*4.2. Glia Pathology*

Astroglia and oligodendroglia are essential in neural metabolic homeostasis to maintain behavior and higher cognitive functions. Astroglia and oligodendroglia produce anti-inflammatory cytokines that regulate harmful inflammation [14,72,73]. Animal and human studies report astroglial pathology in psychiatric disorders like MDD and their models [74]. For example, post-mortem studies of MDD subjects implicated reduced oligodendroglial density in the prefrontal cortex and amygdala. Accordingly, it has been suggested that glial loss may contribute to neuroinflammation in psychiatric disorders by several mechanisms [75]. Indeed, using glia-specific genetically modified mice revealed that glial cells such as oligodendrocytes, astrocytes, and microglia affect neuronal function and are involved in the underlying pathobiology of psychiatric disorders [76]. In a model of chronic stress which, as mentioned above, is assumed to be relevant in studying the role of neuroinflammation associated with depression, [77] opted to study whether physiological conditions such as stress enhance susceptibility to inflammation in the substantia nigra, where dopaminergic neuron death occurs in Parkinson's disease. In a rat model of induced stress and inflammation they found higher TNF-α, IL-1β, IL-6, and iNOS levels in the substantia nigra. Likewise, microglial activation was significantly increased in the infralimbic, cingulate, and medial orbital cortices, nucleus accumbens, caudate putamen, amygdala, and hippocampus of the mice brain following unpredictable chronic mild stress—a reliable model to study depression-induced neuroinflammation [78].

Multiple studies, including some mentioned above, use animal models of depression induced by LPS, which also induces neuroinflammation. In the nonhuman-primate brain, LPS-induced systemic inflammation produces a robust increase in the level of TSPO (detected by PET), reflecting the state of neuroinflammation changes [67]. For example, doxycycline prevented and reversed LPS-induced changes in immobility time on the forced swimming test (FST), and in brain IL1β [79]. Likewise, minocycline also attenuated LPS-induced behavioral changes and markers of neuroinflammation in mice [80].

#### *4.3. Increased Oxidative Stress*

At the time of microglial activation, pro-inflammatory cytokines and NO production might increase oxidative stress. Namely, pro-inflammatory cytokines and high NO levels may promote ROS formation which, in turn, accelerates lipid peroxidation, damaging membrane phospholipids and their membrane-bound monoamine neurotransmitter receptors and depleting endogenous antioxidants. The consequence of increased production of pro-inflammatory cytokines via stimulation of NF-κB and enhanced microglial activation caused by the increase in ROS products might be increased prevalence of psychiatric disorders [81]. Indeed, studying MMD patients' fibroblasts, Scapagnini et al. [82] reported an increase in oxidative stress independent of glutathione levels. Moreover, diseases such as MDD, BD, and schizophrenia might go through increased oxidative stress due to mitochondrial dysfunction. Consistent with the high prevalence of psychiatric disturbances in primary mitochondrial disorders, there are reports [82–84] of abnormalities in mitochondrial DNA in these disorders. Alternatively, as data in Ott et al. [82,83] imply, there might be mechanistic links among neuroinflammation, mitochondrial dysfunction, and oxidative stress, meriting further investigation of these intersecting pathogenic pathways in human psychiatric disorders.

#### *4.4. BBB Dysfunction*

MDD-related clinical and experimental studies indicate indirectly that increased oxidation might contribute to endothelial dysfunction. Moreover, oxidation-mediated endothelial dysfunction might contribute to the pathophysiology of BBB dysfunction in psychiatric disorders [85,86]. In a prolonged learned helplessness depression model in mice, the non-recovered group had, within 4 weeks, higher hippocampal levels of TNFα, IL-17A, and IL-23, increased permeability of the BBB and lower levels of the BBB tight junction protein claudin-5 and the tight junction receptors occludin and zonula occludens protein 1 (ZO1), as compared with mice that recovered and with control mice, [87].

As for the BBB in BD, in a recent study [88], bipolar patients and control subjects matched for sex, age, and metabolic status underwent contrast-enhanced dynamic MRI scanning to quantitate their BBB leakage. Nearly 30% of the patients exhibited significantly higher percentages of brain volume with BBB leakage. This subgroup had more severe depression and anxiety and a more chronic course of illness.
