http://www.loc.gov/mods/v3 http://www.loc.gov/standards/mods/v3/mods-3-2.xsd
role of tumor necrosis factor-alpha in maladaptive spinal plasticity
Previous work has shown that the spinal cord is capable of supporting a simple form of instrumental learning. Subjects that receive controllable shock to an extended hind limb will increase the duration of limb flexion over time in order to reduce net shock exposure. Exposure to as little as 6 minutes of uncontrollable stimulation prior to instrumental testing can elicit a long-lasting learning deficit. Prior work has suggested that this deficit may reflect an overexcitation of spinal neurons akin to central sensitization, and that learning is inhibited by the saturation of plasticity. The experiments in this dissertation were designed to test the role of the cytokine tumor necrosis factor alpha (TNF[alpha]) in the induction and expression of the deficit. It is believed that the inflammatory properties of TNF[alpha] may mediate the excitatory processes that lead to maladaptive spinal functioning. Experiments 1 and 2 tested the necessity of endogenous TNF[alpha] in the deficit produced by uncontrollable shock. These experiments showed that the inhibition of endogenous TNF[alpha] blocks both the induction and expression of the shock-induced deficit, suggesting a necessary role for TNF[alpha] in mediating the inhibition of spinal learning. Conversely, Experiment 3 was designed to test the sufficiency for TNF[alpha] in producing a learning deficit. I found that treatment with exogenous TNF[alpha] undermined spinal learning in a dose-dependent fashion, whether given immediately, or 24 hours prior to testing. Experiment 4 demonstrated that the long-term TNF[alpha]-induced deficit is mediated by TNF[alpha] receptor activity, as a TNF inhibitor given prior to testing blocked the expression of this deficit. As TNF[alpha] has been shown to be predominantly of glial origin, I next assessed the role that glia play in the TNFa-induced deficit. Experiment 5 showed that inhibiting glial metabolism prior to TNFa treatment blocked the capacity for TNFa to produce a long-term deficit. Experiment 6 assessed the potential for TNF[alpha] inhibition to block the deficit induced by lipopolysaccharide (LPS), an agent known to induce TNF[alpha]. TNF[alpha] has also been shown to drive neural excitation by increasing the trafficking of calciumpermeable AMPA receptors to the active zone of the post-synaptic bouton. Experiment 7 showed that selectively antagonizing these receptors prior to testing blocked the TNF[alpha]- induced deficit, suggesting a possible post-synaptic mechanism by which TNF[alpha] exerts its effects. Finally, histological evidence was sought to reinforce the previous behavioral findings. Experiment 8 used quantitative RT-PCR to assess the differential expression of TNF[alpha] mRNA in uncontrollably shocked subjects as compared to those receiving controllable shock and no shock. To determine concentrations of TNF[alpha] protein, an ELISA was run in Experiment 9 comparing uncontrollably shocked subjects to unshocked controls.
Doctor of Philosophy Texas A&M University 2010 http://hdl.handle.net/1969.1/ETD-TAMU-2010-12-8594