p11 in cholinergic interneurons of the nucleus accumbens is essential for dopamine responses to rewarding stimuli

Abstract

A recent study showed that p11 expressed in cholinergic interneurons (CINs) of the nucleus accumbens (NAc) is a key regulator of depression-like behaviors. Dopaminergic neurons projecting to the NAc are responsible for reward-related behaviors, and their function is impaired in depression. The present study investigated the role of p11 in NAc CINs in dopamine responses to rewarding stimuli. The extracellular dopamine and acetylcholine (ACh) levels in the NAc were determined in freely moving male mice using in vivo microdialysis. Rewarding stimuli (cocaine, palatable food and female mouse encounter) induced an increase in dopamine efflux in the NAc of wild-type mice. The dopamine responses were attenuated (cocaine) or abolished (food and female mouse encounter) in constitutive p11 KO mice. The dopamine response to cocaine was accompanied by an increase in ACh NAc efflux, whereas the attenuated dopamine response to cocaine in p11 KO mice was restored by activation of nicotinic or muscarinic ACh receptors in the NAc. Dopamine responses to rewarding stimuli and ACh release in the NAc were attenuated in mice with deletion of p11 from cholinergic neurons (ChAT-p11 cKO mice), whereas gene delivery of p11 to CINs restored the dopamine responses. Furthermore, chemogenetic studies revealed that p11 is required for activation of CINs in response to rewarding stimuli. Thus, p11 in NAc CINs plays a critical role in activating these neurons to mediate dopamine responses to rewarding stimuli. The dysregulation of mesolimbic dopamine system by dysfunction of p11 in NAc CINs may be involved in pathogenesis of depressive states.

Significance Statement p11 is a critical regulator of CIN activity as measured by the dopamine response of the mesolimbic dopamine pathway to rewarding stimuli. p11 is required for reward-mediated NAc CIN activation and induction in ACh release, resulting in the enhancement of dopamine release. The reduction of p11 expression in NAc CINs is tightly associated with anhedonia as well as other depression-like symptoms of behavioral despair. To improve therapeutic efficacy of antidepressants for anhedonia, a new type of antidepressant directly or indirectly acting on the mesolimbic dopamine pathway needs to be developed. For this purpose, therapeutic strategies that increase the function of p11 and its signaling pathway in NAc CINs may have an impact on antidepressant efficacy.