Browsing by Subject "instrumental learning"
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Item Neuropathic pain and the inhibition of learning within the spinal cord(Texas A&M University, 2004-09-30) Ferguson, Adam RichardPrior work from our laboratory has shown that the spinal cord is capable of supporting a simple form of instrumental (response-outcome) learning. In a typical experiment, animals are given a spinal transection at the second thoracic vertebra, and tested 24 h after surgery. If animals are given shock when their leg is in a resting position (controllable shock), they quickly learn to maintain the leg in a flexed position, thereby minimizing shock exposure. Animals exposed to shock that is independent of leg position (uncontrollable shock) fail to learn. This learning deficit can be induced by as little as 6 minutes of shock to either limb or to the tail, and lasts for up to 48 h. The aim of this dissertation was to explore whether the deficit shares behavioral features and pharmacological mechanisms similar to those involved in the induction of neuropathic pain. Work within the pain literature has identified a spinal hyperexcitability that is induced by intense stimulation of pain fibers. This phenomenon, known as central sensitization, is characterized by an increase in tactile reactivity (allodynia) that can be induced by shock or peripheral inflammation. Pharmacological findings have revealed that central sensitization depends on the activation of the N-methyl-D-aspartate (NMDA) and group I metabotropic glutamate receptors (mGluRs). Experiment 1 showed that uncontrollable shock induces a tactile allodynia similar to that observed in central sensitization. Experiment 2 showed that peripheral inflammation caused by a subcutaneous injection of formalin generates a dose-dependent deficit. Experiment 3 indicated that the formalin-induced deficit was observed 24 h after delivery of the stimulus. Experiments 4-8 revealed that the NMDA and group I mGluRs are involved in the deficit. The NMDA receptor was found to be necessary (Experiment 4), but only sufficient to induce a deficit at neurotoxic doses (Experiment 5). Both of the group I mGluRs (subtypes, mGluR1 and mGluR5) were found to be necessary (Experiments 6 & 7). A general group I mGluR agonist summated with a subthreshold intensity of shock to produce a robust deficit (Experiment 8), suggesting shock and mGluR activation produce a deficit through a common mechanism.Item The Role of Tumor Necrosis Factor-Alpha in Maladaptive Spinal Plasticity(2012-02-14) Huie, John RussellPrevious 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 (TNFa) in the induction and expression of the deficit. It is believed that the inflammatory properties of TNFa may mediate the excitatory processes that lead to maladaptive spinal functioning. Experiments 1 and 2 tested the necessity of endogenous TNFa in the deficit produced by uncontrollable shock. These experiments showed that the inhibition of endogenous TNFa blocks both the induction and expression of the shock-induced deficit, suggesting a necessary role for TNFa in mediating the inhibition of spinal learning. Conversely, Experiment 3 was designed to test the sufficiency for TNFa in producing a learning deficit. I found that treatment with exogenous TNFa undermined spinal learning in a dose-dependent fashion, whether given immediately, or 24 hours prior to testing. Experiment 4 demonstrated that the long-term TNFa-induced deficit is mediated by TNFa receptor activity, as a TNF inhibitor given prior to testing blocked the expression of this deficit. As TNFa 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 TNFa inhibition to block the deficit induced by lipopolysaccharide (LPS), an agent known to induce TNFa. TNFa 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 TNFa- induced deficit, suggesting a possible post-synaptic mechanism by which TNFa 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 TNFa mRNA in uncontrollably shocked subjects as compared to those receiving controllable shock and no shock. To determine concentrations of TNFa protein, an ELISA was run in Experiment 9 comparing uncontrollably shocked subjects to unshocked controls.