Biology subjects

Zieba, M.

Publications and source records attributed to Zieba, M..

3 recordsLinked to original sources

bioRxiv2025

Risperidone regulates the expression of schizophrenia-related genes in the murine forebrain

Risperidone acts on monoaminergic signaling to alleviate psychosis. At the cellular level, through both direct and indirect effects, the drug induces a specific pattern of gene expression, which differs between the basal ganglia and frontal cortex. These risperidone-regulated changes influence neuronal plasticity and are crucial for both its antipsychotic and extrapyramidal effects. Here, we employed sequencing-based spatial transcriptomics to comprehensively characterize gene expression changes in the male mouse (Mus musculus L.) forebrain after an acute dose of risperidone (0.5 mg/kg, i.p.). The transcriptional patterns were structure-specific, and unsupervised clustering of spatial profiles accurately identified cortical divisions, layers, and basal ganglia subregions. Differential gene expression was subsequently analyzed within each anatomically defined cluster using a customized statistical framework. Risperidone significantly altered the levels of 95 transcripts across 12 brain regions. The largest number of changes was observed in ventral brain areas, including the olfactory tubercle (25 differentially regulated transcripts), the diagonal band nucleus (22), the corpus callosum and commissures (13), and the lateral septal nucleus (9). Notably, 21 of the 95 differentially expressed genes were previously associated with schizophrenia, including Olig2, Smpd3, and Cacna1i. Overall, our results indicate that the strongest effects of risperidone are in medial and ventral brain regions rich in oligodendrocytes and glial cells. Furthermore, the enrichment analysis provides robust evidence of a molecular link between the drugs mechanism of action and genetic factors involved in schizophrenia. HighlightsO_LIUnsupervised clustering accurately identifies transcripts localization in the brain C_LIO_LIAcute risperidone treatment alters spatial transcriptional patterns of 95 genes C_LIO_LIRisperidone-regulated transcripts include 21 genes previously linked to schizophrenia C_LIO_LISpatial gene expression analysis offers novel insight into the drug action mechanism C_LI

pharmacology and toxicology↗

bioRxiv2025

L-DOPA induces spatially discrete changes in gene expression in the forebrain of mice with a progressive loss of dopaminergic neurons

L-3,4-Dihydroxyphenylalanine (L-DOPA) is effective at alleviating motor impairments in Parkinsons disease (PD) patients but has mixed effects on nonmotor symptoms and causes adverse effects after prolonged treatment. Here, we analyzed the spatial profile of L-DOPA-induced gene expression in the forebrain of mice with an inducible progressive loss of dopaminergic neurons (the TIF-IADATCreERT2 strain), with a focus on the similarities and differences in areas relevant to different PD symptoms. The animals received a 14-day L-DOPA treatment, and 1 h after the final drug injection, a spatial transcriptome analysis was performed on coronal forebrain sections. A total of 121 genes were identified as being regulated by L-DOPA. We found that the treatment had widespread effects extending beyond the primary areas involved in dopamine-dependent movement control. An unsupervised clustering analysis of the transcripts recapitulated the forebrain anatomy and indicated both ubiquitous and region-specific effects on transcription. The changes were most pronounced in layers 2/3 and 5 of the dorsal cortex and the dorsal striatum, where a robust increase in the abundance of activity-regulated transcripts, including Fos, Egr1, and Junb, was observed. Conversely, transcripts with a decreased abundance, e.g., Plekhm2 or Pgs1, were identified primarily in the piriform cortex, the adjacent endopiriform nucleus, and the claustrum. Taken together, our spatial analysis of L-DOPA-induced alterations in gene expression reveals the anatomical complexity of treatment effects, identifying novel genes affected by the drug, as well as molecular activation in brain areas relevant to the nonmotor symptoms of PD.

neuroscience↗

bioRxiv2024

μ-Opioid receptor transcriptional variants in the murine forebrain and spinal cord

BackgroundOprm1, the gene encoding the -opioid receptor, has multiple reported transcripts, with a variable 3 region and many alternative sequences encoding the C-terminus of the protein. The functional implications of this variability remain mostly unexplored, though a recurring notion is that it could be exploited by developing selective ligands with improved clinical profiles. Here, we comprehensively examined Oprm1 transcriptional variants in the murine central nervous system. MethodsRNA-seq transcription analyses were performed based on Oxford Nanopore Sequencing (ONS) and 10x Genomics Visium spatial transcriptomics data. The spatial distribution of Oprm1 exons was evaluated via RNAscope in situ hybridization. Tissue and cell-type specificity was assessed based on reanalysis single-cell RNAseq databases. ResultsWe detected a mismatch between transcripts annotated in GRCm38/mm10 and RNA-seq results. Sequencing data indicated that the primary Oprm1 transcript has a 3 terminus located on chr10:6,860,027, which is ~9.5 kilobases downstream of the longest annotated exon 4 end. Long-read sequencing confirmed that the final Oprm1 exon included a 10.2 kilobase long 3 untranslated region. The presence of the long variant was unambiguously confirmed using RNAscope in situ hybridization. The long variant was observed in the thalamus, striatum, cortex and spinal cord. Expression of additional variants of the Oprm1 gene was close to the detection limit. Reanalysis of single-cell sequencing data confirmed these observations and indicated that Oprm1 was expressed mainly in parvalbumin-, somatostatin- and VIP-positive cells. ConclusionThe primary transcript of the Oprm1 mouse gene is a variant with a long 3 untranslated region. Author SummaryOpioids are essential for the management of pain and have multiple other medical indications; however, their addictive properties and widespread misuse have led to a severe modern health crisis. Accordingly, there has been a major effort to develop novel compounds that retain clinical effectiveness while diminishing their addictive potential and other adverse effects. One of the potential avenues for safer opioid drugs is developing compounds that are selective for a specific group of the main targets of opioid medications--the -opioid receptors. Multiple variants the -opioid receptor have been reported, encoded by different transcripts of the Oprm1 gene. Here, we used RNA transcript sequencing and in situ hybridization with probes to detect different parts of Oprm1 transcripts to validate the existence of various reported isoforms. Our main finding is that the primary transcript of the receptor is much longer than the current reference sequences annotated in the mouse genome and has an over 10,000-base-long noncoding sequence at the 3 terminus. Several other types of transcripts are also expressed; however, they represent approximately 15% or less of the total transcript content in each of the examined brain regions. In the context of future research on opioid drugs, these results indicate that it is unlikely that different subpopulations of receptors could be targeted.

genomics↗