The Long-lasting Sequelae of Perinatal Fentanyl Exposure and Restoration by Environmental Enrichment

Abstract

One consequence of the opioid epidemic are the lasting neurodevelopmental sequelae of perinatal opioid exposure. Fentanyl, a synthetic opioid has recently increased in use, resulting in coinciding increases in perinatally-exposed infants. A translationally relevant and developmentally accurate preclinical model is needed to understand the long-lasting neurobiological abnormalities resulting from perinatal fentanyl exposure, as well as treatment interventions that can ameliorate these deficits. In Chapter 1, we develop a model of perinatal fentanyl exposure. Our data reveal that fentanyl has several developmental consequences to sensory function and behavior. Newborn mice exhibit somatic withdrawal and weight fluctuations. During adolescence, they display decreased grooming and anxiety-like behavior. By adulthood, they display impaired auditory discrimination. As fentanyl exposure does not affect maternal health or behavior, these effects appear to result from direct actions of perinatal fentanyl on the developing brain. In Chapter 2, we demonstrate that perinatal fentanyl exposure impairs somatosensory circuit function and behavior. We found a long-lasting reduction of synaptic excitation of primary somatosensory (S1) layer 5 neurons, as evidenced by decreases in stochastic and evoked excitatory release probability, and NMDA receptor-mediated postsynaptic currents. In contrast, anterior cingulate cortical neurons exhibit increased synaptic excitation. Analysis of electrocorticograms revealed suppressed ketamine-evoked γ oscillations. Morphological analysis of S1 layer 5 pyramidal neurons indicate reduced dendritic complexity, length, and soma size. Further, we detected abnormal cortical mRNA expression of key receptors involved in synaptic transmission and neuronal growth and development. These findings demonstrate the lasting sequelae of perinatal fentanyl exposure on sensory processing and function. In Chapter 3, we demonstrate that developmental exposure to environmental enrichment ameliorates many of fentanyl’s deleterious behavioral effects, including hyperactivity, sensitivity to anxiogenic conditions, and sensory maladaptation. We found that perinatal fentanyl increases stochastic excitatory release probability and impairs long-term potentiation in S1 layer 2/3 neurons. These changes in synaptic activity were restored by environmental enrichment. These results demonstrate that the lasting somatosensory-related effects of fentanyl can be ameliorated with a non-invasive intervention introduced during early development. These findings can inform ongoing efforts to develop actionable steps toward mitigating the consequences of opioid abuse among pregnant women.