Sean Krivitsky, Class of 2026

Every year, three million people in the United States alone are diagnosed with major depressive disorder (MDD). MDD is a serious form of mental illness that impacts countless facets of people’s lives, characterized by a persistently low mood and general impairment of daily routines. Interestingly, glial cells, generally known for their roles in regulation and support of neuronal networks in the brain, have been implicated in the pathophysiology of MDD. Specifically, microglia, which serve as the brain’s immune cells, are activated and upregulated in response to the chronic stress that is often associated with MDD. This microglial activity has been suggested to cause stress susceptibility through synaptic pruning. They have also been shown to affect oligodendrocytes, which can play an additional immune role in the brain and are also important for maintaining the myelin network that supports neuronal signaling. 

Researchers from the Nadkarni Lab at SBU sought to better understand this poorly-characterized interplay between microglia and immune-expressing oligodendrocytes (ImOLs) in a chronic stress mouse model. After stimulating repeated or chronic social defeat stress (RSDS/CSDS) in certain mice by means of exposure to more aggressive mice and administration of stress hormones, mouse behavior was analyzed and compared to another condition with artificially depleted microglia induced by treatment with PLX5622, a colony stimulating factor-1 receptor inhibitor. This was then followed by cell-based assays and analyses of dissected mouse brains from the various experimental conditions.

This study revealed that chronic stress, widely recognized as a major factor leading to the onset of MDD, stimulated the establishment of a neuroinflammatory environment necessary to induce the activation of immune functions of oligodendroglial lineage (OLN) cells. Specifically, this neuroinflammation, which is primarily the result of chronic stress-reactive microglia activation, causes OLN cells to express the immune proteasome, a key organelle involved in the antigen-presenting capabilities of OLN cells through major histocompatibility complex (MHC) receptors. This was supported by decreased immune proteasome expression in OLN cells, increased presence of later stage OLNs, and the secretion of interferon gamma, a cytokine crucial for inducing OLN MHC expression, following artificial microglia depletion. 

Overall, this study implicates OLNs as playing a crucial role in MDD stress susceptibility downstream of microglia and potentially contributing to the process of discrete alterations to white matter characteristic of MDD. It also helps identify novel targets to combat MDD treatment resistance by further unraveling the mechanisms underlying its onset.

Figure 1: Fluorescent staining of neurons and glial cells in mouse brain tissue.

Works Cited:

[1] Madeira, M. M., Hage, Z., Kokkosis, A. G., Nnah, K., Guzman, R., Schappell, L. E., Koliatsis, D., Resutov, E., Nadkarni, N. A., Rahme, G. J., & Tsirka, S. E. (2024). Oligodendroglia are primed for antigen presentation in response to chronic stress‐induced microglial‐derived inflammation. Glia. https://doi.org/10.1002/glia.24661 

[2] Image retrieved from: https://commons.wikimedia.org/wiki/File:Chk-UCH1-GFAP-20X-1.jpg