because the original learned associations continue to exist. In particular, cues previously associated with food can later stimulate appetite and food consumption in the absence of hunger. Renewal, or reinstatement, of extinguished conditioned behaviors may help explain the mechanisms underlying persistent responding to food cues and difficulty associated with changing unhealthy eating habits. The aim of this dissertation was to determine key components in the neural circuitry mediating renewal of responding to food cues. The main focus was on the ventromedial prefrontal cortex (vmPFC; includes the infralimbic (ILA) and prelimbic (PL) areas) because that region was selectively recruited during context-dependent renewal (Chapter 3). In all of the experiments, the behavior and neural substrates of male and female rats were compared. It was important to examine both males and females because sex differences in context-mediated renewal were recently established: males consistently show renewal responding while females fail to do so (Chapters 2 and 3). The first study in this dissertation examined whether behavioral sex differences were driven by estradiol (Chapter 2) and whether the vmPFC is recruited during renewal responding (Fos induction; Chapter 3). Then, to establish the vmPFC is causal in driving the behavioral responding during renewal in a sex-specific way (Chapter 4), the vmPFC was silenced in males and stimulated it in females. This was accomplished using a chemogenetic methodology, DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). Inhibiting the vmPFC in males blocks renewal responding. Reversely, stimulating the vmPFC in females resulted in renewal of responding. To determine key components of the vmPFC circuitry mediating renewal and whether these were different in males and females the experiments in Chapter 5 examined activation of PL inputs using a retrograde tract tracing combined with Fos detection design. The pathways to the PL from the ventral hippocampal formation (subiculum and CA1), the thalamus (anterior paraventricular nucleus), and the amygdala (anterior basolateral nucleus) were recruited in males and not recruited in females. This lack of recruitment could explain the lack of behavioral responding during renewal for females. Taken together, there are distinct and sex-specific circuitries recruited during context-mediated renewal. The findings from these experiments advanced our understanding of the neural mechanisms underlying sex differences in associative memory and contextual processing. They are also important for our understanding of the resilience of food cue to influence our consumption and diet choices.