Perinatal Opioid Exposure Results in Persistent Hypoconnectivity of Excitatory Circuits and Reduced Activity...

Opioid use by pregnant women results in neonatal opioid withdrawal syndrome (NOWS) and lifelong neurobehavioral deficits including language impairments. Animal models of NOWS show impaired performance in a two-tone auditory discrimination task, suggesting abnormalities in sensory processing in the auditory cortex. To investigate the consequences of perinatal opioid exposure on auditory cortex circuits, we administered fentanyl to mouse dams in their drinking water throughout gestation and until litters were weaned at postnatal day (P)21. We then used in vivo two-photon Ca²⁺ imaging in adult animals of both sexes to investigate how primary auditory cortex (A1) function was altered. Perinatally exposed animals showed fewer sound-responsive neurons in A1, and the remaining sound-responsive cells exhibited lower response amplitudes but normal frequency selectivity and stimulus-specific adaptation (SSA). Populations of nearby layer 2/3 (L2/3) cells in exposed animals showed reduced correlated activity, suggesting a reduction of shared inputs. We then investigated A1 microcircuits to L2/3 cells by performing laser-scanning photostimulation (LSPS) combined with whole-cell patch-clamp recordings from A1 L2/3 cells. L2/3 cells in exposed animals showed functional hypoconnectivity of excitatory circuits of ascending inputs from L4 and L5/6 to L2/3, while inhibitory connections were unchanged, leading to an altered excitatory/inhibitory balance. These results suggest a specific reduction in excitatory ascending interlaminar cortical circuits resulting in decreased activity correlations after fentanyl exposure. We speculate that these changes in cortical circuits contribute to the impaired auditory discrimination ability after perinatal opioid exposure.SIGNIFICANCE STATEMENT This is the first study to investigate the functional effects of perinatal fentanyl exposure on the auditory cortex. Experiments show that perinatal fentanyl exposure results in decreased excitatory functional circuits and altered population activity in primary sensory areas in adult mice. These circuit changes might underlie the observed language and cognitive deficits in infants exposed to opioids.