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Prolonged microgliosis in the rhesus monkey central nervous system after traumatic brain injury
Kumi Nagamoto-Combs1, David W McNeal, Robert J Morecraft
1Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA.
Abstract:
Impaired fine motor functions after traumatic brain injury (TBI) in humans and non-human primates often continue to improve months after injury. To initiate a series of studies in the primate model designed to investigate possible involvement of microglia/macrophage in the long-term recovery processes, changes in these cells were studied in the rhesus monkey central nervous system at 1, 6, and 12 months after a combined unilateral lesion of the arm area of the primary motor cortex and arm area of the lateral premotor cortex. Immunohistological studies showed profound CD68 immunoreactivity in the lesion area and the contralateral lateral corticospinal tract in the spinal cord at all time points, demonstrating that microglia/macrophage remain reactive at the sites of injury and axonal degeneration/survival for at least 12 months. We also observed marked increases in brain-derived neurotrophic factor (BDNF) and its receptor subtypes, TrkB[gp145] and TrkB[TK-], around the cortical lesion site after 6-month survival. Similar increases were also observed in the spinal cord, although it was less apparent for TrkB[gp145]. Double-labeling revealed that a subpopulation of CD68-immunoreacitve microglia/macrophage co-expressed BDNF in the cortex and spinal cord, and also TrkB[gp145] or TrkB[TK-] in the spinal cord. In contrast, cytokine expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) at these time intervals was less prominent, suggesting that immediate inflammatory responses had subsided. These results demonstrate that microglia/macrophage undergo prolonged activation after TBI in the non-human primate brain and express BDNF and its receptors, suggesting their tropic/trophic roles in the long-term recovery processes.
Insights
Microglia/macrophages remain active for over 12 months after traumatic brain injury (TBI) in non-human primates. These cells express brain-derived neurotrophic factor (BDNF), suggesting a role in long-term motor function recovery after TBI.
Area of Science:
- Neuroscience
- Immunology
- Traumatic Brain Injury Research
Background:
- Fine motor function deficits following traumatic brain injury (TBI) can persist long-term.
- Microglia/macrophages are key immune cells in the central nervous system (CNS) and their role in TBI recovery is under investigation.
- Non-human primate models offer valuable insights into human TBI recovery due to physiological similarities.
Purpose of the Study:
- To investigate the prolonged activation of microglia/macrophages after TBI in a non-human primate model.
- To examine the expression of brain-derived neurotrophic factor (BDNF) and its receptors by these immune cells.
- To explore the potential role of microglia/macrophages in long-term motor recovery following TBI.
Main Methods:
- Rhesus monkeys with combined cortical lesions underwent immunohistological analysis at 1, 6, and 12 months post-injury.
- CD68 immunoreactivity was used to identify microglia/macrophage activation.
- Expression of BDNF, TrkB receptors, and inflammatory cytokines (TNF-α, IL-1β, IL-6) was assessed.
Main Results:
- Profound CD68 immunoreactivity persisted in lesion sites and corticospinal tracts for at least 12 months, indicating sustained microglia/macrophage activation.
- Marked increases in BDNF and its receptors (TrkB[gp145], TrkB[TK-]) were observed around the cortical lesion and in the spinal cord.
- A subpopulation of activated microglia/macrophages co-expressed BDNF and TrkB receptors, while pro-inflammatory cytokine levels were less prominent at later time points.
Conclusions:
- Microglia/macrophages exhibit prolonged activation for at least 12 months post-TBI in non-human primates.
- Activated microglia/macrophages express BDNF and its receptors, suggesting a potential neurotrophic role in long-term recovery processes.
- These findings highlight the sustained involvement of the immune system in TBI recovery and suggest therapeutic targets.
