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RUNNING HEAD: MICROGLIA’S ROLE IN SUICIDE SYMPTOMOLOGY

Microglia’s Role in Suicide Symptomology

Elainna Simpson
Loras College
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MICROGLIA’S ROLE IN SUICIDE SYMPTOMOLOGY

Microglia’s Role in Suicide Symptomology

Introduction

Suicide is a prevalent issue throughout the United States. According to the National

Institute of Mental Health (2019), 1.4 million adults attempted suicide during 2019 alone.

Despite its prevalence, the neurobiological correlates of suicide are mostly unknown, but one

commonality within the literature is an increase in activated microglia. Despite these findings,

suicidal behaviors have not been explicitly connected to microglial activation. It is important to

further understand the role of microglia within suicide symptomology to facilitate more research

and to create treatments or interventions for those who are suicidal.

Brain Inflammation

Microglia is essentially the brain’s immune system, it detects and resolves any injury

within the brain in order to protect it. When microglia respond to an injury, they usually create

inflammation to heal it. This neuroinflammation can become excessive and impair functioning

within the brain. Microglia are the central nervous system’s (CNS) main producers of cytokines

which are signaling proteins that can affect inflammation (Frank et al., 2007). These cytokines

are usually pro-inflammatory (IL-1β, IL-6, and TNF-α) or anti-inflammatory (IL-10) in nature.

Stress-induced alterations in the hypothalamic-pituitary-adrenal (HPA) axis can cause a change

in cytokine levels and functioning, usually inducing a pro-inflammatory response (Pandey et al.,

2018; Pandey et al., 2012). Chronic stress can cause the whole brain’s homeostatic environment

to change which can then cause neuropsychiatric disorders which then can impair quality of life.

Microglia then uses inflammation to cope with that change in homeostasis (McKim et al., 2016;

Frick, Williams, & Pittenger, 2013). Yet, over-activation of microglia can lead to increased
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MICROGLIA’S ROLE IN SUICIDE SYMPTOMOLOGY

neuroinflammation which can cause neuronal and synaptic dysfunction which is characteristic of

several neuropsychiatric disorders. It still remains unclear if microglial activation causes a

psychiatric disorder or if microglial activation is the result of a psychiatric disorder (Frick et al.,

2013).

Microglial Activity in Suicidal Behaviors

Microglia have a role within psychiatric disorders, and therefore, may also be implicated

in suicide. There appears to be a direct relationship between suicide and an increase in microglia.

The release of cytokines, nitric oxide, and other factors from microglial cells can modulate the

neurotransmission of serotonin and noradrenaline which could be a trigger of suicidal behavior

(Steiner et al., 2008). Although it is clear that over inflammation can cause suicide it is also

believed that microglia could be suicide-preventative. Some research in the field of suicide

neurobiology supports that microglia in non-suicidal depressed patients can act restoratively and

microglia in depressed suicides acted neurodegeneratively (Brisch et al., 2017). If microglia have

the capacity to either prevent suicide or help cause it, it is important to find out more about

microglia and how to balance the extremes.

To evaluate the differences between suicide and non-suicide post-mortem brains, Brisch

et. al (2017) evaluated microglial activation within the dorsal raphe nucleus to examine the effect

on serotonin as well as the deteriorating impact of microglia on rDNA. Their study showed an

increase in microglia in depressed subjects who committed suicide compared to non-suicidal

depressed subjects. These results demonstrate that the non-suicidal group had microglia that had

a suicide-preventative effect compared to the suicide group. Not many studies have focused on

the white matter of post-mortem suicide brains, despite the knowledge that microglia are more
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abundant there and that white matter has been used as an indicator of damage. Schnieder et al.

(2014) demonstrated that there is a significant density of activated microglia in the ventral

prefrontal white matter and microglia-like cells that were in contact with the blood vessel walls

of the dorsal prefrontal white matter.

Post mortem studies and microglial studies have set the foundation for understanding the

biological mechanisms behind suicide. To prevent the unnecessary loss of life, it is imperative to

understand the biological mechanisms that affect the behavioral symptomology of suicide. If

connections in biology and symptoms can be identified, then targeted treatments could help those

symptoms from evolving into suicidal ideation and eventually death.

Depression and Stress Symptomology of Suicide

Depression rates and increased chronic stress have been associated with higher suicide

vulnerability (Bradvik, 2018; Polanco-Roman et al., 2016). Due to this association, targeting

depression and stress-related symptoms through microglial activation could provide a possible

treatment for suicide. Depressed suicide brains indicated an imbalance between pro- and anti-

inflammatory cytokines with a decrease in anti-inflammatory cytokines and an increase in pro-

inflammatory cytokines. An increase in cytokines has been shown to lead to sickness behavior

which is similar in symptomology to depression (Pandey et al., 2018). This indicates a direct

relationship between neurobiological factors and suicide symptoms. Another example of this is

that suicide vulnerability (found in the orbitofrontal cortex) can be caused by serotonin

dysfunction, impulsivity, or childhood trauma; all of these can cause the perception of a threat

that can lead to suicidal ideation. Suicide ideation could then lead to an activation of the

biological stress response which includes inflammation (Courtet et al., 2016).

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MICROGLIA’S ROLE IN SUICIDE SYMPTOMOLOGY

In order to replicate suicidal symptomology in mice, the social defeat model has been

used to understand chronic stress. The social defeat model is a creation of social conflict between

either animals or humans. Brief social defeat can cause anxiety-like behaviors and enduring

social defeat can cause depressive-like behaviors. This model has been shown to induce

microglia activation in the brain, making it a good model for suicide research (Stein et al., 2017).

Pittenger & Duman (2008) as cited in Frick et al. (2013) identified activated microglia in the

prefrontal cortex of mice due to chronic psychological stress. Within a similar stress model

utilizing social defeat, they found an increase in cytokines associated with cytotoxic microglial

activation in the amygdala, prefrontal cortex, and hippocampus. Evidence of these cytokines

shows that microglia may be attacking cells in brain structures that play a role in stress. These

studies indicate the correlation between stress and microglial activation within rodents and that

human brains most likely act similarly to these models.

Decision Making & Working Memory Symptomology in Suicide

Suicide victims have impairment of their decision-making and working memory abilities

(Bridge, et al., 2012; Richard-Devantoy, Berlim, & Jollant, 2014). One experiment was done on

adult males who were given minocycline, a known microglial inhibitor, and then were given

scales that analyzed their decision-making and personality during a stressful situation. The

minocycline did not change personality but did significantly change their decision-making,

which was more concerned with anxiety and trustworthiness compared to the non-treatment

group. These results suggest social-decision making in stressful situations is unconsciously

controlled by microglia. This leads to a hypothesis of early life experience of psychological

stress and trauma could activate microglia and create a memorized connection and can determine

personality and social behaviors later in life. This is an interesting connection to the activated
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microglia within suicide because this could mean that stress can activate microglia which can

cause a personality that is vulnerable to suicide (Kato et al., 2012).

Minocycline was also used to increase working-memory in chronically stressed mice.

Mice were chronically stressed which caused an increase in activated microglia in the medial

prefrontal cortex (mPFC) and a decline in working memory. The treatment of minocycline was

able to inhibit the microglia’s inflammatory effect and allow for an increase in working memory

(Hinwood, Morandini, & Walker, 2012). This research can be associated with suicide due to past

research on impairment of memory, especially working memory, in suicidal individuals

(Richard-Devantoy et al., 2014).

Impulsivity & Aggression Symptomology in Suicide

Impulsivity and aggression have been shown to be increased among suicidal victims. To

understand these traits of suicide in relation to increased inflammation, Isung et al. (2014)

studied these traits and IL-6 levels in cerebrospinal fluid (CSF) and plasma of violent suicide

attempters. They found that suicide attempters with more impulsive and sensation-seeking

personality traits (monotony avoidance) had significantly higher plasma levels of IL-6. Plasma

IL-6 was significantly correlated with impulsivity (p < 0.01) and monotony avoidance (p < 0.01).

CSF IL-6 was correlated with monotony avoidance (p < 0.05). There was no correlation between

CSF IL-6 and impulsivity but researchers suggest that this is due to a smaller sample size of the

CSF group (Figure 1). This research may indicate that IL-6, which promotes inflammation, may

be associated with certain aspects of suicidality like impulsivity and monotony avoidance, which

could also impact the violence of how someone commits suicide.

Conclusion
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MICROGLIA’S ROLE IN SUICIDE SYMPTOMOLOGY

The studies presented in this review conclude that microglia are a neurobiological

indicator of suicide. Activated microglia have been closely related to common suicide symptoms

like chronic stress, impaired decision making and working memory, and increased impulsivity

and aggression. Some studies indicated that minocycline, a microglial inhibitor, may be utilized

as a treatment to improve decision-making and working memory in suicides (Hinwood et al.,

2012; Kato et al., 2012). Utilization of minocycline as an additive suicidal treatment could help

to prevent suicidal symptomology and suicidal actions. Future research should focus on other

connections between suicide symptomology and microglial activation that allows for novel

treatments or neurobiological indicators that suicide may occur. Due to the connection of

activated microglia in suicide, this could be a helpful neurobiological indicator to determine

people at risk of suicide. This could be analyzed through PET scans or in vivo imaging which

can help to create therapeutic interventions that could limit the harmful effects of microglia and

increase the positive effects (Schneider, et.al, 2014). After obtaining immunological proof one

could undergo individualized treatment of abnormal microglia that can reduce the number of

neurodegenerative acting microglia and growth in restorative microglia (Brisch, et. al, 2017).

Suicide is a very prevalent cause of death and can be extremely devastating to families, so it is

important to identify a treatment for clinical trials to avoid untimely and unfortunate death. This

improved understanding of a neurobiological correlate of suicide can help by indicating those

that are at a higher risk of suicide and finding a treatment before they take their own lives.

References
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MICROGLIA’S ROLE IN SUICIDE SYMPTOMOLOGY

National Institute of Mental Health. 2019. Suicide.

https://www.nimh.nih.gov/health/statistics/suicide.shtml

Bridge, J. A., McBee-Strayer, S. M., Cannon, E. A., Sheftall, A. H., Reynolds, B., Campo, J. V.,

Pajer, K. A., Barbe, R. P., & Brent, D. A. (2012). Impaired decision making in adolescent

suicide attempters. Journal of the American Academy of Child & Adolescent Psychiatry,

51(4), 394–403. doi:10.1016/j.jaac.2012.01.002

Bradvik, L. (2018). Suicide risk and mental disorders. International Journal of Environmental

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Brisch, R., Steiner, J., Mawrin, C., Krzyżanowska, M., Jankowski, Z., & Gos, T. (2017).

Microglia in the dorsal raphe nucleus plays a potential role in both suicide facilitation and

prevention in affective disorders. European Archives of Psychiatry and Clinical

Neuroscience, 267(5), 403-415.

Courtet, P., Giner, L., Seneque, M., Guillaume, S., Olie, E., & Ducasse, D. (2016).

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MICROGLIA’S ROLE IN SUICIDE SYMPTOMOLOGY

Hinwood, M., Morandini, J., Day, T. A., & Walker, F. R. (2011). Evidence that microglia

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Isung, J., Aeinehband, S., Mobarrez, F., Nordström, P., Runeson, B., Åsberg, M., Piehl, F., &

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Kato, T. A., Watabe, M., Tsuboi, S., Ishikawa, K., Hashiya, K., Monji, A., Utsumi, H., & Kanba,

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McKim, D. B., Niraula, A., Tarr, A. J., Wohleb, E. S., Sheridan, J. F., & Godbout, J. P. (2016).

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defeat. Journal of Neuroscience, 36(9), 2590-2604.

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& Dwivedi, Y. (2012). Proinflammatory cytokines in the prefrontal cortex of teenage

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MICROGLIA’S ROLE IN SUICIDE SYMPTOMOLOGY

Polanco-Roman, L., Gomez, J., Miranda, R., & Jeglic, E. (2016). Stress-related symptoms and

suicidal ideation: The roles of rumination and depressive symptoms vary by gender.

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Stein, D. J., Vasconcelos, M. F., Albrechet-Souza, L., Ceresér, K. M., & de Almeida, R. M.

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Figure 1: Correlation between IL-6 and Suicide Personality Traits of Impulsivity and

Monotony Avoidance (Isung et al, 2014)

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MICROGLIA’S ROLE IN SUICIDE SYMPTOMOLOGY

Figure 1: Plasma IL-6 was significantly correlated

with impulsivity (p < 0.01) (Fig. 2a) and

monotony avoidance (p < 0.01) (Fig. 2b). CSF

IL-6 was correlated with monotony avoidance

(p < 0.05) (Fig. 2c). There was no correlation

between CSF IL-6 and impulsivity but

researchers suggest that this is due to a smaller

sample size of the CSF group. These graphs

indicate that IL-6, a pro-inflammatory

cytokine, may be connected to suicidal

personality traits like impulsivity and

monotony avoidance.