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Environmental enrichment modulates chronic poststroke inflammation and links white matter TREM2-positive microglia in recovery in mice

Camprubí-Ferrer, Lluís LU ; Kolbay, Ömer K. LU ; Quattromani, Miriana J. LU ; Wieloch, Tadeusz LU ; Ruscher, Karsten LU and Deierborg, Tomas LU orcid (2026) In Neuroprotection 4(1). p.65-79
Abstract

Background: Environmental enrichment (EE) has been widely reported to improve functional recovery after stroke, yet its effects on chronic inflammation and white matter pathology remain less well defined. The aim of this study was to investigate whether poststroke EE modulates chronic neuroinflammation and white matter pathology and how these changes relate to functional recovery. Methods: Here, we investigated how EE influences the microglial response and myelin integrity during the recovery phase after photothrombotic stroke in male C57Bl/6J mice. Mice were randomized by using a computer-generated sequence into standard environment (SE) or EE housing conditions 2 days poststroke (SE: n = 6; EE: n = 7 for histological analyses;... (More)

Background: Environmental enrichment (EE) has been widely reported to improve functional recovery after stroke, yet its effects on chronic inflammation and white matter pathology remain less well defined. The aim of this study was to investigate whether poststroke EE modulates chronic neuroinflammation and white matter pathology and how these changes relate to functional recovery. Methods: Here, we investigated how EE influences the microglial response and myelin integrity during the recovery phase after photothrombotic stroke in male C57Bl/6J mice. Mice were randomized by using a computer-generated sequence into standard environment (SE) or EE housing conditions 2 days poststroke (SE: n = 6; EE: n = 7 for histological analyses; behavioral data unavailable for 2 SE mice). Sensorimotor performance was assessed at 7, 14, and 21 days poststroke using paw placement, foot fault, and limb symmetry tests, integrated into a composite Neuroscore. Housing in EE improved and sustained behavioral recovery up to 21 days. To explore whether specific microglial subpopulations are involved in tissue reorganization and functional outcome, immunofluorescence was performed for ionized calcium binding adaptor molecule 1 (Iba1), galectin-3 (Gal3), purinergic receptor P2Y12 (P2RY12), cluster of differentiation 68 (CD68), and triggering receptor expressed on myeloid cells 2 (TREM2), together with Black Gold myelin staining, in peri-infarct and white matter regions. Statistical analyses included correlation analyses and analysis of covariance (ANCOVA). Results: In SE mice, the inflammatory microglial marker Gal3 and the phagocytic marker CD68 correlated positively with infarct size (r = 0.937, p = 0.006; r = 0.845, p = 0.034, respectively), and the accumulation of myelin debris (r = 0.865, p = 0.026) together with loss of myelin coverage (r = −0.907, p = 0.013) followed lesion-driven trajectories. By contrast, these correlations were absent in EE mice (r = −0.028, p = 0.953; r = 0.671, p= 0.099; r = 0.053, p = 0.910; r = 0.292, p = 0.525) indicating that enrichment attenuated lesion-driven inflammatory responses and myelin damage. Importantly, Gal3 expression correlated specifically with peri-infarct myelin debris (r = 0.82, p = 0.048), reinforcing its role as a pro-inflammatory mediator. Finally, correlation analysis between Neuroscore and both microglial and myelin markers revealed a unique positive association between TREM2 coverage in white matter and improved Neuroscore in EE mice (r = 0.890, p = 0.007; ANCOVA p = 0.039). Conclusion: These results support the idea that EE modulates processes of chronic post-stroke inflammation, peri-infarct myelin debris clearance and demyelination, and highlight white matter TREM2-positive microglia as a potential cellular link to functional recovery.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
environmental enrichment, galectin-3, neuroinflammation, stroke recovery, white matter
in
Neuroprotection
volume
4
issue
1
pages
15 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105031155603
ISSN
2770-7296
DOI
10.1002/nep3.70028
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2026 The Author(s). Neuroprotection published by John Wiley & Sons Ltd on behalf of Chinese Medical Association.
id
b198c4b5-5a3b-4e2c-be60-0c4568b6e479
date added to LUP
2026-04-09 13:59:44
date last changed
2026-04-09 13:59:58
@article{b198c4b5-5a3b-4e2c-be60-0c4568b6e479,
  abstract     = {{<p>Background: Environmental enrichment (EE) has been widely reported to improve functional recovery after stroke, yet its effects on chronic inflammation and white matter pathology remain less well defined. The aim of this study was to investigate whether poststroke EE modulates chronic neuroinflammation and white matter pathology and how these changes relate to functional recovery. Methods: Here, we investigated how EE influences the microglial response and myelin integrity during the recovery phase after photothrombotic stroke in male C57Bl/6J mice. Mice were randomized by using a computer-generated sequence into standard environment (SE) or EE housing conditions 2 days poststroke (SE: n = 6; EE: n = 7 for histological analyses; behavioral data unavailable for 2 SE mice). Sensorimotor performance was assessed at 7, 14, and 21 days poststroke using paw placement, foot fault, and limb symmetry tests, integrated into a composite Neuroscore. Housing in EE improved and sustained behavioral recovery up to 21 days. To explore whether specific microglial subpopulations are involved in tissue reorganization and functional outcome, immunofluorescence was performed for ionized calcium binding adaptor molecule 1 (Iba1), galectin-3 (Gal3), purinergic receptor P2Y12 (P2RY12), cluster of differentiation 68 (CD68), and triggering receptor expressed on myeloid cells 2 (TREM2), together with Black Gold myelin staining, in peri-infarct and white matter regions. Statistical analyses included correlation analyses and analysis of covariance (ANCOVA). Results: In SE mice, the inflammatory microglial marker Gal3 and the phagocytic marker CD68 correlated positively with infarct size (r = 0.937, p = 0.006; r = 0.845, p = 0.034, respectively), and the accumulation of myelin debris (r = 0.865, p = 0.026) together with loss of myelin coverage (r = −0.907, p = 0.013) followed lesion-driven trajectories. By contrast, these correlations were absent in EE mice (r = −0.028, p = 0.953; r = 0.671, p= 0.099; r = 0.053, p = 0.910; r = 0.292, p = 0.525) indicating that enrichment attenuated lesion-driven inflammatory responses and myelin damage. Importantly, Gal3 expression correlated specifically with peri-infarct myelin debris (r = 0.82, p = 0.048), reinforcing its role as a pro-inflammatory mediator. Finally, correlation analysis between Neuroscore and both microglial and myelin markers revealed a unique positive association between TREM2 coverage in white matter and improved Neuroscore in EE mice (r = 0.890, p = 0.007; ANCOVA p = 0.039). Conclusion: These results support the idea that EE modulates processes of chronic post-stroke inflammation, peri-infarct myelin debris clearance and demyelination, and highlight white matter TREM2-positive microglia as a potential cellular link to functional recovery.</p>}},
  author       = {{Camprubí-Ferrer, Lluís and Kolbay, Ömer K. and Quattromani, Miriana J. and Wieloch, Tadeusz and Ruscher, Karsten and Deierborg, Tomas}},
  issn         = {{2770-7296}},
  keywords     = {{environmental enrichment; galectin-3; neuroinflammation; stroke recovery; white matter}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{65--79}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Neuroprotection}},
  title        = {{Environmental enrichment modulates chronic poststroke inflammation and links white matter TREM2-positive microglia in recovery in mice}},
  url          = {{http://dx.doi.org/10.1002/nep3.70028}},
  doi          = {{10.1002/nep3.70028}},
  volume       = {{4}},
  year         = {{2026}},
}