Major Depressive Disorder (MDD) is a chronic debilitating illness affecting yearly 300 million people worldwide. Oligodendrocyte-lineage cells have emerged as important neuromodulators in synaptic plasticity and crucial components of MDD pathophysiology. Using the repeated social defeat (RSDS) mouse model, we demonstrate that chronic psychosocial stress induces long-lasting losses and transient proliferation of oligodendrocyte-precursor cells (OPCs), aberrant differentiation into oligodendrocytes, and severe hypomyelination in the prefrontal cortex. Exposure to chronic stress results in OPC morphological impairments, excessive oxidative stress, and oligodendroglial apoptosis, implicating integrative-stress responses in depression. Analysis of single-nucleus transcriptomic data from MDD patients revealed oligodendroglial-lineage dysregulation and the presence of immune-oligodendrocytes (Im-OL), a novel population of cells with immune properties and myelination de cits. Im-OL were also identi ed in mice after RSDS, where oligodendrocyte-lineage cells expressed immune-related markers. Our ndings demonstrate cellular and molecular changes in the oligodendroglial lineage in response to chronic stress and associate hypomyelination with Im-OL emergence during depression.
Adult neural stem cells (NSCs) reside in a specialized microenvironment, the subventricular zone (SVZ), which provides them with unique signaling cues to control their basic properties and prevent their exhaustion. While the signaling mechanisms that regulate NSC lineage progression are well characterized, the molecular mechanisms that trigger the activation of quiescent NSCs during homeostasis and tissue repair are still unclear. Here, we uncovered that the NSC quiescent state is maintained by Rho-GTPase Cdc42, a downstream target of non-canonical Wnt signaling. Mechanistically, activation of Cdc42 induces expression of molecules involved in stem cell identity and anchorage to the niche. Strikingly, during a demyelination injury, downregulation of non-canonical Wnt-dependent Cdc42 activity is necessary to promote activation and lineage progression of quiescent NSCs, thereby initiating the process of tissue repair.
Adult oligodendrocyte progenitor cells are uniformly distributed in both gray and white matter, displaying robust proliferative and migratory potential during health and disease. Recently, developments in new experimental approaches have brought about several novel insights about NG2-glia and myelinating oligodendrocytes, indicating a diverse toolkit of functions in experience-dependent myelination and homeostasis in the adult CNS. In this review, we summarize some of the topical studies that highlight newly emerging findings that implicate oligodendroglia-lineage cells in brain plasticity, homeostasis and pathophysiology of neuropsychiatric disorders.
Innate and adaptive immune mechanisms have emerged as critical regulators of CNS homeostasis and mental health. A plethora of immunologic factors have been reported to interact with emotion-and behavior-related neuronal circuits, modulating susceptibility and resilience to mental disorders. However, it remains unclear whether immune dysregulation is a cardinal causal factor or an outcome of the pathologies associated with mental disorders. Emerging variations in immune regulatory pathways based on sex differences provide an additional framework for discussion in these psychiatric disorders. In this review, we present the current literature pertaining to the effects that disrupted immune pathways have in mental disorder pathophysiology, including immune dysregulation in CNS and periphery, microglial activation, and disturbances of the blood-brain barrier. In addition, we present the suggested origins of such immune dysregulation and discuss the gender and sex influence of the neuroimmune substrates that contribute to mental disorders. The findings challenge the conventional view of these disorders and open the window to a diverse spectrum of innovative therapeutic targets that focus on the immune-specific pathophenotypes in neuronal circuits and behavior. SIGNIFICANCE STATEMENT The involvement of gender-dependent inflammatory mechanisms on the development of mental pathologies is gaining momentum. This review addresses these novel factors and presents the accumulating evidence introducing microglia and proinflammatory elements as critical components and potential targets for the treatment of mental disorders.
Background & ObjectiveMajor depressive disorder (MDD) is a chronic debilitating illness affecting yearly 350 million people worldwide. Although the underlying mechanisms of depression are still not well defined, it has been suggested that psychosocial and oxidative stressors act as depression mediators of inflammatory responses and promote neuronal and glial malfunctions. We have recently established an important association of oligodendrocyte progenitor cells (NG2‐glia) with depression‐like behavior in an adult murine depression model of chronic stress (repeated social defeat stress, RSDS). The aim of the present study is the time‐dependent characterization of the RSDS‐induced inflammatory responses on the NG2‐glial homeostasis.MethodsThe RSDS paradigm (10 days) was utilized to characterize the NG2‐glial dynamics during the early (5 days) and post RSDS stages (10+2 days and 10+15 days) in 8–12 weeks old male C57BL/6J and CSPG4‐EGFP+ mice. Throughout the RSDS, groups were given access ad libitum to BrdU (5‐bromo‐2′‐deoxyuridine) in drinking water to monitor cell proliferation. Social interaction test (SI) and several behavioral tests (BH) were performed at the end of the paradigm to categorize the defeated mice to susceptible (S) and resilient (R) mice. Mice were then euthanized, and brains were isolated to study the MDD‐affected area of Prefrontal Cortex (PFC; n=4–6/per group). Data analysis was blinded and performed by 2 different investigators in each experiment. For the morphology analyses 6–8 traced cells per mouse were analyzed by Neurolucida software.ResultsInflammatory responses were observed in the PFC area, as depicted by the microglial recruitment (Iba1), activation (reactive morphology) and inflammatory markers during the RSDS in the S groups. A time‐dependent decrease of NG2‐glial density (PDGFRα marker and CSPG4‐EGFP+ reporter line) was observed in the PFC in S groups. Given the highly proliferative profiles of NG2 glia in adult CNS, the mitotic capacity (BrdU and Ki67) was examined during chronic stress. Time‐dependent alterations in proliferation capacity were evident in the S groups. In addition, BrdU labeling retention revealed the NG2‐glial fate and responses in this model of chronic stress. Remarkably, in the S groups increased NG2‐glial differentiation was observed towards oligodendrocytes (GST‐pi) in the early RSDS stages, and a concomitant switch towards NG2‐glial production in the post RSDS stages. In addition, chronic stress also induced alterations in the NG2‐glial morphology and branching in the S groups, which are crucial features of NG2‐glial proliferation and communication with the rest of glia and neurons.ConclusionsChronic stress induces inflammatory responses mediated by microglial activation and recruitment, and NG2‐glial cellular homeostasis is swiftly compromised leading to time‐dependent alterations of proliferation, viability and progeny contributing to the onset of depressive‐like behavior in mice.Support or Funding InformationThis work was supported by: ‐ AMERICAN HEART ASSOCIATION GRANT # 19PRE34370044/2019 ‐ R01 RMH099384A(AA) ‐ Scholars in BioMedical Sciences Program (AGK) Graphic outline of experiments.imageGraphic outline of experiments.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Repeated stress can lead to the development of anxiety and is considered a risk factor for major depressive disorder (MDD). Clinical studies and animal models of repeated and chronic stress have reported that symptom severity is correlated with microglial activation and upregulation of neuroinflammatory cytokine signaling in brain areas implicated in mood regulation. Despite mounting evidence implicating impairments of neuroplasticity and synaptic signaling deficits into the pathophysiology of stress-related mental disorders, whether microglial activation modulates neuronal homeostasis in response to chronic stress has been debated. Here, using the repeated social defeat stress (RSDS) mouse model we demonstrate that microglial activation and related inflammatory responses are regulating neuronal plasticity associated with depressive-like behavior. Specifically, we show that chronic stress induces a swift activation and proliferation of microglia as well as macrophage infiltration in the mPFC, which are spatially related to neuronal activation. Moreover, we report a remarkable association of microglial spectrum of reactivity and concomitant inflammatory responses with susceptibility or resilience to chronic stress. In addition, we find that exposure to chronic stress exacerbates phagocytosis of synaptic elements and significant neuronal plasticity deficits associated with depressive-like behavior. Importantly, by utilizing two different CSF1R inhibitors (the brain penetrant PLX5622 and the non-penetrant PLX73086) we determine the contributions of microglial and infiltrating macrophages in the depression pathophenotype. Our findings highlight a crucial role for microglia (and secondarily macrophages) in catalyzing the pathological manifestations of depression in response to chronic stress by promoting neuroinflammation and neuronal deficits in mPFC.
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