Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward

Abstract

Background: Neuronal primary cilia are being recognized for their role in mediating signaling associated with a variety of neurobehaviors, including responses to drugs of abuse. They function as signaling hubs, enriched with a diverse array of G-protein coupled receptors (GPCRs), including several associated with motivation and drug-related behaviors. However, our understanding of how cilia regulate neuronal function and behavior is still limited. Aims: The objective of the current study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to cocaine. Methods: To test the consequences of cilia loss on cocaine-induced locomotion and reward-related behavior, we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in mice. Results: Cilia ablation on either population of neurons failed to significantly alter acute locomotor responses to cocaine at a range of doses. With repeated administration, mice lacking cilia on GAD2-GABAergic neurons showed no difference in locomotor sensitization to cocaine compared to wild-type (WT) littermates, whereas mice lacking cilia on dopaminergic neurons exhibited reduced locomotor sensitization to cocaine at 10 and 30 mg/kg. Mice lacking cilia on GAD2-GABAergic neurons showed no difference in cocaine conditioned place preference (CPP), whereas mice lacking cilia on dopaminergic neurons exhibited reduced CPP compared to WT littermates. Conclusions: Combined with previous findings using amphetamine, our results show that behavioral effects of cilia ablation are cell- and drug type-specific, and that neuronal cilia contribute to modulation of both the locomotor-inducing and rewarding properties of cocaine.

Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder

“…A possible link to CUD provide neuronal primary cilia, known as key signaling hubs on somata enriched for G-protein-coupled receptors (GPCRs) 44 . As INPP5E is required for proper trafficking of GPCRs along ciliary microtubules 45 , deregulation of INPP5E might lead to aberrant ciliary signaling that has recently gained attention in the addiction field: cell type-specific ablation of neuronal primary cilia in mice was shown to affect body weight as well as locomotor response to psychostimulants such as cocaine 46 and amphetamine 47 . In humans, further studies on INPP5E are required to evaluate its role in SUDs.…”

Postnatal Dynamic Ciliary ARL13B and ADCY3 Localization in the Mouse Brain

“…These included cilia enriched with only ARL13B (red cilia, hereafter ARL13B+), cilia enriched with only ADCY3 (green cilia, hereafter ADCY3+), and cilia localizing both ARL13B and ADCY3 (orange cilia, hereafter COLO) (Figure 2A,B) [28,36,38]. We chose to focus on several brain regions where cilia have been implicated in behaviors such as feeding and reward [39][40][41]. These brain regions include the hypothalamic nuclei, such as the arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH), and suprachiasmatic nucleus (SCN), as well as the shell (NAs) and core (NAc) of the nucleus accumbens (Figure 2C).…”