Single-cell transcriptome analysis reveals characteristic transcription factors in polydactyly.

OBJECTIVE: The study aims to provide guidance on the identification of multiple-digit malformations as potential biomarkers and therapeutic targets. MATERIALS AND METHODS: Single-cell RNA sequencing (scRNA-seq) data of four multiple-finger malformation samples were downloaded from the GEO public database. Fibroblasts and keratinocytes were divided into cellular subpopulations and the transcription factors of different subpopulations were analyzed. The regulatory network of transcription factors and their target genes were constructed to analyze the functionality of regulons. RESULTS: Examination of the transcriptional profile data from 11,806 single cells uncovered significant associations between regulons and cell function in polydactyly. Specifically, the analysis highlighted the involvement of HOX family members and GLI2 transcription factors, including HOXD13, MSX2, LHX2, EMX2, LEF1, CREB3L2, and LHX2, in the polydactyly process within fibroblast cells. Furthermore, it sheds light on the roles of HES2 and GLIS1 in the formation and development of keratinocytes. CONCLUSIONS: Significant presence of transcription factors, especially HOXD13, MSX2, and LHX2, may be strongly related to the development of polydactyly.

Evidence that mesolimbic dopaminergic activation underlies the locomotor stimulant action of nicotine in rats.

L-Nicotine stimulates locomotor activity in rats which have had prior experience of the drug. The present study investigated whether this behavioral effect is related to activation of the mesolimbic dopamine system. In the first experiment, l-nicotine (0.2-0.8 mg/kg s.c.) stimulated locomotor activity and increased dopamine utilization in the olfactory tubercle, as judged by the ratio of the concentration of dihydroxyphenylacetic acid to dopamine. In other experiments, l-nicotine (0.1-0.4 mg/kg) stimulated locomotor activity in a dose-related, stereoselective manner; after pretreatment with the l-aromatic amino acid decarboxylase inhibitor NSD-1015, l-nicotine increased 3,4-dihydroxyphenylalanine/dopamine ratios in olfactory tubercle and nucleus accumbens, suggesting increased dopamine utilization, although absolute concentrations of 3,4-dihydroxyphenylalanine and dopamine were in general not significantly altered. This neurochemical action of l-nicotine was dose-dependent, stereoselective and absent in the caudate-putamen at the doses tested. l-Nicotine did not alter indices of 5-hydroxytryptamine utilization. The locomotor stimulant effect of l-nicotine was abolished by bilateral intra-accumbens microinjection of 6-hydroxydopamine, which depleted markedly mesolimbic terminal areas of dopamine. Thus, in rats which have been chronically treated with l-nicotine, a selective activation of mesolimbic dopamine appears to mediate the locomotor stimulant effect of this drug.

Tolerance to haloperidol-induced increases in dopamine metabolites: fact or artifact?

Haloperidol increased 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations in the striatum, nucleus accumbens and olfactory tubercle of both drug-naive rats and rats pretreated with haloperidol (10 injections). The increases in metabolite concentrations were greater in all brain regions of the naive rats, suggesting that haloperidol pretreatment resulted in a decreased responsiveness to the drug (tolerance). However, subchronic haloperidol injections also resulted in decreased basal metabolite concentrations in rats killed 48 h after the last injection. While the response of drug-experienced rats to haloperidol was attenuated relative to that of drug-naive rats, this difference could be accounted for entirely by the decreased basal metabolite concentrations that occur after repeated haloperidol injections.