An, K. | bioRxiv Science

bioRxiv2021

Prenatal immune stress induces a prolonged blunting of microglia activation that impacts striatal connectivity

Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function1-3. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood4,5. Several maternal environmental factors, such as aberrant microbiome, immune activation, and poor nutrition, can influence prenatal brain development6-8. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that after maternal immune activation (MIA) microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was concomitant with changes in the chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single cell RNA sequencing revealed that MIA does not induce a distinct subpopulation but rather decreases the contribution to inflammatory microglia states. Prenatal replacement of MIA microglia with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment impacts the long-term microglia reactivity and proper striatal circuit development.

neuroscience↗

bioRxiv2021

Anterior insula-associated social novelty recognition: orchestrated regulation by a local retinoic acid cascade and oxytocin signaling

BackgroundDeficits in social cognition consistently underlie functional disabilities in a wide range of psychiatric disorders. Neuroimaging studies have suggested that the anterior insula is a common core brain region that is impaired across neurological and psychiatric disorders, which include social cognition deficits. Nevertheless, neurobiological mechanisms of the anterior insula for social cognition remain elusive. MethodsTo determine the role of anterior insula in social cognition, we manipulated expression of Cyp26B1, an anterior insula-enriched molecule that is crucial for retinoic acid degradation and involved in the pathology of neuropsychiatric conditions. Social cognition was mainly assayed using the three-chamber social interaction test. We conducted multimodal analyses at the molecular, cellular, circuitry, and behavioral levels. ResultsAt the molecular/cellular level, anterior insula-mediated social novelty recognition is maintained by proper activity of the layer 5 pyramidal neurons, for which retinoic acid-mediated gene transcription can play a role. We also demonstrate that oxytocin influences the anterior insula-mediated social novelty recognition, not by direct projection of oxytocin neurons, nor by direct diffusion of oxytocin to the anterior insula, which contrasts the modes of oxytocin regulation onto the posterior insula. Instead, oxytocin affects oxytocin receptor-expressing neurons in the dorsal raphe nucleus where serotonergic neurons are projected to the anterior insula. Furthermore, we show that serotonin 5HT2C receptor expressed in the anterior insula influences social novelty recognition. ConclusionsAnterior insula plays a pivotal role in social novelty recognition that is partly regulated by a local retinoic acid cascade, but also remotely regulated by oxytocin via a non-classic mechanism.

animal behavior and cognition↗