Biology subjects

Le, N. N.

Publications and source records attributed to Le, N. N..

2 recordsLinked to original sources

bioRxiv2026

A human CHRNA6 3' UTR variant alters the molecular environment and microRNA engagement of the adolescent VTA without changing Chrna6 transcript abundance

A single nucleotide polymorphism (rs2304297) in the 3' untranslated region (UTR) of CHRNA6, encoding the alpha6 nicotinic acetylcholine receptor subunit, is associated with adolescent smoking behavior. Humanized rats carrying the 'C' or 'G' allele show sex- and genotype-dependent responses to adolescent nicotine, yet the variant does not alter the protein sequence and the mechanism has remained unknown. We examined the molecular consequences of rs2304297 in vivo in the adolescent ventral tegmental area (VTA). Chrna6 transcript abundance did not differ by genotype, nor did transcript stability or polyadenylation site selection. The variant was instead associated with a transcriptional signature spanning myelin maintenance (Enpp6), lipid metabolism (Retsat), and genomic repair (Polq), and with elevated basal lipid peroxidation in alpha6GG animals. Computational folding predicted greater conformational flexibility of the 'G' allele, and spatial colocalization of Chrna6 with miRNA-365-5p was reduced in alpha6GG animals of both sexes. Coordinated expression of the two transcripts, however, followed a sex-by-genotype pattern, absent in alpha6CC females and alpha6GG males. These same groups showed elevated tyrosine hydroxylase expression and dopaminergic neuron number, and expansion of the Chrna6 co-expression network following nicotine. We propose that rs2304297 acts through two distinct layers: genotype determines spatial engagement of miRNA-365-5p with the transcript, while sex determines whether that engagement produces functional regulation. These findings identify a post-transcriptional mechanism for a non-coding nicotine addiction risk variant and demonstrate that its molecular effect can be uniform while its consequences are not.

neuroscience↗

bioRxiv2023

Striatal enkephalin supports maintenance of conditioned cocaine reward during extinction

Drug predictive cues and contexts exert powerful control over behavior and can incite drug seeking and taking. This association and the behavioral output are encoded within striatal circuits, and regulation of these circuits by G-protein coupled receptors affects cocaine-related behaviors. Here, we investigated how opioid peptides and G-protein coupled opioid receptors expressed in striatal medium spiny neurons (MSNs) regulate conditioned cocaine seeking. Augmenting levels of the opioid peptide enkephalin in the striatum facilitates acquisition of cocaine conditioned place preference (CPP). In contrast, opioid receptor antagonists attenuate cocaine CPP and facilitate extinction of alcohol CPP. However, whether striatal enkephalin is necessary for acquisition of cocaine CPP and maintenance during extinction remains unknown. We generated mice with a targeted deletion of enkephalin from dopamine D2-receptor expressing MSNs (D2-PenkKO) and tested them for cocaine CPP. Low striatal enkephalin levels did not attenuate acquisition or expression of CPP; however, D2-PenkKOs showed faster extinction of cocaine CPP. Single administration of the non-selective opioid receptor antagonist naloxone prior to preference testing blocked expression of CPP selectively in females, but equally between genotypes. Repeated administration of naloxone during extinction did not facilitate extinction of cocaine CPP for either genotype, but rather prevented extinction in D2-PenkKO mice. We conclude that while striatal enkephalin is not necessary for acquisition of cocaine reward, it maintains the learned association between cocaine and its predictive cues during extinction learning. Further, sex and pre-existing low striatal enkephalin levels may be important considerations for use of naloxone in treating cocaine use disorder.

neuroscience↗