Re-establishment of Anxiety in Stress-Sensitized Mice Is Caused by Monocyte Trafficking from the Spleen to the Brain
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Background Persistent anxiety-like symptoms may have an inflammatory-related pathophysiology. Our previous work using repeated social defeat (RSD) in mice showed that recruitment of peripheral myeloid cells to the brain is required for the development of anxiety. Here, we aimed to determine if 1) RSD promotes prolonged anxiety through redistribution of myeloid cells and 2) prior exposure to RSD sensitizes the neuroimmune axis to secondary subthreshold stress.Methods Mice were subjected to RSD and several immune and behavioral parameters were determined .5, 8, or 24 days later. In follow-up studies, control and RSD mice were subjected to subthreshold stress at 24 days.Results Repeated social defeat-induced macrophage recruitment to the brain corresponded with development and maintenance of anxiety-like behavior 8 days after RSD, but neither remained at 24 days. Nonetheless, social avoidance and an elevated neuroinflammatory profile were maintained at 24 days. Subthreshold social defeat in RSD-sensitized mice increased peripheral macrophage trafficking to the brain that promoted re-establishment of anxiety. Moreover, subthreshold social defeat increased social avoidance in RSD-sensitized mice compared with naïve mice. Stress-induced monocyte trafficking was linked to redistribution of myeloid progenitor cells in the spleen. Splenectomy before subthreshold stress attenuated macrophage recruitment to the brain and prevented anxiety-like behavior in RSD-sensitized mice.Conclusions These data indicate that monocyte trafficking from the spleen to the brain contributes re-establishment of anxiety in stress-sensitized mice. These findings show that neuroinflammatory mechanisms promote mood disturbances following stress-sensitization and outline novel neuroimmune interactions that underlie recurring anxiety disorders such as posttraumatic stress disorder.
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The resulting proinflammatory skew in the whole body monocyte pool persists for the life of the cells, which can sequester in reservoirs such as the spleen and reemerge months later in response to social threat.
“The resulting proinflammatory skew in the composition of the whole body monocyte pool persists for the life of the cells, which can sequester in reservoirs such as the spleen and reemerge months later in response to social threat [35].”
From Human Social Genomics (2014) · cites this paper as [35]
CSDS promotes recruitment of circulating monocytes and macrophages into the brain perivascular space via complement 3 receptor and CX3C chemokine receptor 1 signaling.
“CSDS promotes recruitment of circulating monocytes and macrophages into the brain perivascular space via complement 3 receptor and CX3C chemokine receptor 1 signaling [181–183].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [182]
A single episode of stress does not trigger an immune response that is critical for anxiety.
“For example, a single episode of stress does not trigger an immune response that is critical for anxiety, but it is sufficient to induce social avoidance [29].”
From Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety (2019) · cites this paper as [29]
Social avoidance behavior after repeated social defeat stress is regulated by a mechanism different from anxiety.
“It is important to note that social avoidance behavior after repeated social defeat stress is regulated by a mechanism different from anxiety.”
From Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety (2019) · cites this paper as [29]
A single episode of stress is sufficient to induce social avoidance.
“For example, a single episode of stress does not trigger an immune response that is critical for anxiety, but it is sufficient to induce social avoidance [29].”
From Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety (2019) · cites this paper as [29]
This primed or 'sensitized' profile of microglia in psychological stress was responsible for the long-term re-establishment of anxiety in mice initially exposed to repeated social defeat stress.
“This primed or 'sensitized' profile of microglia in psychological stress was responsible for the long-term re-establishment of anxiety in mice initially exposed to repeated social defeat stress (Wohleb et al, 2014).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Wohleb et al, 2014
Primed microglia from the stress-exposed mice, but not naive mice, elicited an exaggerated inflammatory response to acute social defeat stress, and this response was sufficient for the recurrence of anxiety-like behavior.
“For example, primed microglia from the stressexposed mice, but not naive mice, elicited an exaggerated inflammatory response to acute social defeat stress, and this response was sufficient for the recurrence of anxiety-like behavior (Wohleb et al, 2014).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Wohleb et al, 2014
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“Along these same lines, RSD primes and activates peripherally derived monocytes inducing increased cytokine expression and resistance to the immunosuppressive effects of GCs (Engler et al., 2005; Wohleb et al., 2011, 2014a; Powell et al., 2013).”
BackgroundMethodInfluentialSelf-citationSocial Stress Mobilizes Hematopoietic Stem Cells to Establish Persistent Splenic Myelopoiesis
McKim, D. B., Yin, W., Wang, Y., Cole, S. W., Godbout, J. P., & Sheridan, J. F. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.102 · Cited by 153 · see citing works
Self-citationNiraula, A., Wang, Y., Godbout, J. P., & Sheridan, J. F. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.2568-17.2018 · Cited by 137 · see citing works
Self-citationSympathetic Release of Splenic Monocytes Promotes Recurring Anxiety Following Repeated Social Defeat
McKim, D. B., Patterson, J. M., Wohleb, E. S., Jarrett, B. L., Reader, B. F., Godbout, J. P., & Sheridan, J. F. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.07.010 · Cited by 137 · see citing works
Self-citationThe neuroimmunology of social-stress-induced sensitization
Biltz, R. G., Sawicki, C. M., Sheridan, J. F., & Godbout, J. P. (2022) · Nature Immunology · doi:10.1038/s41590-022-01321-z · Cited by 132 · see citing works
Self-citationBrain-spleen axis in health and diseases: A review and future perspective
Wei, Y., Wang, T., Liao, L., Fan, X., Chang, L., & Hashimoto, K. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.02.008 · Cited by 134 · see citing works
Gur, T. L., Palkar, A. V., Rajasekera, T., Allen, J., Niraula, A., Godbout, J., & Bailey, M. T. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.06.025 · Cited by 127 · see citing works
Niraula, A., Witcher, K. G., Sheridan, J. F., & Godbout, J. P. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.09.030 · Cited by 124 · see citing works
Self-citationLiu, J., Buisman-Pijlman, F., & Hutchinson, M. R. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00309 · Cited by 119 · see citing works
Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance
Ramirez, K., Shea, D. T., McKim, D. B., Reader, B. F., & Sheridan, J. F. (2015) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.01.016 · Cited by 108 · see citing works
Self-citationRamirez, K., Niraula, A., & Sheridan, J. F. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.08.011 · Cited by 101 · see citing works
Self-citationSawicki, C. M., McKim, D. B., Wohleb, E. S., Jarrett, B. L., Reader, B. F., Norden, D. M., Godbout, J. P., & Sheridan, J. F. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2014.10.004 · Cited by 101 · see citing works
GSK3β: a master player in depressive disorder pathogenesis and treatment responsiveness
Duda, P., Hajka, D., Wójcicka, O., Rakus, D., & Gizak, A. (2020) · Cells · doi:10.3390/cells9030727 · Cited by 84 · see citing works
Neuroinflammatory basis of depression: learning from experimental models
Afridi, R., & Suk, K. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.691067 · Cited by 82 · see citing works
Sun, N., Hu, H., Wang, F., Li, L., Zhu, W., Shen, Y., Xiu, J., & Xu, Q. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.11.032 · Cited by 75 · see citing works
Mapping of Pituitary Stress-Induced Gene Regulation Connects Nrcam to Negative Emotions
Olsen, M. B., Sannes, A.-C., Yang, K., Nielsen, M. B., Einarsen, S. V., Christensen, J. O., Pallesen, S., Bjørås, M., & Gjerstad, J. (2022) · iScience · doi:10.1016/j.isci.2022.104953 · Cited by 9 · see citing works
Horikawa, I., Nagai, H., Taniguchi, M., Chen, G., Shinohara, M., Suzuki, T., Ishii, S., Katayama, Y., Kitaoka, S., & Furuyashiki, T. (2024) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2024.02.010 · Cited by 8 · see citing works
Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility
Russo, S., Cathomas, F., Lin, H.-Y., Chan, K., Li, L., Durand-de Cuttoli, R., Parise, L., Aubry, A., Muhareb, S., Desland, F., et al. (2023) · doi:10.21203/rs.3.rs-1647827/v1 · Cited by 189 · see citing works
“These findings, which emphasize the role of peripheral myeloid cells in stress-linked disorders such as MDD, are in line with several pre-clinical studies 13,34,12,35 and studies in humans 36,37,38 .”
ResultStress-induced blood brain barrier disruption: Molecular mechanisms and signaling pathways
Welcome, M. O., & Mastorakis, N. E. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104769 · Cited by 139 · see citing works
- Authors
- Wohleb, E. S., McKim, D. B., Shea, D. T., Powell, N. D., Tarr, A. J., Sheridan, J. F., & Godbout, J. P.
- Affiliations
- Institute for Behavioral Medicine (US)
- Corresponding author
- Godbout, Jonathan P.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 75
- Issue
- 12
- Pages
- 970-981
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4084643
- OpenAlex
- W1963708297
- Cited by
- 300
- References
- 64
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 17 · 2023: 26 · 2022: 29 · 2021: 30 · 2020: 31 · 2019: 23 · 2018: 27 · 2017: 23 · 2016: 24 · 2015: 18 · 2014: 11
- FWCI
- 7.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01-MH-093473, R01-097243, R01-AG033028, F31-MH09547301)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- anxiety, repeated social defeat, monocyte trafficking, spleen, neuroinflammation, neuroimmune axis, stress sensitization, social avoidance, myeloid progenitor cells, splenectomy, post-traumatic stress disorder, mood disorders
- MeSH terms
- Animals, Anxiety, Brain, Cell Movement, Macrophages, Male, Monocytes, Social Behavior, Spleen, Splenectomy, Stress, Psychological, Mice, Central Nervous System Sensitization
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