Food-Seeking Behavior Is Mediated by Fos-Expressing Neuronal Ensembles Formed at First Learning in Rats

Abstract

Neuronal ensembles in the infralimbic cortex (IL) develop after prolonged food selfadministration training. However, rats demonstrate evidence of learning the food selfadministration response as early as day 1, with responding quickly increasing to asymptotic levels. Since the contribution of individual brain regions to task performance shifts over the course of training, it remains unclear whether IL ensembles are gradually formed and refined over the course of extensive operant training, or if functionallyrelevant ensembles might be recruited and formed as early as the initial acquisition of food self-administration behavior. Here, we aimed to determine the role of IL ensembles at the earliest possible point after demonstrable learning of a response-outcome association. We first allowed rats to lever press for palatable food pellets and stopped training rats once their behavior evidenced the response-outcome association (learners). We compared their food-seeking behavior and neuronal activation (Fos protein expression) to similarly trained rats that did not form this association (nonlearners). Learners had greater food-seeking behavior and neuronal activation within the medial prefrontal cortex (mPFC), suggesting that mPFC subregions might encode initial food self-administration memories. To test the functional relevance of mPFC Fosexpressing ensembles to subsequent food seeking, we tested region-wide inactivation of the IL using muscimol+baclofen and neuronal ensemble-specific ablation using the Daun02 inactivation procedure. Both region-wide inactivation and ensemble-specific inactivation of the IL significantly decreased food seeking. These data suggest that IL neuronal ensembles form during initial learning of food self-administration behavior, and furthermore, that these ensembles play a functional role in food-seeking. Significance statementNeuronal ensembles within the infralimbic cortex (IL) play a causal role in mediating established food self-administration and food seeking. Here, we conducted region-wide and neuronal ensemble specific inactivation within the IL to determine whether IL neuronal ensembles are involved initial acquisition of food self-administration behavior.We demonstrate that neuronal ensembles within the IL control initial learning of food self-administration behavior.

Prefrontal cortex melanocortin 4 receptors (MC4R) mediate food intake behavior in mice

“…Importantly, we show that an increase in food intake is seen only when deletion of MC4R is restricted to the ventral region of the mPFC, not when the deletion includes both prelimbic and infralimbic regions. This reinforces previous research showing that manipulation of neurons in the whole mPFC enhances food seeking behavior, but does not change food intake [20,21]. Furthermore, these results suggest that food-intake related behavior, potentially related to cognitive functions, are differentially regulated by mPFC subregions, conceptually consistent with results supporting distinct roles for mPFC subregions important for the expression of appetitive vs. aversive instrumental behaviors [16-18, 22, 23].…”

Prelimbic Ensembles Mediate Cocaine Seeking After Behavioral Acquisition and Once Rats Are Well-Trained

“…These results are congruent with our previous findings that ensembles in the mPFC modulate cocaine SA (Warren et al, 2019 ; Kane et al, 2021 ). Furthermore, these findings suggest that Fos-expressing neuronal ensembles within the PL are critical for mediating reward seeking, even after a single day of motivated self-administration (Quintana-Feliciano et al, 2021 ).…”

“…We have also shown that the mPFC more broadly houses ensembles that mediate recently acquired goal-oriented responding. For instance, using a similar acquisition paradigm we have found that the infralimbic cortex (IL) is necessary for initial food and oxycodone seeking (Quintana-Feliciano et al, 2021 ; Gobin et al, 2022 ). Our current findings expand this literature and support the hypothesis that ensembles in the mPFC and specifically in the PL are formed and become behaviorally relevant early in the learning process.…”

“…We allowed rats between 1 and 12 days to reach the acquisition criteria defined as ≥30 active lever presses and ≥70% of total lever responses on the active lever. We chose these criteria based on previous studies that used similar acquisition criteria (Mitchell et al, 2005 ; Taylor et al, 2010 ; Quintana-Feliciano et al, 2021 ).…”

Comparison of prefrontal cortex sucrose seeking ensembles engaged in multiple seeking sessions: Context is key

“…Whole‐brain networks are necessary to process, modulate, and execute complex behaviors like reward seeking. Several studies have implicated the medial prefrontal cortex (mPFC) in promoting drug (reviewed in [Kalivas & McFarland, 2003; Mantsch et al, 2016; Peters et al, 2009; Van den Oever et al, 2010]) and sucrose (Brebner et al, 2020; Caballero et al, 2019; Quintana‐Feliciano et al, 2021) seeking. The OFC and dorsal and ventral (PrL and IL) mPFC contain neurons that respond to sucrose cues (Moorman & Aston‐Jones, 2015; Stalnaker et al, 2006), and the number of Fos positive cells in these regions correlates with the degree of sucrose seeking (Grimm et al, 2016).…”