Accumbal Cholinergic Interneurons Differentially Influence Motivation Related to Satiety Signaling

Satiety, rather than all or none, can instead be viewed as a cumulative decrease in the drive to eat that develops over the course of a meal. The nucleus accumbens (NAc) is known to play a critical role in this type of value reappraisal, but the underlying circuits that influence such processes are unclear. Although NAc cholinergic interneurons (CINs) comprise only a small proportion of NAc neurons, their local impact on reward-based processes provides a candidate cell population for investigating the neural underpinnings of satiety. The present research therefore aimed to determine the role of NAc-CINs in motivation for food reinforcers in relation to satiety signaling. Through bidirectional control of CIN activity in mice, we show that when motivated by food restriction, increasing CIN activity led to a reduction in palatable food consumption while reducing CIN excitability enhanced food intake. These activity-dependent changes developed only late in the session and were unlikely to be driven by the innate reinforcer strength, suggesting that CIN modulation was instead impacting the cumulative change in motivation underlying satiety signaling. We propose that on a circuit level, an overall increase in inhibitory tone onto NAc output neurons played a role in the behavioral results, as activating NAc-CINs led to an inhibition of medium spiny neurons that was dependent on nicotinic receptor activation. Our results reveal an important role for NAc-CINs in controlling motivation for food intake and additionally provide a circuit-level framework for investigating the endogenous cholinergic circuits that signal satiety. Significance Statement The decrease in the drive to eat is not all or none but instead develops over the course of a meal, where with each bite the incentive value of food is reduced, eventually resulting in the state of being sated. Such reappraisal of value is a process that has been strongly attributed to nucleus accumbens function and provides a motivation-based framework for investigating the neural underpinnings of satiety. Nicotine, by acting on central nicotinic acetylcholine receptors, is well know to be a potent anorectic; nevertheless precisely how cholinergic brain circuits regulate appetite is poorly understood. The aim of this study was therefore to determine the endogenous cholinergic circuits that underlie satiety signaling.