Fig. 1: Pathophysiological mechanisms involved in mood disorders.

A HPA axis. In case of inflammation, in response to pro-inflammatory cytokines (especially IL-1, IL-6, TNF-α, and IFN-α), there is increased secretion of corticotrophin-releasing hormone, adrenocorticotropic hormone, and cortisol [157, 158]. Normally, glucocorticoids then act as negative feedback on the inflammatory response [159] to avoid the deleterious effects of excessive production of inflammatory mediators. However, in case of prolonged inflammation (i) chronic high levels of glucocorticoids cause resistance to glucocorticoid feedback on the HPA axis, thus allowing pro-inflammatory signaling pathways to avoid normal feedback inhibition [160]; (ii) the pro-inflammatory cytokines themselves decrease the expression, translocation and downstream effects of glucocorticoid receptors, thereby blunting the negative feedback loop of the HPA axis allowing for further elevation of cortisol levels [161]. Accordingly, increased cortisol levels that are resistant to regulatory feedback by the HPA axis are among the most consistently replicated markers of mood disorder [62]. B Microglia. Neuroinflammation can induce microglial activation. Under physiological conditions, microglia monitors the integrity of synapses [162], removes apoptotic and necrotic cells, and promotes the maintenance of synaptic homeostasis [163]. In turn, microglial activation amplifies the innate immune response by the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [164], thus increasing the production of reactive oxygen and nitroxygen species [165]. Currently, it seems that the dualistic classification of microglia activation is not fully representative of the wide repertoire of microglial states and functions in development, plasticity, aging, and disease [166], and further research is then needed to clarify the role of microglia in mood disorders. Prolonged microglial activation induces pathological neuronal apoptotic mechanisms destroying functional neuronal pathways and inhibiting the construction of new pathways, which may manifest in reduced neural plasticity and brain connectivity [167], leading to suboptimal brain function and maladaptive behaviors [168, 169]. Of notice, microglial activation in mood disorders, despite associating with depressive psychopathology, could also play a protective role in counteracting the detrimental effects of yet undefined brain insults, as observed in some brain inflammatory conditions [170]. Increased microglial activation in association with high levels of IL-6 and TNF-α has been observed in mood episodes [171]. PET studies of 17-kDa translocator protein (TSPO) binding, confirmed the presence of a microglial activation both during acute illness episodes and in euthymia [93, 172, 173]. Moreover, microglia activation was found to be associated with cognitive dysfunctions [174], the severity of depression [175], and suicide [176], in agreement with post-mortem findings of higher density of activated microglia in patients with mood disorders who died of suicide [177]. Inhibiting microglial activation with the broadly anti-inflammatory minocycline leads to better neuroplasticity and normalization of the kynurenine pathway in animal models of depression [153, 154], whereas, in treatment-resistant patients with activated peripheral markers of inflammation [155] it has an antidepressant effect. C Plasticity. In the case of inflammation, synaptic plasticity, learning, and memory are inhibited [178]. Pro-inflammatory cytokines affect the availability of brain-derived neurotrophic factor (BDNF), which is the main responsible for structural and functional cellular support [179]. Changes in BDNF levels have been widely reported in depression and have been suggested to underlie the behavioral and mood changes observed in the disorder [180]. Another marker of neuroplasticity is S100B whose effects depend on its concentration. Nanomolar concentrations are associated with the activation of growth and differentiation of neurons and astrocytes whereas micromolar concentrations cause apoptosis of cells, can be neurotoxic, and stimulate the expression of pro-inflammatory cytokines [181]. High serum S100B levels have been reported in major depressive and manic episodes but not in current euthymic mood disorder suggesting glial involvement in the pathogenesis of mood disorders [182]. D Kynurenine Pathway. Inflammatory cytokines (more specifically Interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-δ) increase the conversion of tryptophan to kynurenine by activating the indolamine 2,3-dioxygenase [183, 184]. This mechanism causes the depletion of tryptophan and a subsequent decrease in serotonin levels [185]. Moreover, kynurenine degradation leads to the formation of 3- hydroxykynurenine (3-HK) and quinolinic acid (QUIN) or kynurenic acid (KA) [185]. While KA shows a neuroprotective effect, competitively antagonizing NMDA glutamate receptors, 3-HK and QUIN seem to exert neurotoxic effects [186]. Furthermore, IL-6 and TNF-α have been shown to directly increase serotonin turnover by facilitating its release and conversion into 5-hydroxyindoleacetic acid [187, 188]. Of note, serotoninergic abnormalities are a well-established feature of mood disorders pathophysiology [189, 190], with a relative decrease in cortical 5-HT stimulation during depression [191], and excessive activation of the kynurenine pathway, which seems to be shifted towards its neurotoxic branch and contribute to lower the availability of 5-HT [192, 193]. Furthermore, TNF-α, IL-8, IFN-γ, and activation of the kynurenine pathway, have been associated with white matter microstructure alteration in mood disorders [127,128,129,130], a phenotype linking response to antidepressant treatment [101, 131, 132], cognitive impairment [133], exposure to childhood traumatic experiences [134, 135], and severe depressive psychopathology [136]. Effects of inflammatory markers on white matter could also contribute to the association of brain microstructure with depression, as observed in depressive syndromes secondary to medical illnesses involving increased systemic inflammation [194].