Docosahexaenoic acid reduces microglia phagocytic activity via miR-124 and induces neuroprotection in rodent models of spinal cord contusion injury

Microglia are activated after spinal cord injury (SCI), but their phagocytic mechanisms and link to neuroprotection remain incompletely characterized. Docosahexaenoic acid (DHA) has been shown to have significant neuroprotective effects after hemisection and compression SCI and can directly affect microglia in these injury models. In rodent contusion SCI, we demonstrate that DHA (500 nmol/kg) administered acutely post-injury confers neuroprotection and enhances locomotor recovery, and also exerts a complex modulation of the microglial response to injury. In rodents, at 7 days after SCI, the level of phagocytosed myelin within Iba1-positive or P2Y12-positive cells was significantly lower after DHA treatment, and this occurred in parallel with an increase in intracellular miR-124 expression. Furthermore, intraspinal administration of a miR-124 inhibitor significantly reduced the DHA-induced decrease in myelin phagocytosis in mice at 7 days post-SCI. In rat spinal primary microglia cultures, DHA reduced the phagocytic response to myelin, which was associated with an increase in miR-124, but not miR-155. A similar response was observed in a microglia cell line (BV2) treated with DHA, and the effect was blocked by a miR-124 inhibitor. Furthermore, the phagocytic response of BV2 cells to stressed neurones was also reduced in the presence of DHA. In peripheral monocyte-derived macrophages, the expression of the M1, but not the M0 or M2 phenotype, was reduced by DHA, but the phagocytic activation was not altered. These findings show that DHA induces neuroprotection in contusion injury. Furthermore, the improved outcome is via a miR-124-dependent reduction in the phagocytic response of microglia.US Department of Defence CDMRP/SCIRP award (W81XWH-10-1-1040 to P.K.Y., T.B. and A.M.T.); The Barts and London Charity (to P.K.Y. and A.M.T.); Rod Flower Vacation Scholarship (to A.L.B.); International Spinal Research Trust (to J.H. and P.G.P.); Ray W. Poppleton Endowment (to P.G.P.); Chang Gung Memorial Hospital, Taiwan (CMRPG3A1051–1054 to Z.-H.L.). M.A.B. is funded by the Spanish Ministry of Economy and Competitivity (Programa Ramón y Cajal: RYC-2017-21804)

Studies on long term behavioural changes in group-housed rat models of brain and spinal cord injury using an automated home cage recording system.

BACKGROUND: Neurotrauma patients face major neurological sequelae. The failure in the preclinical-to-clinical translation of candidate therapies could be due to poor evaluation of rodent behaviours after neurotrauma. NEW METHOD: A home cage automated system was used to study the long term behaviour of individual rats with traumatic brain injury (TBI), spinal cord injury (SCI) and non-CNS injured controls, whilst group-housed in their home cages. Naïve rats were used as baseline controls. Automated locomotor activity and body temperature recordings were carried out 24 h /day for 3 days/week during 12 weeks post-injury. Behavioural patterns, including aggression, rearing, grooming, feeding and drinking were analysed from automated video recordings during week 1, 6 and 12. RESULTS: SCI animals showed a lower locomotor activity compared to TBI or control animals during light and dark phases. TBI animals showed a higher aggression during the dark phase in the first week post-injury compared to SCI or control animals. Individual grooming and rearing were reduced in SCI animals compared to TBI and control animals in the first week post-injury during the dark phase. No differences in drinking or feeding were detected between groups. Locomotor activity did not differ between naïve male and female rats, but body temperature differ between light and dark phases for both. STANDARD METHODS: Injury severity was compared to standard SCI and TBI behaviour scores (BBB and mNSS, respectively) and histological analysis. CONCLUSIONS: This study demonstrates the practical benefits of using a non-intrusive automated home cage recording system to observe long term individual behaviour of group-housed SCI and TBI rats