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Author Spotlight: Induced Microglia-Like Cell Technology to Shed Light on the Role of Microglial Dysfunction in Neuropsychiatric Disorders
Published on: September 6, 2024
Microglia of prefrontal white matter in suicide
Tatiana P Schnieder1, Iskra Trencevska, Gorazd Rosoklija
1From the Division of Molecular Imaging and Neuropathology, Departments of Psychiatry (TPS, GR, JJM, AJD) and Pathology and Cell Biology (AJD), Columbia University, New York; Department of Psychology, Graduate Center, City University of New York (TPS, JS); and New York State Psychiatric Institute (GR, JJM, AJD), New York, New York; and Neuropathology of Psychiatric Disorders, Nathan Kline Institute (JS), Orangeburg, New York; and School of Medicine, University "Ss. Cyril and Methodius" (GR, AS, AJD); Psychiatric Hospital (IT); and Macedonian Academy of Sciences and Arts (GR, AJD), Skopje, Macedonia.
Abstract:
Immune functions in the brain are associated with psychiatric illness and temporary alteration of mental state. Microglia, the principal brain immunologic cells, respond to changes in the internal brain milieu through a sequence of activated states, each with characteristic function and morphology. To assess a possible association of frontal white matter pathology with suicide, we stained autopsy brain tissue samples from 11 suicide and 25 nonsuicide subjects for ionized calcium-binding adapter molecule 1, cluster of differentiation 68, and myelin. Groups were matched by age, sex, and psychiatric diagnosis. We classified ionized calcium-binding adapter molecule 1-immunoreactive cells based on shape, immunoreactivity to cluster of differentiation 68, and association with blood vessels to obtain stereologic estimates of densities of resting microglia, activated phagocytes, and perivascular cells. We found no effect of psychiatric diagnosis but 2 statistically significant effects of suicide: 1) The dorsal-ventral difference in activated microglial density was reversed such that, with suicide, the density was greater in ventral prefrontal white matter than in dorsal prefrontal white matter, whereas in the absence of suicide, the opposite was true; and 2) with suicide, there was a greater density of ionized calcium-binding adapter molecule 1-immunoreactive cells within or in contact with blood vessel walls in dorsal prefrontal white matter. These observations could reflect a mechanism for the stress/diathesis (state/trait) model of suicide, whereby an acute stress activates a reactive process in the brain, either directly or by compromising the blood-brain barrier, and creates a suicidal state in an individual at risk. They also indicate the theoretical potential of imaging studies in living vulnerable individuals for the assessment of suicide risk. Further studies are needed to investigate specific phenotypes of perivascular cells and blood-brain barrier changes associated with suicide.
Insights
Suicide is linked to altered microglial cell distribution in the prefrontal white matter, specifically increased activated microglia in ventral regions and more perivascular cells in dorsal regions. These findings suggest potential brain mechanisms underlying suicide risk.
Area of Science:
- Neuroscience
- Immunology
- Psychiatry
Background:
- Brain immune functions, particularly involving microglia, are implicated in psychiatric disorders and altered mental states.
- Microglia, the brain's primary immune cells, exhibit dynamic changes in morphology and function in response to internal milieu alterations.
- Frontal white matter pathology is being investigated for its potential association with suicide.
Purpose of the Study:
- To investigate the association between frontal white matter pathology and suicide.
- To examine microglial cell densities and distributions in the prefrontal white matter of suicide and non-suicide subjects.
Main Methods:
- Autopsy brain tissue samples from suicide (n=11) and non-suicide (n=25) subjects were stained for ionized calcium-binding adapter molecule 1 (Iba1), cluster of differentiation 68 (CD68), and myelin.
- Subjects were matched for age, sex, and psychiatric diagnosis.
- Stereologic estimates of resting microglia, activated phagocytes, and perivascular cells were obtained by classifying Iba1-immunoreactive cells based on morphology, CD68 immunoreactivity, and proximity to blood vessels.
Main Results:
- No significant effect of psychiatric diagnosis on microglial cell densities was observed.
- Suicide was associated with a reversed dorsal-ventral difference in activated microglial density, with higher density in ventral prefrontal white matter compared to dorsal.
- Suicide was also associated with a greater density of Iba1-immunoreactive cells within or contacting blood vessel walls in the dorsal prefrontal white matter.
Conclusions:
- The observed changes in microglial distribution and perivascular cell density in the prefrontal white matter may reflect a mechanism contributing to suicide, potentially related to stress-induced brain reactivity or blood-brain barrier compromise.
- These findings support the stress/diathesis model of suicide and suggest potential for neuroimaging studies in living individuals to assess suicide risk.
- Further research is warranted to elucidate specific perivascular cell phenotypes and blood-brain barrier alterations associated with suicide.
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