Environmental enrichment mitigatesthe long-lasting sequelae of perinatal fentanyl exposure

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- 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 {micro}g/mL, per os) across pregnancy and until weaning (PD 21). Perinatally-exposed adolescent mice displayed hyperactivity (PD 45), enhanced sensitivity to anxiogenic environments (PD 46), and sensory maladaptation (PD 47) - sustained behavioral effects that were completely normalized by environmental enrichment (PD 21-45). Additionally, environmental enrichment normalized the fentanyl-induced changes in the frequency of miniature excitatory postsynaptic currents of layer 2/3 neurons in the primary somatosensory cortex (S1). We also demonstrate that fentanyl impairs short- and long-term potentiation 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 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 non-invasive intervention introduced during early development. Significance StatementIllicit 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.