Biology subjects

Gonzalez-Padilla, D.

Publications and source records attributed to Gonzalez-Padilla, D..

3 recordsLinked to original sources

bioRxiv2025

Transcriptional response to chronic long-access fentanyl self-administration in rat habenula and amygdala

Fentanyl is a potent synthetic opioid associated with overdose. However, little is known about fentanyl-induced molecular adaptations in the habenula and amygdala, two brain regions implicated in opioid use and withdrawal. We performed bulk RNA-sequencing in the rat habenula and amygdala to identify transcriptomic changes associated with fentanyl intake. Rats self-administered intravenous saline or fentanyl over 22-24 days. Ninety minutes following the final session, brains were collected for transcriptomic profiling. In Hb, we identified 453 differentially expressed genes (DEGs) between saline and fentanyl rats, with upregulated genes associated with synaptic transmission and ionic conductance. In amygdala, we identified 3,041 fentanyl-associated DEGs with upregulated genes implicated in metabolic and vesicular functions. Downregulated genes in both regions were enriched for extracellular matrix functions. Integration of DEGs with single-cell RNA-sequencing data from rodents and humans revealed that fentanyl DEGs were enriched in specific habenula and amygdala cell type markers. Furthermore, fentanyl downregulated DEGs in amygdala were enriched in genes associated with risk for substance use disorders. Together, we define how fentanyl intake alters transcriptional programs in the rat habenula and amygdala, and we link these changes to specific human cell types and risk genes for neuropsychiatric disorders and addiction.

neuroscience↗

bioRxiv2025

Integrated QTL mapping and CRISPR screening in pooled iPSC-derived microglia reveals genetic drivers of neurodegenerative risk

Mounting evidence implicates microglia in neurodegeneration, but linking disease-associated genetic variants to target genes and cellular phenotypes is hindered by the inaccessibility of these cells. We differentiated 261 human iPSC lines into microglia-like cells (iMGL) in pools with phenotypic (differentiation, phagocytosis and migration) and single-cell transcriptomic readouts. Burden analysis of deleterious variants detected 36 genes influencing microglial phenotypes. Expression quantitative trait locus (eQTL) analysis found 7,121 eGenes, and 79 colocalizations across four neurodegenerative disease GWAS, half of which had limited prior evidence of causality. Integration of eQTL and phenotypic associations highlighted the role of disease-relevant variants including LRRK2 and TREM2 acting via microglial phagocytosis. A coupled CRISPR screen identified a role of TREM2 in phagocytosis and highlighted the importance of cellular state in directionality of phenotype. By contextualizing variant effects within disease-relevant microglial states, we provide a comprehensive framework for interpreting the function of risk loci in neurodegenerative disorders.

genomics↗

bioRxiv2024

Molecular impact of nicotine and smoking exposure on the developing and adult mouse brain

Maternal smoking during pregnancy (MSDP) is associated with significant cognitive and behavioral effects on offspring. While neurodevelopmental outcomes have been studied for prenatal exposure to nicotine, the main psychoactive component of cigarette smoke, its contribution to MSDP effects has never been explored. Comparing the effects of these substances on molecular signaling in the prenatal and adult brain may provide insights into nicotinic and broader tobacco consequences that are developmental-stage specific or age-independent. Pregnant mice were administered nicotine or exposed to chronic cigarette smoke, and RNA-sequencing was performed on frontal cortices of postnatal day 0 pups born to these mice, as well as on frontal cortices and blood of the adult dams. We identified 1,010 and 4,165 differentially expressed genes (DEGs) in nicotine and smoking-exposed pup brains, respectively (FDR<0.05, Ns = 19 nicotine-exposed vs 23 vehicle-exposed; 46 smoking-exposed vs 49 controls). Prenatal nicotine exposure (PNE) alone was related to dopaminergic synapses and long-term synaptic depression, whereas MSDP was associated with the SNARE complex and vesicle transport. Both substances affected SMN-Sm protein complexes and postsynaptic endosomes. Analyses at the transcript, exon, and exon-exon junction levels supported gene level results and revealed additional smoking-affected processes. No DEGs at FDR<0.05 were found in adult mouse brain for any substance (12 nicotine-administered vs 11 vehicle-administered; 12 smoking-exposed vs 12 controls), nor in adult blood (12 smoking-exposed vs 12 controls), and only 3% and 6.41% of the DEGs in smoking-exposed pup brain replicated in smoking-exposed blood and human prenatal brain, respectively. Together, these results demonstrate variable but overlapping molecular effects of PNE and MSDP on the developing brain, and attenuated effects of both smoking and nicotine on adult versus fetal brain.

neuroscience↗