Soluble TNFa in the development of autonomic dysreflexia after spinal cord injury

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PROJECT SUMMARY Cardiovascular disease and susceptibility to infection are two leading causes of morbidity and mortality for individuals with spinal cord injury (SCI). One of the major contributors to SCI-associated cardiovascular disease and immune deficiency is the syndrome autonomic dysreflexia (AD), an amplified reaction of the autonomic nervous system in response to sensory stimuli below the injury that manifests in 70%-90% of people who have sustained a high SCI. AD is hallmarked by extreme, sudden bouts of hypertension and reflexive bradycardia (i.e. heart rate decrease). Over time, AD events become more severe. These chronic, frequent episodes of hypertension are thought to lead to peripheral vascular dysfunction and immune suppression that contribute to cardiovascular disease and susceptibility to infection, respectively. Merely limiting AD intensity may have significant therapeutic value and improve SCI patients' overall health. The gradual exacerbation of AD is thought to be driven by plasticity of circuits below the lesion that results in an exaggerated spinal sympathetic reflex. Unfortunately, the mechanisms that trigger this maladaptive plasticity are still poorly understood, limiting the development of prophylactic treatments. Interestingly, an activated neuroimmune system is thought to be an underlying factor in aberrant plasticity and hyperexcitable circuits correlated with other pathologies. The pro-inflammatory, soluble form of the cytokine tumor necrosis factor α (sTNFα) has been implicated in initiating inflammation in many contexts. Furthermore, sTNFα is associated with various forms of plasticity that could increase neuronal excitability. We hypothesize that sTNFα in spinal cord below a SCI plays a crucial role in triggering aberrant plasticity that leads to hyperactivity of the spinal sympathetic circuit after SCI and the secondary, intensification phase of AD. Moreover, this proposal will focus on the hypothesis that sTNFa/TNFR1 signaling in neurons involved in the circuit is central to the exacerbation. We will test our hypotheses using an established adult rodent spinal cord thoracic level 3 transection model that reliably results in AD. The overall goals of this multi-PI proposal are to: 1) further interrogate the therapeutic potential of inhibiting sTNFα to reduce AD (Aim 1); 2) investigate the mechanisms underlying how neuronal sTNFα/TNFR1 mediates AD (Aims 2 and 3).