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Translational animal models for studying post-traumatic stress disorder (PTSD) are valuable for elucidating the poorly understood neurobiology of this neuropsychiatric disorder. These models should encompass crucial features, including persistence of PTSD-like phenotypes triggered after exposure to a single traumatic event, trauma susceptibility/resilience and predictive validity. Here we propose a novel arousal-based individual screening (AIS) model that recapitulates all these features. The AIS model was designed by coupling the traumatization (24 h restraint) of C57BL/6 J mice with a novel individual screening. This screening consists of z-normalization of post-trauma changes in startle reactivity, which is a measure of arousal depending on neural circuits conserved across mammals. Through the AIS model, we identified susceptible mice showing long-lasting hyperarousal (up to 56 days post-trauma), and resilient mice showing normal arousal. Susceptible mice further showed persistent PTSD-like phenotypes including exaggerated fear reactivity and avoidance of trauma-related cue (up to 75 days post-trauma), increased avoidance-like behavior and social/cognitive impairment. Conversely, resilient mice adopted active coping strategies, behaving like control mice. We further uncovered novel transcriptional signatures driven by PTSD-related genes as well as dysfunction of hypothalamic–pituitary–adrenal axis, which corroborated the segregation in susceptible/resilient subpopulations obtained through the AIS model and correlated with trauma susceptibility/resilience. Impaired hippocampal synaptic plasticity was also observed in susceptible mice. Finally, chronic treatment with paroxetine ameliorated the PTSD-like phenotypes of susceptible mice. These findings indicate that the AIS model might be a new translational animal model for the study of crucial features of PTSD. It might shed light on the unclear PTSD neurobiology and identify new pharmacological targets for this difficult-to-treat disorder.

The pharmacological treatment of cognitive impairments associated with schizophrenia is still a major unmet clinical need. Indeed, treatments with available antipsychotics generate highly variable cognitive responses among patients with schizophrenia. This has led to the general assumption that antipsychotics are ineffective on cognitive impairment, although personalized medicine and drug repurposing approaches might scale down this clinical issue. In this scenario, evidence suggests that cognitive improvement exerted by old and new atypical antipsychotics depends on dopaminergic mechanisms. Moreover, the newer antipsychotics brexpiprazole and cariprazine, which might have superior clinical efficacy on cognitive deficits over older antipsychotics, mainly target dopamine receptors. It is thus reasonable to assume that despite more than 50 years of elusive efforts to develop novel non-dopaminergic antipsychotics, dopamine receptors remain the most attractive and promising pharmacological targets in this field. In the present review, we discuss preclinical and clinical findings showing dopaminergic mechanisms as key players in the cognitive improvement induced by both atypical antipsychotics and potential antipsychotics. We also emphasize the concept that these mechanistic advances, which help to understand the heterogeneity of cognitive responses to antipsychotics, may properly guide treatment decisions and address the unmet medical need for the management of cognitive impairment associated with schizophrenia.

Extracellular matrix (ECM) represents an essential component of the cellular niche. In this conditioned microenvironment, the proliferation rates and differentiation states of stem cells are regulated by several factors. In contrast, in in vitro experimental models, cell growth, or induction procedures toward specific cell lines usually occur in contact with plastic, glass, or biogel supports. In this study, we evaluated the effect of a decellularized ECM, derived from bone marrow stem cells, on the neuronal differentiation of mesenchymal stem cells (MSCs) extracted from dental pulp (Dental Pulp Stem Cells -DPSCs). Since DPSCs derive from neuroectodermal embryonic precursors, they are thought to have a greater propensity toward neuronal differentiation than MSCs isolated from other sources. We hypothesized that the presence of a decellularized ECM scaffold could act positively on neuronal-DPSC differentiation through reproduction of an in vivo-like microenvironment. Results from scanning electron microscopy, immunofluorescence, and gene expression assays showed that ECM is able to positively influence the morphology of cells and their distribution and the expression of specific neuronal markers (i.e., NF-L, NF-M, NF-H, PAX6, MAP2).

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