Dissecting the Long-Term Effect of Stress Early in Life on FKBP5: The Role of miR-20b-5p and miR-29c-3p.

Exposure to early-life stress (ELS) has been related to an increased susceptibility to psychiatric disorders later in life. Although the molecular mechanisms underlying this association are still under investigation, glucocorticoid signaling has been proposed to be a key mediator. Here, we used two preclinical models, the prenatal stress (PNS) animal model and an in vitro model of hippocampal progenitor cells, to assess the long-term effect of ELS on FKBP5, NR3C1, NR3C2, and FoxO1, four stress-responsive genes involved in the effects of glucocorticoids. In the hippocampus of male PNS rats sacrificed at different time points during neurodevelopment (PND 21, 40, 62), we found a statistically significant up-regulation of FKBP5 at PND 40 and PND 62 and a significant increase in FoxO1 at PND 62. Interestingly, all four genes were significantly up-regulated in differentiated cells treated with cortisol during cell proliferation. As FKBP5 was consistently modulated by PNS at adolescence (PND 40) and adulthood (PND 62) and by cortisol treatment after cell differentiation, we measured a panel of miRNAs targeting FKBP5 in the same samples where FKBP5 expression levels were available. Interestingly, both miR-20b-5p and miR-29c-3p were significantly reduced in PNS-exposed animals (both at PND40 and 62) and also in the in vitro model after cortisol exposure. Our results highlight the key role of miR-20b-5p and miR-29c-3p in sustaining the long-term effects of ELS on the stress response system, representing a mechanistic link possibly contributing to the enhanced stress-related vulnerability to mental disorders.

Depression in Women: Potential Biological and Sociocultural Factors Driving the Sex Effect.

Important sex-related differences have been observed in the onset, prevalence, and clinical phenotype of depression, based on several epidemiological studies. Social, behavioural, and educational factors have a great role in underlying this bias; however, also several biological factors are extensively involved. Indeed, sexually dimorphic biological systems might represent the underlying ground for these disparities, including cerebral structures and neural correlates, reproductive hormones, stress response pathways, the immune system and inflammatory reaction, metabolism, and fat distribution. Furthermore, in this perspective, it is also important to consider and focus the attention on specific ages and life stages of individuals: indeed, women experience during their life specific periods of reproductive transitional phases, which are not found in men, that represent windows of particular psychological vulnerability. In addition to these, other biologically related risk factors, including the occurrence of sleep disturbances and the exposure to childhood trauma, which are found to differentially affect men and women, are also putative underlying mechanisms of the clinical bias of depression. Overall, by taking into account major differences which characterize men and women it might be possible to improve the diagnostic process, as well as treat more efficiently depressed individuals, based on a more personalized medicine and research.

Neurotrophic factors, childhood trauma and psychiatric disorders: A systematic review of genetic, biochemical, cognitive and imaging studies to identify potential biomarkers.

BACKGROUND: Exposure to traumatic experience represents one of the key environmental factors influencing the risk for several psychiatric disorders, in particular when suffered during childhood, a critical period for brain development, characterized by a high level of neuroplasticity. Abnormalities affecting neurotrophic factors might play a fundamental role in the link between childhood trauma (CT) and early life stress (ELS) and psychiatric disorders. METHODS: A systematic review was conducted, considering genetic, biochemical and expression studies along with cognitive and brain structure imaging investigations, based on PubMed and Web of Science databases (available up until November 2021), to identify potential neuroplasticity related biomarkers associated both with CT/ELS and psychiatric disorders. The search was followed by data abstraction and study quality assessment (Newcastle-Ottawa Scale). RESULTS: 103 studies met our eligibility criteria. Among them, 65 were available for genetic, 30 for biochemical and 3 for mRNA data; 45 findings were linked to specific symptomatology/pathologies, 16 with various cognitive functions, 19 with different brain areas, 6 on methylation and 36 performed on control subjects for the Brain Derived Neurotrophic Factor (BDNF); whereas 4 expression/biochemical studies covered Neurotrophin 4 (NT-4), Vascular Endothelium Growth Factor (VEGF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), and Transforming Growth Factor ß1 (TGF-ß1). LIMITATIONS: Heterogeneity of assessments (biological, psychological, of symptomatology, and CT/ELS), age range and ethnicity of samples for BDNF studies; limited studies for other neurotrophins. CONCLUSIONS: Results support the key role of BDNF (in form of Met allele) as biomarker, both at genetic and biochemical level, in mediating the effect of CT/ELS in psychiatric disorders, passing through specific cognitive functions and specific brain region architecture.

Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can exert antidepressant, anti-inflammatory and neuroprotective properties, but the exact molecular mechanism underlying their effects is still not fully understood. We conducted both in vitro and clinical investigations to test which EPA or DHA metabolites are involved in these anti-inflammatory, neuroprotective and antidepressant effects. In vitro, we used the human hippocampal progenitor cell line HPC0A07/03C, and pre-treated cells with either EPA or DHA, followed by interleukin 1beta (IL1ß), IL6 and interferon-alpha (IFN-α). Both EPA and DHA prevented the reduction in neurogenesis and the increase in apoptosis induced by these cytokines; moreover, these effects were mediated by the lipoxygenase (LOX) and cytochrome P450 (CYP450) EPA/DHA metabolites, 5-hydroxyeicosapentaenoic acid (HEPE), 4-hydroxydocosahexaenoic acid (HDHA), 18-HEPE, 20-HDHA, 17(18)-epoxyeicosatetraenoic acid (EpETE) and 19(20)-epoxydocosapentaenoic acid (EpDPA), detected here for the first time in human hippocampal neurones using mass spectrometry lipidomics of the supernatant. In fact, like EPA/DHA, co-treatment with these metabolites prevented cytokines-induced reduction in neurogenesis and apoptosis. Moreover, co-treatment with 17(18)-EpETE and 19(20)-EpDPA and the soluble epoxide hydroxylase (sEH) inhibitor, TPPU (which prevents their conversion into dihydroxyeicosatetraenoic acid (DiHETE)/ dihydroxydocosapentaenoic acid (DiHDPA) metabolites) further enhanced their neurogenic and anti-apoptotic effects. Interestingly, these findings were replicated in a sample of n = 22 patients with a DSM-IV Major Depressive Disorder, randomly assigned to treatment with either EPA (3.0 g/day) or DHA (1.4 g/day) for 12 weeks, with exactly the same LOX and CYP450 lipid metabolites increased in the plasma of these patients following treatment with their precursor, EPA or DHA, and some evidence that higher levels of these metabolites were correlated with less severe depressive symptoms. Overall, our study provides the first evidence for the relevance of LOX- and CYP450-derived EPA/DHA bioactive lipid metabolites as neuroprotective molecular targets for human hippocampal neurogenesis and depression, and highlights the importance of sEH inhibitors as potential therapeutic strategy for patients suffering from depressive symptoms.

A systematic, integrative review of the effects of the endocannabinoid system on inflammation and neurogenesis in animal models of affective disorders.

The endocannabinoid (eCB) system is considered relevant in the pathophysiology of affective disorders, and a potential therapeutic target, as its hypoactivity is considered an important risk factor of depression. However, the biological mechanisms whereby the eCB system affects mood remain elusive. Through a systematic review, thirty-seven articles were obtained from the PubMed/Medline, Web of Science, Embase, PsychInfo, and CINAHL databases, investigating the role of the eCB system on the immune system and neurogenesis, as well as resulting behavioural effects in rodent models of affective disorders. Overall, activation of the eCB system appears to decrease depressive-like behaviour and to be anti-inflammatory, while promoting neuro- and synaptogenesis in various models. Activation of cannabinoid receptors (CBRs) is shown to be crucial in improving depressive-like and anxiety-like behaviour, although cannabidiol administration suggests a role of additional mechanisms. CB1R signalling, as well as fatty acid amide hydrolase (FAAH) inhibition, are associated with decreased pro-inflammatory cytokines. Moreover, activation of CBRs is required for neurogenesis, which is also upregulated by FAAH inhibitors. This review is the first to assess the association between the eCB system, immune system and neurogenesis, alongside behavioural outcomes, across rodent models of affective disorders. We confirm the therapeutic potential of eCB system activation in depression and anxiety, highlighting immunoregulation as an important mechanism whereby dysfunctional behaviour and neurogenesis can be improved.

Pro- and anti-inflammatory properties of interleukin (IL6) in vitro: relevance for major depression and for human hippocampal neurogenesis.

BACKGROUND: Although the pro-inflammatory cytokine, interleukin (IL)6, has been generally regarded as "depressogenic", recent research has started to question this assumption, in light of the fact that this cytokine can also have anti-inflammatory properties. This bimodal action seems to be dependent on its concentration levels, and on the concomitant presence of other pro-inflammatory cytokines. METHODS: We exposed a human hippocampal progenitor cell line HPC0A07/03C to cytokine levels described in depressed patients (IL6 5pg/ml with IL1ß 10pg/ml or Macrophage Migration Inhibitory Factor (MIF) 300pg/ml), in healthy subjects (IL6 with IL1ß, 1pg/ml or MIF 10pg/ml), as well as to the potentially anti-inflammatory, much higher concentrations of IL6 (50000pg/ml). RESULTS: Treatment with high concentrations of IL6 with IL1ß or MIF (resembling depressed patients) decreases neurogenesis when compared with low concentrations of the same cytokines (healthy subjects), and that this is mediated via production of, respectively, IL8 and IL1ß in cell supernatant. Instead, treatment with the very high, anti-inflammatory concentration of IL6 (50000pg/ml) together with high IL1ß or MIF prevents the decrease in neurogenesis and reduces both IL8 and IL1ß. When the high concentrations of both IL1ß and MIF were used in co-treatment, as a model of treatment resistant depression, we also demonstrate a reduction in neurogenesis, and that this is mediated via a decrease in IL4; moreover, co-treatment with high IL1ß and MIF and the very high concentration of IL6 prevents the reduction in neurogenesis, and increases IL4. CONCLUSIONS: Our results demonstrate that IL6 can exert both pro- and anti-inflammatory (potentially antidepressant) properties, depending on its concentrations and combinations with other inflammatory cytokines.

Nutritional and immunological factors in breast milk: A role in the intergenerational transmission from maternal psychopathology to child development.

Perinatal psychopathologies affect more than 25% of women during and after their gestational period. These psychiatric disorders can potentially determine important biological variations in their organisms, affecting many different physiological and metabolic pathways. Of relevance, any of these changes occurring in the mother can alter the normal composition of breast milk, particularly the concentration of nutritional and inflammatory components, which play a role in child brain functioning and development. Indeed, there is evidence showing that changes in milk composition can contribute to cognitive impairments and alterations in mental abilities in children. This review aims to shed light on the unique intergenerational role played by breast milk composition, from maternal psychopathologies to child development.