Medial prefrontal cortex involvement in the expression of extinction and ABA renewal of instrumental behavior for a food reinforcer

Abstract

Instrumental renewal, the return of extinguished instrumental responding after removal from the extinction context, is an important model of behavioral relapse that is poorly understood at the neural level. In two experiments, we examined the role of the dorsomedial prefrontal cortex (dmPFC) and the ventromedial prefrontal cortex (vmPFC) in extinction and ABA renewal of instrumental responding for a sucrose reinforcer. Previous work, exclusively using drug reinforcers, has suggested that the roles of the dmPFC and vmPFC in expression of extinction and ABA renewal may depend at least in part on the type of drug reinforcer used. The current experiments used a food reinforcer because the behavioral mechanisms underlying the extinction and renewal of instrumental responding are especially well worked out in this paradigm. After instrumental conditioning in context A and extinction in context B, we inactivated dmPFC, vmPFC, or a more ventral medial prefrontal cortex region by infusing baclofen/muscimol (B/M) just prior to testing in both contexts. In rats with inactivated dmPFC, ABA renewal was still present (i.e., responding increased when returned to context A); however responding was lower (less renewal) than controls. Inactivation of vmPFC increased responding in context B (the extinction context) and decreased responding in context A, indicating no renewal in these animals. There was no effect of B/M infusion on rats with cannula placements ventral to the vmPFC. Fluorophore-conjugated muscimol was infused in a subset of rats following test to visualize infusion spread. Imaging suggested that the infusion spread was minimal and mainly constrained to the targeted area. Together, these experiments suggest that there is a region of medial prefrontal cortex encompassing both dmPFC and vmPFC that is important for ABA renewal of extinguished instrumental responding for a food reinforcer. In addition, vmPFC, but not dmPFC, is important for expression of extinction of responding for a food reinforcer. The role of the medial prefrontal cortex in renewal in the original conditioning context may depend in part on control over excitatory context-response or context-(response-outcome) relations that might be learned in acquisition. The role of the vmPFC in expression of extinction may depend on its control over inhibitory context-response or context-(response-outcome) relations that are learned in extinction.

How contexts promote and prevent relapse to drug seeking

“…Importantly for the present purposes, it extends to context-induced reinstatement of cocaine (Fuchs et al 2005) and alcohol (Willcocks & McNally 2013) seeking. It has also been observed for context-induced reinstatement of seeking a food reinforcer (Eddy et al 2016). These findings support the claim that PL PFC may be part of a final common pathway for reinstatement of drug seeking.…”

“…This role for IL in extinction of drug seeking depends on glutamatergic and -adrenergic signaling (LaLumiere et al 2010) and can be enhanced by positive allosteric modulation of IL function . This role for IL has also been observed for extinction of responding for a food reinforcer (Eddy et al 2016). However, others have reported opposing or no effects of IL manipulations on extinction of drug seeking.…”

Sex specific recruitment of a medial prefrontal cortex-hippocampal-thalamic system during context-dependent renewal of responding to food cues in rats

“…Inactivation of the vmPFC disrupted context-mediated reinstatement of alcohol and drug seeking (Bossert, Stern, Theberge, Cifani, Koya, Hope, and Shaham, 2011; Willcocks and McNally, 2013), and reduced ABA renewal of instrumental responding to a sucrose reinforcer (Eddy et al, 2016). Specific ILA lesions enhanced renewal of responding compared to sham-lesioned animals (Rhodes and Killcross, 2007).…”

“…We hypothesized the ventromedial prefrontal cortex (vmPFC) is critical during renewal and would be a site of sex differences due to its well-known executive function in decision-making and behavioral guidance (Dalley, Cardinal, and Robbins, 2004; O’Doherty, 2011) and its role in associative learning, including renewal (Eddy, Todd, Bouton, and Green, 2016; Willcocks and McNally, 2013). Additionally, we examined three areas connected with the vmPFC and important for associative learning, contextual processing, and the control of food consumption: the hippocampal formation, thalamus, and amygdala.…”

Feeding-modulatory effects of mu-opioids in the medial prefrontal cortex: a review of recent findings and comparison to opioid actions in the nucleus accumbens

“…In a general sense, medial PFC plays a prominent role in modulating ongoing behavior, and inhibiting disadvantageous behavior, to match prevailing (and often changing) contingencies; examples include the regulation of set-shifting (Birrell and Brown 2000; Dalley et al 2004; Floresco et al 2008; Ragozzino et al 1999) and the expression of extinction learning (Eddy et al 2016; Peters et al 2008; Quirk et al 2006; Rhodes and Killcross 2007). With regard to ingestive behaviors, recent findings that inhibition of ventromedial PFC disturbs the temporal distribution of licking bouts in an incentive-contrast paradigm, ‘misaligning’ licking bout durations to high and low concentrations of sucrose (Parent et al 2015).…”