Conference Agenda

Neurodevelopmental disorders (NDDs) comprise a heterogeneous group of disorders whose intricacy is complicated by a high comorbidity with diverse conditions (e.g., psychiatric, immunological, gastrointestinal). Given that the prevalence rate of NDDs fluctuates between 2-4% of the worldwide population and given their high substantial individual burden and societal costs, it is paramount to identify specific predictive risk factors implicated in the aetiology of NDDs to facilitate earlier detection, to decipher endophenotypes and to design earlier and more effective interventions. Experimental and epidemiological studies suggest that perinatal exposure to paracetamol (PAE), among the diverse environmental risks factors that impact neurodevelopment, might alter fetal ontogenesis, thereby increasing the risks of certain NDDs. However, paracetamol is still regarded as the only option by regulatory bodies for use in pregnancy for the treatment of pain and fever. Here we show that offspring of paracetamol-exposed dams, a rat PAE model, exhibit changes in the developmental trajectory of dopaminergic neurons of the ventral tegmental area. These alterations are associated with phenotypes of abnormal social play behavior and endophenotypes at-risk for stress-induced sensorimotor gating deficits during pre-adolescence. Since impairments in social cognition fall in NDDs, the relationship between deterioration of sensorimotor gating function to social deficits and the derangement of dopamine developmental trajectory becomes of interest.

Low doses of dopamine D1 receptor agonists, such as SKF 38393, stimulate working memory (WM), that is, the ability to retain one or more pieces of information through the activation of D1 receptors in the fronto-striatal region. However, high doses of the same drug produce WM deficits, opening the elusive question on the mechanism underlying the inverted U-shaped dose-response of these drugs. To clarify how different doses of dopaminergic agents exert opposite effects on memory, we tested how microscale intracellular changes are driven by pharmacologically induced reorganizations of the fronto-striatal circuit, using a combination of optogenetic, pharmacogenetic, and phosphoproteomic approaches in mice. Low dose (0.001 mg/kg) of SKF 38393 induced a unique pattern of phosphorylation in the striatum, while the impairing dose (0.1 mg/kg) was very similar to the vehicle. The low dose through selective stimulation of the D1-PKA pathway in the striatum, expanded object memory capacity (MC) beyond its normal limit (from 6 to 8 items) in control mice; the same dose rescued MC deficits in animal models of schizophrenia. In contrast, the high dose of SKF 38393, by concomitantly recruiting the same D1-PKA pathway in the medial prefrontal cortex (mPFC), defused striatal recruitment and impaired MC, via the activation of parvalbumin inhibitory interneurons in the striatum. These results identify a drug-induced functional reorganization in the cortico-striatal pathway underlying the intracellular molecular changes responsible for the pro-cognitive inverted-U dose-effects of dopamine D1 agonists, which are relevant for their clinical use.

Recognition and reaction to other emotional states is a fundamental and evolutionary conserved ability shaping animals’ life and survival. Altered emotion recognition might prevent to assist a conspecific or to escape an imminent threat. Despite this, it is unclear how cell-specific brain circuits might process socially derived information for reliable emotion recognition. Here, I will show how using a combination of anatomical, genetic, chemogenetic, microendoscopic and fiber photometry approaches in mice, we were able to demonstrate the contribution of selective cell populations and brain circuits in the ability to discriminate conspecifics based on their emotional state. The role of oxytocin circuits from the paraventricular nucleus of the hypothalamus to the central amygdala as well as the crucial implication of atypical long-range somatostatin (SOM) inhibitory projections from the medial prefrontal cortex (mPFC) to the retrosplenial cortex (RSC), and an excitatory feedback loop from the RSC to mPFC in emotion discrimination will be presented. Parallel human behavioral and brain imaging assessments linked to animal findings will be presented as well. Overall, our findings provide new insights into the neurobiological mechanisms of emotion recognition, in physiological and pathological conditions.

Microglia play a role in social behavior, but how this is related to emotion recognition is underexplored. Recognition of others’ emotions relies on somatostatin positive (SOM+) neurons' activity in mouse prelimbic (PL) cortex. Here, we assessed the role of microglia function in emotion recognition and in SOM+ neural activity.

Using a pharmacological approach (PLX5622), we obtained brain-wide microglia depletion in adolescent and adult mice before undergoing behavioral tasks to assess social behaviors (sociability, social preference, social memory, emotion discrimination task, EDT). By allowing microglia repopulation, we also assessed whether microglia depletion during adolescence would lead to socio-behavioral deficits in the long term. We expressed the Cre-dependent calcium indicator, GCaMP6m, in PL cortex of SOM+ Cre adolescent mice and used fiber photometry to measure the activity of SOM+ neurons during EDT, in microglia-deplete and control adolescent mice. Through confocal imaging, we compared the density and morphology of dendritic spines in the PL cortex of microglia-deplete and control adolescent mice.

We found that microglia depletion in adolescent mice impairs EDT, which restored upon microglia repopulation; no deficits were observed in other social behaviors. Microglia depletion during adulthood did not affect any social behavior. Calcium imaging revealed opposite patterns of PL SOM+ activity in microglia-deplete and control adolescent mice in response to sniffing a neutral versus emotionally altered conspecific during EDT. Differences in spine density and morphology were found between microglia-deplete and control mice when depletion occurred during early adolescence, but not late adolescence.

Taken together, our results point toward mouse adolescence as a critical period for microglia to shape prefrontal cortex fine-tuning of neural mechanisms involved in higher order social function, such as the recognition of others’ emotion. Further experiment will elucidate the underlying mechanisms, and whether microglia depletion during adolescence set vulnerability for the onset of social-related deficits later in life.