Organization of orbitofrontal-auditory pathways in the Mongolian gerbil.

Sound perception is highly malleable, rapidly adjusting to the acoustic environment and behavioral demands. This flexibility is the result of ongoing changes in auditory cortical activity driven by fluctuations in attention, arousal, or prior expectations. Recent work suggests that the orbitofrontal cortex (OFC) may mediate some of these rapid changes, but the anatomical connections between the OFC and the auditory system are not well characterized. Here, we used virally mediated fluorescent tracers to map the projection from OFC to the auditory midbrain, thalamus, and cortex in a classic animal model for auditory research, the Mongolian gerbil (Meriones unguiculatus). We observed no connectivity between the OFC and the auditory midbrain, and an extremely sparse connection between the dorsolateral OFC and higher order auditory thalamic regions. In contrast, we observed a robust connection between the ventral and medial subdivisions of the OFC and the auditory cortex, with a clear bias for secondary auditory cortical regions. OFC axon terminals were found in all auditory cortical lamina but were significantly more concentrated in the infragranular layers. Tissue-clearing and lightsheet microscopy further revealed that auditory cortical-projecting OFC neurons send extensive axon collaterals throughout the brain, targeting both sensory and non-sensory regions involved in learning, decision-making, and memory. These findings provide a more detailed map of orbitofrontal-auditory connections and shed light on the possible role of the OFC in supporting auditory cognition.

Perinatal Fentanyl Exposure Leads to Long-Lasting Impairments in Somatosensory Circuit Function and Behavior.

One consequence of the opioid epidemic are lasting neurodevelopmental sequelae afflicting adolescents exposed to opioids in the womb. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from this exposure. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. Newborn male and female mice exhibit signs of withdrawal and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams' health or maternal behavior, these effects result from the direct actions of perinatal fentanyl on the pups' developing brain. At adolescence, exposed mice exhibit reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. In vitro electrophysiology demonstrates a long-lasting reduction in S1 synaptic excitation, evidenced by decreases in release probability, NMDA receptor-mediated postsynaptic currents, and frequency of miniature excitatory postsynaptic currents (mEPSCs), as well as increased frequency of miniature inhibitory postsynaptic currents (mIPSCs). In contrast, anterior cingulate cortical neurons exhibit an opposite phenotype, with increased synaptic excitation. Consistent with these changes, electrocorticograms (ECoGs) reveal suppressed ketamine-evoked γ oscillations. Morphologic analysis of S1 pyramidal neurons indicate reduced dendritic complexity, dendritic length, and soma size. Further, exposed mice exhibited abnormal cortical mRNA expression of key receptors involved in synaptic transmission and neuronal growth and development, changes that were consistent with the electrophysiological and morphologic changes. These findings demonstrate the lasting sequelae of perinatal fentanyl exposure on sensory processing and function.SIGNIFICANCE STATEMENT This is the first study to show that exposure to fentanyl in the womb results in behavioral, circuitry, and synaptic effects that last at least to adolescence. We also show, for the first time, that this exposure has different, lasting effects on synapses in different cortical areas.