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

Renewal, or reinstatement, of responding to food cues after extinction may explain the inability to resist palatable foods and change maladaptive eating habits. Previously, we found sex differences in context-dependent renewal of extinguished Pavlovian conditioned responding to food cues. Context-induced renewal involves cue-food conditioning and extinction in different contexts and the renewal of conditioned behavior is induced by return to the conditioning context (ABA renewal). Male rats showed renewal of responding while females did not. In the current study we sought to identify recruitment of key neural systems underlying context-mediated renewal and sex differences. We examined Fos induction within the ventromedial prefrontal cortex (vmPFC), hippocampal formation, thalamus and amygdala in male and female rats during the test for renewal. We found sex differences in vmPFC recruitment during renewal. Male rats in the experimental condition showed renewal of responding and had more Fos induction within the infralimbic and prelimbic vmPFC areas compared to controls that remained in the same context throughout training and testing. Females in the experimental condition did not show renewal or an increase in Fos induction. Additionally, Fos expression differed between experimental and control groups and between the sexes in the hippocampal formation, thalamus and amygdala. Within the ventral subiculum, the experimental groups of both sexes had more Fos compared to control groups. Within the dorsal CA1 and the anterior region of the paraventricular nucleus of the thalamus, in males, the experimental group had higher Fos induction, while both females groups had similar number of Fos-positive neurons. Within the capsular part of the central amygdalar nucleus, females in the experimental group had higher Fos induction, while males groups had similar amounts. The differential recruitment corresponded to the behavioral differences between males and females and suggests the medial prefrontal cortex-hippocampal-thalamic system is a critical site of sex differences during renewal of appetitive Pavlovian responding to food cues. These findings provide evidence for novel neural mechanisms underlying sex differences in food motivation and contextual processing in associative learning and memory. The results should also inform future molecular and translational work investigating sex differences and maladaptive eating habits.

Anderson LC ，Petrovich GD 《-》

Distinct recruitment of the hippocampal, thalamic, and amygdalar neurons projecting to the prelimbic cortex in male and female rats during context-mediated renewal of responding to food cues.

Persistent responding to food cues may underlie the difficulty to resist palatable foods and to maintain healthy eating habits. Renewal of responding after extinction is a model of persistent food seeking that can be used to study the underlying neural mechanisms. In context-mediated renewal, a return to the context in which the initial cue-food learning occurred induces robust responding to the cues that were extinguished elsewhere. Previous work found sex differences in context-mediated renewal and in the recruitment of the ventromedial prefrontal cortex (vmPFC) during that behavior. Males exhibited renewal of responding to food cues and had higher Fos induction in the prelimbic area (PL) of the vmPFC, while females failed to exhibit renewal of responding and had lower Fos induction in the PL. The main aim of the current study was to determine key components of the PL circuitry mediating renewal. The focus was on inputs from three areas important in appetitive associative learning and contextual processing: the amygdala, ventral hippocampal formation, and the paraventricular nucleus of the thalamus. The goal was to determine whether neurons from these areas that send direct projections to the PL (identified with a retrograde tracer) are selectively activated (Fos induction) during renewal and whether they are differently recruited in males and females. The Fos induction patterns demonstrated that the PL-projecting neurons in each of these areas were recruited in a sex-specific way that corresponded to the behavioral differences between males and females. These pathways were selectively activated in the male experimental group-the only group that showed renewal behavior. The findings suggest the pathways from the ventral hippocampal formation, paraventricular nucleus of the thalamus, and basolateral amygdala to the PL mediate renewal in males. The lack of recruitment in females suggests that under activation of these pathways may underlie their lack of renewal.

Anderson LC ，Petrovich GD 《-》

Renewal of conditioned responding to food cues in rats: Sex differences and relevance of estradiol.

Cues associated with food can stimulate food anticipation, procurement, and consumption, independently of hunger. These and other behaviors driven by learned cues are persistent and can reappear after extinction, because the original learned associations continue to exist. Renewal, or reinstatement, of extinguished conditioned behavior may explain the inability to change maladaptive eating habits driven by food cues, similar to the mechanisms of drug use relapse. Here, we investigated sex differences in context-induced renewal of responding to food cues, and the role of estradiol in females in a Pavlovian conditioning preparation. We compared adult male and female rats because there is evidence for sex differences in learning and memory and in the control of feeding. Context-induced renewal involves conditioning and extinction in different contexts and the renewal of conditioned behavior is induced by return to the conditioning context ("ABA renewal"; experimental groups). Control groups remain in the same context during conditioning, extinction, and test. In Experiment 1, male and female rats were trained to associate a tone with food pellets during acquisition, and after extinction with tone only presentations, were tested for renewal of responding to the tone. Learning was assessed through the expression of the conditioned response, which included approach and activity directed at food receptacle (food cup behavior). Males and females learned the acquisition and extinction of tone-food associations similarly, but there were sex differences during renewal of the conditioned responses to the food cue. Males showed robust renewal of responding, while renewal in intact females was inconsistent. Males in the experimental group had significantly higher food cup behavior compared to males in the control group, while females in both groups showed similar levels of food cup behavior during the tone. In Experiment 2, we examined a potential role of estradiol in renewal, by comparing intact females with ovariectomized females with, and without, estradiol replacement. Rats in all groups acquired and extinguished tone-food associations similarly. During the test for renewal, the ovariectomized rats with estradiol replacement in the experimental group showed renewal of responding, evidenced by significantly higher food cup behavior compared to the control group. Intact and ovariectomized rats in the experimental groups had similar rates of food cup behavior as their corresponding control groups. These results provide novel evidence for sex differences and relevance of estradiol in renewal of responding to food cues and more broadly in contextual processing and appetitive associative learning, potentially relevant to maladaptive eating habits and eating disorders.

Anderson LC ，Petrovich GD 《-》

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

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.

Eddy MC ，Todd TP ，Bouton ME ，Green JT ... -  《-》

Ventromedial prefrontal cortex mediates sex differences in persistent cognitive drive for food.

Anderson LC ，Petrovich GD 《Scientific Reports》