Environmental Enrichment Mitigates the Long-Lasting Sequelae of Perinatal Fentanyl Exposure in Mice

The opioid epidemic is a rapidly evolving societal issue driven, in part, by a surge in synthetic opioid use. A rise in fentanyl use among pregnant women has led to a 40-fold increase in the number of perinatally-exposed infants in the past decade. These children are more likely to develop mood-related and somatosensory-related conditions later in life, suggesting that fentanyl may permanently alter neural development. Here, we examined the behavioral and synaptic consequences of perinatal fentanyl exposure in adolescent male and female C57BL/6J mice and assessed the therapeutic potential of environmental enrichment to mitigate these effects. Dams were given ad libitum access to fentanyl (10 µg/ml, per os) across pregnancy and until weaning [postnatal day (PD)21]. Perinatally-exposed adolescent mice displayed hyperactivity (PD45), enhanced sensitivity to anxiogenic environments (PD46), and sensory maladaptation (PD47), sustained behavioral effects that were completely normalized by environmental enrichment (PD21-PD45). Additionally, environmental enrichment normalized the fentanyl-induced changes in the frequency of miniature EPSCs (mEPSCs) of layer 2/3 neurons in the primary somatosensory cortex (S1). We also demonstrate that fentanyl impairs short-term potentiation (STP) and long-term potentiation (LTP) in S1 layer 2/3 neurons, which, instead, exhibit a sustained depression of synaptic transmission that is restored by environmental enrichment. On its own, environmental enrichment suppressed long-term depression (LTD) of control S1 neurons from vehicle-treated mice subjected to standard housing conditions. These results demonstrate that the lasting effects of fentanyl can be ameliorated with a noninvasive intervention introduced during early development.SIGNIFICANCE STATEMENT Illicit use of fentanyl accounts for a large proportion of opioid-related overdose deaths. Children exposed to opioids during development have a higher risk of developing neuropsychiatric disorders later in life. Here, we employ a preclinical model of perinatal fentanyl exposure that recapitulates these long-term impairments and show, for the first time, that environmental enrichment can reverse deficits in somatosensory circuit function and behavior. These findings have the potential to directly inform and guide ongoing efforts to mitigate the consequences of perinatal opioid exposure.