Neuropsychological deficits have been reported after spinal cord injury (SCI) without concurrent head injury; although most such studies reflect patient self-reports, more formal neuropsychological testing has demonstrated performance impairments with an associated high risk of dementia including deficits in learning and memory. On the other hand, patients with dementia, such as that resulting from Alzheimer?s disease (AD), could have higher risk of falls, and therefore increased risk of SCI. Little research has addressed potential mechanisms for such neuropsychiatric changes or their implications for targeted therapy. There is an urgent need for such studies, as posttraumatic dementia such as cognitive and psychiatric changes negatively impact rehabilitation and impair recovery. The purpose of this study is to identify the mechanisms responsible for these less well examined yet important consequences of SCI and test the hypothesis that SCI-triggered release of CCL21 in the brain contributes to spreading neuroinflammation with cognitive dysfunction and depressive-like behavior, which can be improved by targeting specific mechanisms of neuroinflammation. We will use transgenic mice and molecular interventions to delineate the role of CCL21 as a key regulator of brain microglial activation and related down-stream injury mechanisms in SCI.
Aim 1 will identify that SCI-induced CCL21 elevation mediates detrimental microglial activation in the brain through NOX2 activity. Multiple quantitative assessments of microglia activation will be combined with a molecular/genetic intervention targeting CCL21 to test the hypothesis that SCI-induced release of CCL21 in key regions of the brain contributes to detrimental microglial activation through NOX2 activity.
Aim 2 will demonstrate that genetic depletion or pharmacological inhibition of CCL21/NOX2 reduces detrimental microglial activation, resulting in improved cognitive decline and depressive-like behavior. Complimentary pharmacological, molecular, and genetic approaches will be used to test the hypothesis that brain CCL21/NOX2-mediated inflammation after SCI causes chronic neurodegeneration associated with cognitive decline and depressive-like behavior.
Aim 3 will determine that genetic or pharmacological microglial ablation after SCI reduces brain neuroinflammation leading to improved functional recovery. Using genetic or pharmacological microglia-deletion, we will examine the role of resident microglia in SCI-mediated neuroinflammation in the brain and functional outcomes. The information gained from these studies would have an important positive impact by identifying the key mechanisms involved in important yet largely ignored brain changes after SCI and identifying potential therapeutic interventions.
Spinal cord injury (SCI) causes dementia such as cognitive decline and depression; all of these changes appear to be linked to extensive microglia activation in the brain associated with chronic neurodegeneration. The aim of our research is to understand the mechanisms responsible for microglia activation-induced inflammation in key brain centers after SCI in order to allow future development of novel therapies. In particular, we will target SCI-triggered release of CCL21/NOX2 in key brain regions, in order to decrease damage and increase functional recovery after SCI.
