Co-Ultramicronized Palmitoylethanolamide/Luteolin Restores Oligodendrocyte Homeostasis via Peroxisome Proliferator-Activated Receptor-α in an In Vitro Model of Alzheimer's Disease.

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 (Aß) 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 Aß1-42 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 Aß1-42 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 Aß1-42-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 Aß1-42 on astrocyte/oligodendrocyte crosstalk and discloses a never-explored co-ultra PEALut ability in restoring oligodendrocyte homeostasis.

Social Defeat Stress During Early Adolescence Confers Resilience Against a Single Episode of Prolonged Stress in Adult Rats.

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.

Sex-divergent long-term effects of single prolonged stress in adult rats.

Single prolonged stress (SPS) is an experimental model that recapitulates in rodents some of the core symptoms of post-traumatic stress disorder (PTSD). Although women have a two-fold greater risk to develop PTSD, most preclinical studies have been carried out in males. Furthermore, the long-term effects of behavioral alterations induced by SPS have been rarely investigated. Here, we evaluated the long-term effects of SPS on PTSD-relevant behavioral domains in rats and whether these effects were sex-dependent. To this aim, separate cohorts of male and female adult rats were subjected to SPS and, 30 days later, long-term effects were assessed. We found that SPS exposure reduced locomotor activity in both sexes in an open field task. Males only showed increased anxiety-like behavior in the elevated plus maze and marble burying tests, enhanced acoustic startle response and impaired spatial memory retention while females were unaffected. SPS exposure did not alter auditory fear memory dynamics in males, but it did alter extinction retrieval in females. We provide the first evidence that SPS reproduces long-term emotional alterations in male, but not in female, rats which were observed 30 days following trauma exposure, thus resembling some of the hallmark symptoms of PTSD. Furthermore, our results show for the first time a long-term SPS-induced alteration of cued fear extinction in females. Our findings are relevant to future research on trauma-related disorders and may help develop sex-specific interventions to treat PTSD.

Predicting susceptibility and resilience in an animal model of post-traumatic stress disorder (PTSD).

Post-traumatic stress disorder (PTSD) is a psychiatric disorder whose pathogenesis relies on a maladaptive expression of the memory for a life-threatening experience, characterized by over-consolidation, generalization, and impaired extinction, which are responsible of dramatic changes in arousal, mood, anxiety, and social behavior. Even if subjects experiencing a traumatic event during lifetime all show an acute response to the trauma, only a subset of them (susceptible) ultimately develops PTSD, meanwhile the others (resilient) fully recover after the first acute response. However, the dynamic relationships between the interacting brain circuits that might potentially link trauma-related experiences to the emergence of susceptible and resilient PTSD phenotypes in individuals is not well understood. Toward the first step to reach this goal, we have implemented our experimental PTSD model previously developed, making it suitable to differentiate between susceptible (high responders, HR) and resilient (low responders, LR) rats in terms of over-consolidation, impaired extinction, and social impairment long after trauma. Rats were exposed to five footshocks paired with social isolation. One week after trauma but before extinction, animals were tested in the Open Field and Social Interaction tasks for the identification of a predictive variable to identify susceptible and resilient animals before the possible appearance of a PTSD-like phenotype. Our findings show that exploratory activity after trauma in a novel environment is a very robust variable to predict susceptibility towards a PTSD-like phenotype. This experimental model is thus able to screen and differentiate, before extinction learning and potential therapeutic intervention, susceptible and resilient PTSD-like rats.

Amphetamine and the Smart Drug 3,4-Methylenedioxypyrovalerone (MDPV) Induce Generalization of Fear Memory in Rats.

Human studies have consistently shown that drugs of abuse affect memory function. The psychostimulants amphetamine and the "bath salt" 3,4-methylenedioxypyrovalerone (MDPV) increase brain monoamine levels through a similar, yet not identical, mechanism of action. Findings indicate that amphetamine enhances the consolidation of memory for emotional experiences, but still MDPV effects on memory function are underinvestigated. Here, we tested the effects induced by these two drugs on generalization of fear memory and their relative neurobiological underpinnings. To this aim, we used a modified version of the classical inhibitory avoidance task, termed inhibitory avoidance discrimination task. According to such procedure, adult male Sprague-Dawley rats were first exposed to one inhibitory avoidance apparatus and, with a 1-min delay, to a second apparatus where they received an inescapable footshock. Forty-eight hours later, retention latencies were tested, in a randomized order, in the two training apparatuses as well as in a novel contextually modified apparatus to assess both strength and generalization of memory. Our results indicated that both amphetamine and MDPV induced generalization of fear memory, whereas only amphetamine enhanced memory strength. Co-administration of the ß-adrenoceptor antagonist propranolol prevented the effects of both amphetamine and MDPV on the strength and generalization of memory. The dopaminergic receptor blocker cis-flupenthixol selectively reversed the amphetamine effect on memory generalization. These findings indicate that amphetamine and MDPV induce generalization of fear memory through different modulations of noradrenergic and dopaminergic neurotransmission.

Anandamide modulation of circadian- and stress-dependent effects on rat short-term memory.

The endocannabinoid system plays a key role in the control of emotional responses to environmental challenges. CB1 receptors are highly expressed within cortico-limbic brain areas, where they modulate stress effects on memory processes. Glucocorticoid and endocannabinoid release is influenced by circadian rhythm. Here, we investigated how different stress intensities immediately after encoding influence rat short-term memory in an object recognition task, whether the effects depend on circadian rhythm and if exogenous augmentation of anandamide levels could restore any observed impairment. Two separate cohorts of male adult Sprague-Dawley rats were tested at two different times of the day, morning (inactivity phase) or afternoon (before the onset of the activity phase) in an object recognition task. The anandamide hydrolysis inhibitor URB597 was intraperitoneally administered immediately after the training trial. Rats were thereafter subjected to a forced swim stress under low or high stress conditions and tested 1 h after training. Control rats underwent the same experimental procedure except for the forced swim stress (no stress). We further investigated whether URB597 administration might modulate corticosterone release in rats subjected to the different stress conditions, both in the morning or afternoon. The low stressor elevated plasma corticosterone levels and impaired 1 h recognition memory performance when animals were tested in the morning. Exposure to the higher stress condition elevated plasma corticosterone levels and impaired memory performance, independently of the testing time. These findings show that stress impairing effects on short-term recognition memory are dependent on the intensity of stress and circadian rhythm. URB597 (0.3 mg kg-1) rescued the altered memory performance and decreased corticosterone levels in all the impaired groups yet leaving memory unaltered in the non-impaired groups.