Nucleus accumbens dynamics in food reward seeking and regulation by sleep

Abstract

Reward-seeking behavior is essential for survival and is greatly influenced by experience, internal states, and physiological factors such as sleep. The nucleus accumbens (NAc) is reward processing hub that integrates external and internal signals to regulate reward-seeking behaviors. However, it is not well understood how NAc activities during reward seeking may be shaped by learning experience, and to what extent that it may be subject to physiological regulations such as sleep. Here, we used in vivo fiber photometry to monitor calcium (Ca²⁺) activities in the NAc of male and female mice undergoing sucrose self-administration (SA) training. We found that the NAc Ca²⁺ dynamics during sucrose SA were related to the behavioral outcome and evolved over different training stages. Moreover, acute sleep deprivation increased sucrose SA while reduced NAc Ca²⁺ responses and dampened its sensitivity to reward update. Thus, our findings suggest that the NAc response during natural reward seeking is dynamic, adaptive to learning experience, and can be blunted by acute sleep deprivation.

Fig. 1. NAc Ca²⁺ activity during sucrose reward seeking is related to behavioral outcome.

A Surgery, fiber photometry configuration, and experimental timeline. B Diagram of a coronal section containing the NAc, showing the positions of fiber optic tips in Retrievers (red) and Non-retrievers (black). C % Pellets retrieved in the two groups of mice: Retrievers (R) and Non-retrievers (NR). D Left, Representative heat maps of NAc Ca²⁺ Z-scores from a Retriever (R) versus a Non-retriever (NR) mouse during SA training over 30 min. Each row represented an individual trial with ALP aligned at t = 0 s. Right, Group-averaged Z-scores of NAc Ca²⁺ activity from Retriever mice versus Non-retriever mice, shown as Mean +/− SEM from all mice in each group. Yellow shades, periods used for AUC calculations. Green arrow, time of ALP; red arrow, time of sucrose pellet reward delivery. E The Retrievers had greater total Ca²⁺ activity than the Non-retrievers, calculated as AUC from −5 s till 10 s. F The Non-retrievers had greater #ALP than the Retrievers during the test as in D, E. ALP active-lever press, AUC area-under-curve, NAc nucleus accumbens, NR non-retriever, R retriever, SA self-administration. Data were represented as mean ± SEM. Each circle represents a mouse. n = 6 – 12 mice in each group. * p < 0.05, ** p < 0.01, **** p < 0.0001.

Fig. 2. NAc Ca²⁺ activity during sucrose reward seeking is sensitive to training stages.

A Surgery, fiber photometry configuration, and experimental timeline. B Top, Representative heat maps of NAc Ca²⁺ Z-scores from a mouse through the four stages. Each row represented an individual trial with ALP aligned at t = 0 s. Bottom, Averaged NAc Ca²⁺ Z-scores in all the mice across sucrose SA training stages, shown as Mean +/− SEM. Yellow shades, periods used for AUC calculations. Green arrow, time of ALP; red arrow, time of sucrose pellet reward delivery. C AUC of NAc Ca²⁺ Z-score integrated at pre-ALP (−5–0 s) or post-ALP (0–10 s) across stages i to iii. D AUC of NAc Ca²⁺ Z-score integrated at pre-ALP (−5–0 s) or post-ALP (0–10 s) across stages iii to iv. E No changes in #ALP across training stages. F No changes in ALP% at stages i to iii, and a decrease during stage iv. Data were represented as mean ± SEM. Each circle represents a mouse. n = 10 – 12 mice for stages i to iii, and n = 5 for stage iv. ALP active-lever press, AUC area-under-curve, NAc nucleus accumbens, SA self-administration. Post-hoc test # p < 0.05, ## p < 0.01, #### p < 0.0001; ns = not significant.

Fig. 3. Acute sleep deprivation reduces NAc Ca²⁺ activity during sucrose reward seeking.

A Left, Representative heat maps of NAc Ca²⁺ Z-scores from a mouse performing sucrose SA following normal sleep or acute SD. Each row represented an individual trial with ALP aligned at t = 0 s. Right, Averaged NAc Ca²⁺ Z-scores from all the mice during sucrose SA following normal sleep or acute SD, shown as Mean +/− SEM. Yellow shades, periods used for AUC calculations. Green arrow, time of ALP; red arrow, time of sucrose pellet reward delivery. B AUC of NAc Ca²⁺ Z-score integrated at pre-ALP (−5–0 s) or post-ALP (0–10 s) following normal sleep or acute SD. C SD reduced the rise slope of NAc Ca²⁺ responses (−2–0 s). D SD increased #ALP per 30 min. ALP active lever press, AUC area-under-curve, SD sleep deprivation. Data were represented as mean ± SEM. Each circle represents a mouse. n = 9 mice. **p < 0.01.

Fig. 4. Acute sleep deprivation reduces NAc Ca²⁺ responses to reward update.

A Surgery, fiber photometry configuration, and experimental timeline. On the testing day, following normal sleep or acute sleep deprivation, mice were tested for SA without sucrose pellet delivery for ~30 min followed by regular SA with pellet delivery for another ~30 min. B Top, Representative heat maps of NAc Ca²⁺ Z-scores in an example mouse across the four conditions. Each row represented an individual trial with ALP aligned at t = 0 s. Bottom, Averaged NAc Ca²⁺ Z-scores from all the mice during SA following normal sleep or acute sleep deprivation, in the absence or presence of sucrose pellet delivery. Yellow shades, periods used for AUC calculations. Green arrow, time of ALP; red arrow, time of sucrose pellet reward delivery. C Total AUC of NAc Ca²⁺ Z-score (−5–10 s) following normal sleep or sleep deprivation, and in the absence or presence of sucrose pellet deliveries. D #ALP under normal sleep or sleep deprivation in the absence or presence of sucrose pellet delivery. ALP active lever press, AUC area-under-curve, NAc nucleus accumbens, SA self-administration, SD sleep deprivation. Data were represented as mean ± SEM. Each circle represents a mouse. n = 10–11 mice in each condition. Main effect * p < 0.05, ** p < 0.01, post-hoc test # p < 0.05.