Microglia: The Brain’s Immune Cells

By SWA

This is a short extension to Jarred Younger, PhD video: 070 - Why ME/CFS "fatigue" is not normal fatigue.
https://www.youtube.com/watch?v=Nx6qX-9tim4&t=19s

Microglia are specialized immune cells that reside in the central nervous system (CNS), including the brain and spinal cord. They are the brain's primary defense system, constantly surveilling their environment for signs of infection, injury, or abnormality.

When microglia detect a virus, bacterial infection, or other threats (including psychological stress or trauma), they shift from a resting state into an activated inflammatory mode. In this state, they produce and release molecules called pro-inflammatory cytokines, such as:

  • Interleukin-1β (IL-1β)

  • Tumor Necrosis Factor-alpha (TNF-α)

  • Interleukin-6 (IL-6)

Cytokines in the Brain: The Double-Edged Sword

While these cytokines are meant to protect the brain by fighting off pathogens and clearing cellular debris, their presence can also negatively affect brain function, especially when the inflammatory response becomes chronic or excessive.

One of the main consequences of elevated brain cytokines is disruption of neurotransmitter systems, which are critical for mood regulation, cognition, motivation, sleep, appetite, and many other functions.

Let’s explore how cytokines impact serotonin, and then move on to other neurotransmitters and hormones.

Serotonin (5-HT)

  • Role: Regulates mood, sleep, appetite, and general well-being.

  • Impact of Cytokines:

    • Cytokines activate the enzyme indoleamine 2,3-dioxygenase (IDO), which diverts tryptophan (a precursor of serotonin) away from serotonin synthesis and into the kynurenine pathway, leading to neurotoxic metabolites.

    • Result: Tryptophan depletion → less serotonin synthesis.

    • Cytokines can also interfere with serotonin reuptake and receptor sensitivity, impairing signaling.

Consequences:

  • Depression-like symptoms

  • Fatigue

  • Sleep disturbances

  • Reduced motivation

Dopamine

  • Role: Motivation, reward, focus, motor control, and pleasure.

  • Impact of Cytokines:

    • Cytokines reduce the availability of tetrahydrobiopterin (BH4), a cofactor needed for dopamine synthesis.

    • TNF-α and IL-6 can reduce dopamine transporter function, altering dopamine release and reuptake.

    • Inflammatory activity can damage dopaminergic neurons, especially in areas like the prefrontal cortex and striatum.

Consequences:

  • Anhedonia (inability to feel pleasure)

  • Lack of motivation

  • Poor attention and focus

  • Motor impairments (seen in Parkinson’s disease and others)

Norepinephrine (Noradrenaline)

  • Role: Alertness, arousal, stress response, blood pressure regulation.

  • Impact of Cytokines:

    • Cytokine-induced inflammation may downregulate enzymes involved in norepinephrine synthesis.

    • It can also interfere with norepinephrine signaling pathways, reducing responsiveness to stress and environmental stimuli.

Consequences:

  • Brain fog

  • Fatigue

  • Low energy

  • Poor stress tolerance

Glutamate

  • Role: Major excitatory neurotransmitter; critical for learning and memory.

  • Impact of Cytokines:

    • Cytokines can lead to glutamate excitotoxicity by reducing the function of astrocytes, which normally clear excess glutamate from the synapse.

    • Elevated glutamate overstimulates neurons, potentially leading to cell death.

Consequences:

  • Cognitive impairment

  • Neurodegeneration

  • Seizures (in severe cases)

GABA (Gamma-Aminobutyric Acid)

  • Role: The brain’s main inhibitory neurotransmitter; calming, anti-anxiety, sleep regulation.

  • Impact of Cytokines:

    • Inflammation can disrupt GABA receptor expression and GABA synthesis, tilting the brain toward an over-excited state.

    • This imbalance is a contributor to anxiety, insomnia, and irritability.

Consequences:

  • Anxiety

  • Restlessness

  • Insomnia

  • Seizures (in extreme inflammatory cases)

Cortisol and the HPA Axis

  • Role: Cortisol is a hormone produced by the adrenal glands in response to stress; regulated by the hypothalamic-pituitary-adrenal (HPA) axis.

  • Impact of Cytokines:

    • Cytokines can activate the HPA axis, increasing cortisol levels.

    • Chronic inflammation leads to HPA axis dysregulation, which over time can result in either excess cortisol (hypercortisolism) or blunted cortisol response.

Consequences:

  • Chronic stress

  • Immune suppression

  • Depression

  • Metabolic disorders

Melatonin

  • Role: Regulates sleep-wake cycles; antioxidant properties.

  • Impact of Cytokines:

    • Inflammatory cytokines can disrupt melatonin production by affecting the pineal gland.

    • Reduced melatonin contributes to poor sleep, and because melatonin has anti-inflammatory properties, its loss further amplifies inflammation.

Consequences:

  • Insomnia

  • Fatigue

  • Weakened immune system

Summary: The Inflammatory Domino Effect

When microglia detect infection or stress and release cytokines:

  1. Tryptophan is depleted → serotonin drops.

  2. Dopamine, norepinephrine, and GABA synthesis and signaling are impaired.

  3. Glutamate levels rise, leading to excitotoxicity.

  4. The HPA axis is overactivated, disrupting cortisol balance.

  5. Melatonin decreases, worsening sleep and recovery.

This explains why sickness, chronic inflammation, or even psychological stress can lead to symptoms like:

  • Low mood

  • Brain fog

  • Fatigue

  • Anxiety

  • Poor sleep

  • Loss of interest and motivation

Final Thought

Inflammation isn’t just a body issue—it directly alters how your brain works by changing the chemical balance that underpins mood, cognition, and behavior. That’s why chronic inflammation is now considered a major contributor to many psychiatric and neurological conditions, including depression, anxiety, PTSD, and neurodegenerative diseases like Alzheimer’s and Parkinson’s.

References: 

Microglia Activation and Cytokine Production in the Brain

Cytokines Depleting Tryptophan and Reducing Serotonin

  • Reference: Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience, 9(1), 46–56.
    DOI: 10.1038/nrn2297
    https://www.nature.com/articles/nrn2297

Cytokines and Dopamine Dysfunction

Cytokines and Glutamate Excitotoxicity

GABA Disruption by Inflammation

Cytokines, Cortisol, and the HPA Axis

Melatonin Suppression by Inflammation

Disclaimer: By accessing and reading this blog, you acknowledge that the information provided is for general informational purposes only and does not constitute medical advice, diagnosis, or treatment. The content is intended to address commonly asked questions and is derived from reputable scientific literature. Always consult a qualified healthcare professional for medical concerns or conditions.

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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