Oligodendrocytes are cells fundamental for brain functions as they form the myelin sheath and feed axons. They perform these critical functions thanks to the cooperation with other glial cells, mainly astrocytes. The astrocyte/oligodendrocyte crosstalk needs numerous mediators and receptors, such as peroxisome proliferator-activated receptors (PPARs). PPAR agonists promote oligodendrocyte precursor cells (OPCs) maturation in myelinating oligodendrocytes. In the Alzheimer’s disease brain, deposition of beta-amyloid (Aβ) has been linked to several alterations, including astrogliosis and changes in OPCs maturation. However, very little is known about the molecular mechanisms. Here, we investigated for the first time the maturation of OPCs co-cultured with astrocytes in an in vitro model of Aβ_1–42 toxicity. We also tested the potential beneficial effect of the anti-inflammatory and neuroprotective composite palmitoylethanolamide and luteolin (co-ultra PEALut), which is known to engage the isoform alfa of the PPARs. Our results show that Aβ_1–42 triggers astrocyte reactivity and inflammation and reduces the levels of growth factors important for OPCs maturation. Oligodendrocytes indeed show low cell surface area and few arborizations. Co-ultra PEALut counteracts the Aβ_1–42-induced inflammation and astrocyte reactivity preserving the morphology of co-cultured oligodendrocytes through a mechanism that in some cases involves PPAR-α. This is the first evidence of the negative effects exerted by Aβ_1–42 on astrocyte/oligodendrocyte crosstalk and discloses a never-explored co-ultra PEALut ability in restoring oligodendrocyte homeostasis.

Early-life adverse experiences (first hit) lead to coping strategies that may confer resilience or vulnerability to later experienced stressful events (second hit) and the subsequent development of stress-related psychopathologies. Here, we investigated whether exposure to two stressors at different stages in life has long-term effects on emotional and cognitive capabilities, and whether the interaction between the two stressors influences stress resilience. Male rats were subjected to social defeat stress (SDS, first hit) in adolescence and to a single episode of prolonged stress (SPS, second hit) in adulthood. Behavioral outcomes, hippocampal expression of brain-derived neurotrophic factor, and plasma corticosterone levels were tested in adulthood. Rats exposed to both stressors exhibited resilience against the development of stress-induced alterations in emotional behaviors and spatial memory, but vulnerability to cued fear memory dysfunction. Rats subjected to both stressors demonstrated resilience against the SDS-induced alterations in hippocampal brain-derived neurotrophic factor expression and plasma corticosterone levels. SPS alone altered locomotion and spatial memory retention; these effects were absent in SDS-exposed rats later exposed to SPS. Our findings reveal that exposure to social stress during early adolescence influences the ability to cope with a second challenge experienced later in life.

Stress triggers many responses including behavioral strategies to cope with the environment and to maintain homeostasis. Notably, the experience of stressful events is highly subjective. In fact, in susceptible individuals, primary adaptation responses can fail leading to maladaptive mechanisms and to the subsequent development of stress-related disorders (e.g., post-traumatic stress disorder; PTSD). However, the mechanisms underlying interindividual variability in stress adaptation are still to be elucidated. Animal models are widely recognized as essential scientific tools to understand the neurobiological underpinnings of stress susceptibility/resilience, and as tools to identify novel and personalized interventions to treat (and prevent) such disorders in humans. Experimental models have however several limitations, as validity criteria can be very problematic when modeling psychiatric disorders. Also, while sex dimorphism crucially contributes to the risk for stress-related diseases, several frequently used models overlooked sex differences in the interindividual variability in response to stress. In this review, we describe the interindividual and sex differences in susceptibility and resilience in stress-related disorders, with a particular focus on PTSD. Further, we examine aspects of animal models of PTSD that can be improved to obtain higher translational value.