Brain motor and fear circuits orchestrate the immune response to acute stress

While research has demonstrated that stress can impact immune function, the exact mechanisms by which these alterations occur in the brain remain unknown. A new Nature study explores how acute stressors affected mice in terms of their immune responses in specific regions of the brain.

Study: Brain Motor and Fear Circuits Regulate Leukocytes During Acute Stress. Image Credit: Rido / Shutterstock.com

Study: Brain Motor and Fear Circuits Regulate Leukocytes During Acute Stress. Image Credit: Rido / Shutterstock.com

Study findings

Within one hour of exposure to the stressor, mouse blood samples exhibited a significant reduction in peripheral blood mononuclear cells (PBMCs) including monocytes and lymphocytes, whereas neutrophil numbers increased. Thus, PBMCs were found to decline slowly with stress and recover to baseline once the mice started to adjust to the stressor.

Neutrophils increased rapidly to peak levels after only half a minute of restraint-induced stress. Neutrophil levels subsequently declined at the same rate back to baseline.

Other leukocytes exhibited the same pattern as PBMCs, with peak levels reached after only four hours of restraint stress. Thus, during restraint, PBMCs would slowly decline, while neutrophil levels rose rapidly. These changes were due to the recruitment of tissue-resident monocytes and lymphocytes into the blood from where they were temporarily stored in the bone marrow.

Lymphocytes in the lymph nodes and spleen, both of which are secondary lymphoid organs, were significantly reduced for the same reason. This was followed by a slower release from the bone marrow, such that even 40 hours from the stressor exposure, secondary lymphoid organs remained depleted of lymphocytes relative to the numbers before the stress was applied.

Neutrophils were not stored in the spleen, nor did the bone marrow begin to produce these cells at a higher rate. Instead, the sudden increase was due to the trafficking of neutrophils out of the bone marrow to a level that was comparable to the newly gained neutrophils in peripheral organs. This indicates the redistribution of leukocytes of all major types throughout the body with acute mental stress.

The HPA

The researchers also found that the hypothalamic-pituitary-adrenal axis (HPA) modulated leukocyte populations. Corticosterone injections led to an increase in cell numbers in control mice. Comparatively, ablation of the adrenal gland in stressed mice inhibited corticosterone release, which subsequently prevented the decline in mononuclear cells.

The effect of the HPA on cell numbers appeared to be an inherent property of white blood cells, rather than mediated by the glucocorticoid receptors. This was enhanced by the chemokine receptor CXCR4, which causes leukocyte migration and retention to the bone marrow.

Other techniques like chemogenetics and optogenetics showed that neurons in the paraventricular hypothalamus (PVH) of the brain, which produces corticotropin-releasing hormone (CRH), were activated by acute stress. This led to an increase in corticosterone levels in the body and a sharp decline in PBMCs, both of which are mediated by the adrenal gland. This response was due to the release of CRH.

In the absence of CRH, stressed mice were unable to produce corticosterone and did not exhibit any reduction in PBMCs. However, the PVH did not cause a rise in neutrophils and instead reduced the peak. This suggests that the PVH/CRH interaction is essential for the acute stress-induced reduction and migration of mononuclear cells into the bone marrow.

Our study reveals how specific neuron clusters located in diverse regions of the brain relevant to fear and the fight or flight response cause massive changes in leukocyte distribution and function.”

These changes were in response to skeletal muscle-released chemokines CXCL1 and interleukin-16 (IL-16). CXCL1 levels increased in association with neutrophil counts, whereas neutrophilia was prevented by inhibiting CXCL2 activity.

Interestingly, skeletal muscle is not only abundant in the body but is often activated during stress and is a rich source of cytokines and chemokines. CXCL1 gene expression was upregulated rapidly in the muscle, with the quick translation of the muscle CXCL1 protein in this tissue. No lasting or major injury occurred to the muscle.

Nonetheless, running for exercise did not produce a rise in either the messenger ribonucleic acid (mRNA) transcript, protein translation, or blood neutrophil number. The obvious hypothesis is that “very strong muscle activation, as confirmed by [electromyography] EMG telemetry, was required.”

Implications

The study findings demonstrate that the central motor structures are responsible for increased CXCL1 and neutrophil numbers. Conversely, destroying the motor cortex led to less muscle movement, while neutrophilia significantly declined in response to the stress of restraint.

When a muscle relaxant was used with central motor stimulation, neutrophilia was no longer observed – “neutrophilia arises as a consequence of central motor circuit-controlled excessive muscle activity.”

This cellular redistribution was found to protect the mice from the start and progression of the disease, with lower scores of experimental autoimmune encephalomyelitis (EAE) in mice exposed to stress. This was due to the activation of certain brain areas that block the development of autoimmunity.

However, acute stress during a phase when the organism is exposed to a virus predisposes it to infection, as the adaptive immune response of the host is impaired.

These data reveal a pathway linking stress induced PVH CRH neuron activity with corticosterone acting directly on lymphocytes, thus impairing sensitization to viral infection, and aggravating disease.”

Journal reference:
  • Poller, W. C., Downey, J., Mooslechner, A. A., et al. (2022). Brain Motor and Fear Circuits Regulate Leukocytes During Acute Stress. Nature. doi:10.1038/s41586-022-04890-z.
Dr. Liji Thomas

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Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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