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

Abstract

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.

Keywords: Appetitive; Conditioning; Context; Estradiol; Renewal.

Figure 1

Experimental Design. Behavioral training consisted of three phases: conditioning (acquisition), extinction and renewal test. All rats received identical sessions throughout, except that experimental groups received extinction in a context different from the one in which the acquisition occurred, while the control groups remained in the same context throughout all training and testing (“ABA” design; counterbalanced across contexts). Rats received one session per day, and during each session there were presented with 8 tones (CSs) immediately followed by food (US) during acquisition sessions (CS-US pairings), but presented without USs during extinction and renewal.

Figure 2

Conditioned responses during acquisition and extinction in Experiment 1. Percentage of time rats expressed food cup behavior (mean ± SEM) during the preCS and CS periods during training sessions. PreCS values are the average across all sessions for acquisition and extinction, respectively. Acquisition is shown as the average responding during each session. Extinction is shown as the average responding in 4-trial blocks (2 blocks per session; blocks 1&2 were trials during Session 1 and blocks 3&4 during Session 2).

Figure 3

Conditioned responses during the test for renewal in Experiment 1. Percentage of time rats expressed food cup behavior (mean ± SEM) during preCS and CS periods; * indicates p < .001, # indicates within-group preCS vs CS difference p < 0.05.

Figure 4

Conditioned responses during acquisition and extinction in Experiment 2. Percentage of time rats expressed food cup behavior (mean ± SEM) during the preCS and CS periods during training sessions. PreCS values are the average across all sessions for acquisition and extinction, respectively. Acquisition is shown as the average responding during each session. Extinction is shown in 4-trial blocks (2 blocks per session; blocks 1&2 were trials during Session 1 and blocks 3&4 during Session 2).

Figure 5

Conditioned responses during the test for renewal in Experiment 2. Percentage of time rats expressed food cup behavior (mean ± SEM) during PreCS and CS periods; * indicates p < 0.05, # indicates within-group preCS vs CS difference p < 0.05.