The Antidepressant Action of Fluoxetine Involves the Inhibition of Dlx5/6 in Cortical GABAergic Neurons through a TrkB-Dependent Pathway

Cells, Journal Year: 2024, Volume and Issue: 13(15), P. 1262 - 1262

Published: July 26, 2024

Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. Despite the large use antidepressants in current medical practice, neither their mechanisms action nor aetiology MDD are completely understood. Experimental evidence supports involvement Parvalbumin-positive GABAergic neurons (PV-neurons) pathogenesis MDD. DLX5 DLX6 (DLX5/6) encode two homeodomain transcription factors involved cortical differentiation function. In mouse, level expression these genes correlated with density PV-neurons anxiety-like behaviours. The same genomic region generates lncRNA DLX6-AS1, which, humans, participates regulatory module downregulated schizophrenia ASD. Here, we show levels Dlx5/6 adult mouse brain immobility time forced swim test, which used to measure depressive-like We administration antidepressant fluoxetine (Flx) normal mice induces, within 24 h, rapid stable reduction Dlx5, Dlx6 Dlx6-AS1 cerebral cortex through activation TrkB-CREB pathway. Dlx5 overexpression counteracts effects induced by Flx treatment. Our findings one short-term neurons, turn, has direct consequences on PV behavioural profiles. Variants DLX5/6 network could be implicated predisposition depression variability patients’ response

Language: Английский

NG-SEM: an effective non-Gaussian structural equation modeling framework for gene regulatory network inference from single-cell RNA-seq data

Briefings in Bioinformatics, Journal Year: 2023, Volume and Issue: 24(6)

Published: Sept. 22, 2023

Abstract Inference of gene regulatory network (GRN) from expression profiles has been a central problem in systems biology and bioinformatics the past decades. The tremendous emergency single-cell RNA sequencing (scRNA-seq) data brings new opportunities challenges for GRN inference: extensive dropouts complicated noise structure may also degrade performance contemporary models. Thus, there is an urgent need to develop more accurate methods inference while considering at same time. In this paper, we extend traditional structural equation modeling (SEM) framework by flexible strategy, namely use Gaussian mixtures approximate complex stochastic nature biological system, since mixture can be arguably served as universal approximation any continuous distributions. proposed non-Gaussian SEM called NG-SEM, which optimized iteratively performing Expectation-Maximization algorithm weighted least-squares method. Moreover, Akaike Information Criteria adopted select number components mixture. To probe accuracy stability our method, design comprehensive variate control experiments systematically investigate NG-SEM under various conditions, including simulations real sets. Results on synthetic demonstrate that strategy improve model results sets verify outperforms other five state-of-the-art methods.

Language: Английский

TrkB-dependent antidepressants action involves Dlx5/6 inhibition in cortical GABAergic neurons.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 7, 2024

Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. However, both the aetiology MDD mechanisms action antidepressants are not completely understood. Many indications suggest involvement Parvalbumin-positive GABAergic neurons (PV-neurons) in pathogenesis MDD. DLX5 DLX6 (DLX5/6) encode for two homeodomain transcription factors involved cortical differentiation function. In mouse, level expression these genes inversely correlated to density PV-neurons anxiety-like behaviours. The same genomic region generates lncRNA DLX6-AS1 which, humans, has been identified as most central hub gene interneuron module downregulated schizophrenia ASD. inhibitory interneurons affected many neuro-psychiatric conditions including schizophrenia. Here, we show levels Dlx5/6 adult mouse brain with immobility time forced swimming test, an assay used study depressive-like behaviours efficacy anti-depressive drugs rodents. We administration antidepressant Fluoxetine (Flx) normal mice induces, within 24h, rapid stable reduction Dlx5, Dlx6 Dlx6-AS1 cerebral cortex through activation TrkB-CREB cascade can counteract behavioural cellular alterations induced by experimental Dlx5 overexpression. Our findings one short-term effects Flx treatment neurons, turn direct consequences on PV profiles. Variants DLX5/6 regulatory network could be implicated predisposition depression variability patients’ response constitute target further understanding mechanism antidepressants.

Language: Английский