Sex-specific transcriptomic profiling of reward and sensory brain areas in perinatal fentanyl exposed juvenile mice

Abstract

ABSTRACTBACKGROUNDUse of the synthetic opioid fentanyl increased ∼300% in the last decade, including among women of reproductive ages. Adverse neonatal outcomes and long-term behavioral disruptions are associated with perinatal opioid exposure. Our previous work demonstrated that perinatal fentanyl exposed (PFE) mice displayed enhanced negative affect and somatosensory circuit and behavioral disruptions during adolescence. However, little is known about molecular adaptations across brain regions that underlie these outcomes. We performed RNA-sequencing across three reward and two sensory brain areas to study transcriptional programs in PFE juvenile mice.METHODSC57BL/6 pregnant dams received 10μg/ml fentanyl in the drinking water from embryonic day 0 (E0) through gestational periods until weaning at postnatal day 21 (P21). RNA was extracted from nucleus accumbens (NAc), prelimbic cortex (PrL), ventral tegmental area (VTA), somatosensory cortex (S1) and ventrobasal thalamus (VBT) from PFE mice of both sexes at P35. RNA-sequencing was performed, followed by analysis of differentially expressed genes (DEGs) and gene co-expression networks.RESULTSTranscriptome analysis revealed sex-specific DEGs and gene modules significantly associated with PFE. The VTA had the most DEGs, while pronounced gene enrichment occurred in NAc. Genes enriched in mitochondrial respiration were pronounced in NAc and VTA of PFE males, extracellular matrix (ECM) and neuronal migration enrichment were pronounced in NAc and VTA of PFE males, while genes associated with vesicular cycling and synaptic signaling were markedly altered in NAc of PFE female mice. In sensory areas from PFE females, we found alterations in mitochondrial respiration, synaptic and ciliary organization processes.CONCLUSIONOur findings demonstrate sex-specific neuroadaptations in PFE mice. Our studies identify distinct transcriptomes across reward and sensory brain regions that may underlie disrupted behavioral and circuit states in PFE mice.