Long-lasting deficits in hedonic and nucleus accumbens reactivity to sweet rewards by sugar overconsumption during adolescence

Adolescence is a critical period characterized by major neurobiological changes. Chronic stimulation of the reward system might constitute an important factor in vulnerability to pathological development. In spite of the dramatic increase in the consumption of sweet palatable foods during adolescence in our modern societies, the long-term consequences of such exposure on brain reward processing remain poorly understood. Here, we investigated in rats the long-lasting effects of sugar overconsumption during their adolescence on their adult reactivity to the hedonic properties of sweet rewards. Adolescent rats with continuous access to 5% sucrose solution (from postnatal day 30-46) showed escalating intake. At adulthood (post-natal day 70), using two-bottle free choice tests, sucrose-exposed rats showed lower intake than non-exposed rats suggesting decreased sensitivity to the rewarding properties of sucrose. In Experiment 1, we tested their hedonic-related orofacial reactions to intraoral infusion of tasty solutions. We showed that sucrose-exposed rats presented less hedonic reactions in response to sweet tastes leaving the reactivity to water or quinine unaltered. Hence, in Experiment 2, we observed that this hedonic deficit is associated with lower c-Fos expression levels in the nucleus accumbens, a brain region known to play a central role in hedonic processing. These findings demonstrate that a history of high sucrose intake during the critical period of adolescence induces long-lasting deficits in hedonic treatment that may contribute to reward-related disorders

Adaptation to contingency changes.

<p>a) Evolution of the rate of lever-pressing during the session of contingency change in blocks of 5 min. (mean + s.e.), according to lesion and condition b) final rate of response at test. Data are expressed as mean rates of responding. c) Evolution of the rate of entries into the empty magazine during the session of contingency change (mean + s.e.). d) Evolution of absolute number of rewards delivered during the session of contingency change in blocks of 5 min., according to lesion. Equal rewards are delivered in both conditions. Negative: negative contingency condition; Null: null contingency condition.</p

Adaptation to contiguity changes in sham and mPFC-lesioned rats.

<p>Upper panel: Sham, control rats. Lower panel: PFC: rats with lesions of the medial prefrontal cortex. Data points represent average lever-pressing rate across blocks of fixed delay (mean + s.e.). Delay between lever press and reward was increased by 0.5 s after each block of four rewards. Last data points show the recovery of responding with short delays during test on the next day. Grey area shows range of values observed in group no-delay across the whole session (computed over blocks of four rewards).</p

Time line representation of the contingency conditions.

<p>A) During instrumental training (positive contingency), the lever becomes inactive for a variable interval (white rectangle) following each reward delivery. The first lever press after this interval triggers an immediate reward. No reward occurs in the absence of lever press (positive contingency). B) During omission training, rewards are delivered following a 20 s delay without lever press (black rectangle). A lever press during the delay resets the delay. Consecutive rewards are delivered at 20 s intervals in the absence of lever press activity (negative contingency). C) During yoked training, rewards are synchronized to the rewards of another rat trained in omission, regardless of the yoked rat's activity. Rewards may occur at any time with respect to lever presses (null contingency).</p

Schematic representation of the extent of medial prefrontal cortex lesions.

<p>a) minimal (black area) and maximal (gray area) mPFC lesions affected both the prelimbic and infralimbic parts of the medial prefrontal cortex. b) Photomicrograph of a typical mPFC lesion, illustrating cell loss (outlined by arrowheads). Cg1: Cingulate Cortex 1; PL: Prelimbic Cortex; IL: Infralimbic cortex.</p

A Role for Medial Prefrontal Dopaminergic Innervation in Instrumental Conditioning

To investigate the involvement of dopaminergic projections to the prelimbic and infralimbic cortex in the control of goal-directed responses, a first experiment examined the effect of pretraining 6-OHDA lesions of these cortices. We used outcome devaluation and contingency degradation procedures to separately assess the representation of the outcome as a goal or the encoding of the contingency between the action and its outcome. All groups acquired the instrumental response at a normal rate, indicating that dopaminergic activity in the medial prefrontal cortex is not necessary for the acquisition of instrumental learning. Sham-operated animals showed sensitivity to both outcome devaluation and contingency degradation. Animals with dopaminergic lesions of the prelimbic cortex, but not the infralimbic cortex, failed to adapt their instrumental response to changes in contingency, whereas their response remained sensitive to outcome devaluation. In a second experiment, aimed at determining whether dopamine was specifically needed during contingency changes, we performed microinfusions of the dopamine D(1)/D(2) receptor antagonist flupenthixol in the prelimbic cortex only before contingency degradation sessions. Animals with infusions of flupenthixol failed to adapt their response to changes in contingency, thus replicating the deficit of animals with dopaminergic lesions in Experiment 1. These results demonstrate that dissociable neurobiological mechanisms support action-outcome relationships and goal representation, dopamine signaling in the prelimbic cortex being necessary for the former but not the latter

Differences in temperament between the “low responders” and “high responders” during Pavlovian to instrumental transfer.

<p>“Low responders”: individuals who performed the fewest correct responses during CS presentation (N = 9). “High responders”: individuals who performed the most correct responses during CS presentation (N = 10).</p

Parallel Maturation of Goal-Directed Behavior and Dopaminergic Systems during Adolescence

Adolescence is a crucial developmental period characterized by specific behaviors reflecting the immaturity of decision-making abilities. However, the maturation of precise cognitive processes and their neurobiological correlates at this period remain poorly understood. Here, we investigate whether a differential developmental time course of dopamine (DA) pathways during late adolescence could explain the emergence of particular executive and motivational components of goal-directed behavior. First, using a contingency degradation protocol, we demonstrate that adolescent rats display a specific deficit when the causal relationship between their actions and their consequences is changed. When the rats become adults, this deficit disappears. In contrast, actions of adolescents remain sensitive to outcome devaluation or to the influence of a pavlovian-conditioned stimulus. This aspect of cognitive maturation parallels a delayed development of the DA system, especially the mesocortical pathway involved in action adaptation to rule changes. Unlike in striatal and nucleus accumbens regions, DA fibers and DA tissue content continue to increase in the medial prefrontal cortex from juvenile to adult age. Moreover, a sustained overexpression of DA receptors is observed in the prefrontal region until the end of adolescence. These findings highlight the relationship between the emergence of specific cognitive processes, in particular the adaptation to changes in action consequences, and the delayed maturation of the mesocortical DA pathway. Similar developmental processes in humans could contribute to the adolescent vulnerability to the emergence of several psychiatric disorders characterized by decision-making deficits

Pavlovian to instrumental transfer in horses.

<p>Left: Number of correct responses (out of 5) during the 3 presentations of the CS (CS1–CS3, in grey) as compared to the corresponding number during their respective intertrial intervals (ITI1–ITI3, in white). Right: Sum of the correct responses exhibited during the 3 ITI and 3 CS periods.</p

Differences in temperament between the “low performers” and “high performers” during acquisition.

<p>“Low performers”: individuals who performed the fewest correct responses during the first four acquisition sessions (N = 9). “High performers”: individuals who performed the most correct responses during the first four acquisition sessions (N = 10).</p