Regulation of newborn neuron survival and the inflammatory cell response after traumatic brain injury by Suppressor of Cytokine Signalling-2 (SOCS2)
AffiliationAnatomy and Neuroscience
MetadataShow full item record
Document TypePhD thesis
Access StatusOpen Access
© 2015 Dr. Harleen Singh Basrai
Every year, millions of people fall victim to traumatic brain injury (TBI) globally. Despite the large prevalence of this condition and continued research efforts, strategies for its treatment are lacking. The discovery of adult neurogenesis, a process by which new neurons are generated in the adult brain under normal physiological conditions, has opened doors for research into treatments whereby endogenous neural precursor cells (NPCs) may be encouraged to aid neuronal repair following TBI. The two neurogenic regions of the adult brain are the sub-granular zone (SGZ) of the dentate gyrus and the sub-ventricular zone (SVZ) of the lateral ventricles. The brain has been shown to have an inherent capacity to enhance endogenous neurogenesis in these regions in response to TBI. Further, SVZ-derived NPCs are able to migrate to ectopic cortical injury sites after experimental TBI. However, despite this potentially neuroregenerative response, the large majority of injury-induced newborn neurons do not survive to become mature functional cells. Further research is required to better understand the molecular mediators of neurogenesis in the adult brain, in order to harness its therapeutic capacity after TBI. Among the currently identified mediators of endogenous adult neurogenesis is the Suppressor of cytokine signalling-2 (SOCS2). SOCS2 overexpressing (SOCS2Tg) mice show an enhanced survival of newborn adult hippocampal neurons. Also, cultured cortical neurons overexpressing SOCS2 display enhanced neurite outgrowth. Therefore, this thesis aimed to further explore the role of SOCS2 in endogenous adult neurogenesis under both non-injury and injury conditions. In the SOCS2Tg mouse, SOCS2 is overexpressed in all cells of the body including all cells and regions of the brain. Therefore, the improved newborn adult hippocampal neuron survival observed in these mice may have been a function of an altered microenvironment rather than due to neuron-specific SOCS2 overexpression. In an adult WT mouse brain, SOCS2 is expressed at greatest levels in the hippocampal dentate gyrus and CA3 region. Therefore, in Chapter 3, to help establish whether or not there is a newborn hippocampal neuron-specific role for SOCS2, adult hippocampal neurogenesis was examined in SOCS2 null (SOCS2KO) mice, in which the dentate gyrus would likely be the most affected by SOCS2 loss. To examine immature neuron (neuroblast) generation and newborn neuron survival, SOCS2KO mice were administered EdU for 7d to label proliferative NPCs. At 8d newly generated neuroblasts were quantified following doublecortin and EdU co-labelling. At 35d matured newborn neurons were quantified following NeuN and EdU co-labelling. No significant differences were present in neuroblast generation at 8d between genotypes, however at 35d SOCS2KO mice had reduced numbers of mature newborn neurons. The previously defined role for SOCS2 in regulating neurite outgrowth was hypothesised to be important in newborn adult hippocampal neuron development and therefore affected in SOCS2KO mice. No differences in newborn adult hippocampal neuron dendritic tree morphology were found between SOCS2KO and WT mice. However, SOCS2KO dendrites did have a higher density of mushroom morphology spines. This study highlighted a potential role for SOCS2 in regulating newborn adult hippocampal neuron maturation processes, which may be important for early newborn neuron integration required for survival. Given the enhanced newborn neuron survival previously established in SOCS2Tg mice under non-injury conditions, these mice were examined in this thesis for injury-induced SVZ-derived adult cortical neurogenesis. It was hypothesised that SOCS2Tg mice would have improved newborn neuron survival near the injured cortex. Adult SOCS2Tg mice were subjected to a mild (Chapter 4) or moderately-severe (Chapter 5) controlled cortical impact TBI and administered EdU for 7d after TBI to label proliferative cells. At 35d post-mild TBI, no EdU+NeuN+ newborn neurons were observed near the cortical lesion in SOCS2Tg and WT mice. However, SOCS2Tg mice displayed a greatly enhanced number of injury-induced EdU+CD11b+ macrophages/microglia compared to WT mice. Injury-induced astrogliosis, quantified from EdU+GFAP+ co-labelled cells, also displayed a similar pattern but with much smaller cell density. Injury-induced oligodendrogenesis, quantified from EdU+Olig2+ co-labelled cells, showed to genotype differences. Moderately-severe TBI mice were also administered erythropoietin (EPO) for 7d post-injury together with EdU to aid newborn neuron survival. At 35d after moderately-severe TBI, newborn neurons were observed near the cortical lesion but in similar numbers for both SOCS2Tg and WT mice, with or without EPO treatment. EdU+CD11b+ and EdU+GFAP+ cell density was not different between genotypes at 35d after moderately-severe TBI. The same was true for EdU+Olig2+ cells. Motor function testing revealed an improved motor function recovery in SOCS2Tg mice with or without EPO treatment, whereas WT mice showed improved motor function only after EPO treatment. Further, at 7d after moderately-severe TBI, the time point of peak motor function deficit for WT mice, SOCS2Tg mice had a smaller brain lesion area and an increased number of M2-like anti-inflammatory macrophages/microglia surrounding the lesion. This study suggested a novel role for SOCS2 in modulating neuroinflammatory processes, potentially by having an anti-inflammatory effect in a cortical brain injury environment. Overall, this thesis provides further evidence for the role of SOCS2 in regulating adult hippocampal neurogenesis and has also revealed a potential mechanism by which SOCS2 may support newborn neuron maturation. Further, this thesis presents a novel and potentially beneficial role for SOCS2 in regulating TBI-induced neuroinflammation. These findings have important implications in the search for the developing novel therapeutic strategies for the treatment of TBI and other neurodegenerative diseases.
Keywordsneurogenesis; traumatic brain injury; inflammation; Suppressor of Cytokine Signalling-2; SOCS
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