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5-HT6R-ATR-Primary Cilia Network Supports Memory Extinction

ABSTRACT: Drug addiction represents a pathological form of learning and memory with profound implications for individuals and society. The serotonin receptor 5-HT6R, uniquely expressed on primary cilia, is associated with neurological development, cognitive impairments, emotional disorders, and reward memory for cocaine and nicotine. However, its role in morphine-related reward memory remains unclear. This study demonstrated that 5-HT6R expression was downregulated during the early stage of morphine-induced conditioned place preference (CPP) extinction but returned to baseline levels later, with no significant changes observed during CPP establishment or reinstatement. Knocking down 5-HT6R accelerated CPP extinction, while overexpression prolonged the process. Furthermore, primary cilia defects within the mPFC were noted during the early stage of CPP extinction, and the removal of primary cilia expedited this process. Finally, ATR was identified as a novel target molecule of 5-HT6R, and the 5-HT6R-ATR-primary cilia network was found to regulate morphine-induced CPP extinction, offering new insights for opioid addiction therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE273842 | GEO | 2025/09/03

REPOSITORIES: GEO

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Project description:Molecular basis of transition to addiction in vulnerable individuals is largely unknown. We hypothesized that human susceptibility genes can be identified on the basis of conserved molecular mechanisms in rodent brains. We used a short-term cocaine-dependent conditioned place preference (CPP) to identify genetic hallmarks of early steps of reward memory in basal ganglia including accumbens nucleus (NAc), globus pallidus (GP) and subthalamic nucleus (STN). Using genome-wide microarray analysis and CPP as a quantitative trait, we found that synaptic plasticity-related genes are deregulated in these three structures. A significant enrichment in bona fide transcripts involved in dendritic spine local translation was evidenced. mGluR5 is transcriptionally deregulated in Acc and GP of cocaine-treated animals. Grin3a that encodes a NMDA receptor subunit involved in Ca++ permeability is deregulated in NAc. Furthermore, Orexin/Hcrt transcript level is decreased in STN, a region known to be involved in discriminating addictive drugs and natural rewards. We also found that mGluR5 and Grin3a expression deregulation is sufficient to induce changes in synaptic plasticity-related genes. Altogether, these results suggest that a combined deregulation of mGluR5 and Grin3A pathway in NAc, mGluR5 in GP and orexin system in STN may generate an incentive memory contrasted between addictive drugs and natural rewards. Such pathways may include clusters of genes that are potential susceptibility genes for transition to addiction. Agilent Whole Mouse Genome oligomicroarrays (GEO accession no. GPL4134, Agilent Technologies, Palo Alto, CA) were used. They contain 60-mer DNA probes synthesized in situ in a 44k format. Four independent (globus pallidus from mouse treated with cocaine and having a high score of conditioned place preference compared to globus pallidus from mouse treated with saline solution) measurements were carried out for each group of biological conditions using exchanged dye-labeled RNA targets (i.e., Cy3 and Cy5 dyeswapping experiments).

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5-HT6R-ATR-Primary Cilia Network Supports Memory Extinction

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