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Browsing by Author "Oxford, Gerry"
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Item Development, validation, and characterization of a novel preclinical animal model of social familiarity-induced anxiolysis(2017-09-29) Lungwitz, Elizabeth Ann; Shekhar, Anantha; Truitt, William; Oxford, Gerry; Rodd, Zachary; Lapish, ChristopherSocial support is a powerful therapeutic against fear and anxiety and is utilized in many psychotherapies. The concept that a familiar or friendly presence helps a person learn to overcome anxiety has been well-known for decades, yet, the basic neural mechanisms that regulate this psychosocial learning remain unknown. A first step towards elucidating these basic mechanisms is the development of a valid preclinical animal model. However, preclinical behavioral models exploring the use of a social presence in reducing anxiety have not been fully characterized. Therefore, it was our goal to identify a useful way in which to study the mechanisms of how a social presence can induce anxiolysis (the reduction of anxiety). We accomplished this goal by characterizing and validating a preclinical model, as well as demonstrating that the model was capable of measuring deficits in rats given a mild traumatic brain injury. To this end, we identified an existing, but uncharacterized model, the social interaction-habituation model, as an effective model of social familiarity-induced anxiolysis (SoFiA), which demonstrates socially enhanced safety learning, or psychosocial learning. We find that as social familiarity develops across time, anxiolysis develops. We identified that the use of a Bright Light Challenge is a useful anxiogenic stimulus to use during SI-habituation training. The anxiolysis acquired following SI-habituation testing is partner specific, and can be blocked by an inhibition of the medical prefrontal cortex, while it can be enhanced by D-cycloserine. We found that this model identified deficits in SoFiA acquisition in rodents exposed to a mild traumatic brain injury, which, in humans, has been linked to psychosocial deficits. This work is a step in creating ways in which we can study and better understand the regulatory processes of emotions mediated by social behavior.Item The role of Protein Kinase C in the modulation of neuronal sensitivity and neurite morphology following treatment with paclitaxel in cultured sensory neurons(2017-07-13) Darby, Lisa Monique; Fehrenbacher, Jill; Cummins, Theodore; Jerde, Travis; Obukhov, Alexander; Oxford, GerryPaclitaxel is a chemotherapeutic drug that is used in the treatment of solid tumors including breast and ovarian cancer. However, a debilitating and severe side effect associated with paclitaxel treatment is peripheral neuropathy. Clinically, peripheral neuropathy is characterized by a gain and loss of sensory neuronal function with symptoms including burning pain, tingling and numbness, respectively. In addition, paclitaxel also elicits a reduction in the length of intraepidermal nerve fibers. Currently, there are no effective therapies to prevent or alleviate the symptoms of peripheral neuropathy. Further studies are needed to elucidate the mechanisms underlying the changes in neuronal function and neurite morphology induced by paclitaxel in order to develop therapeutics to address the symptoms of peripheral neuropathy. Our laboratory previously demonstrated that paclitaxel altered capsaicin stimulated release of calcitonin gene-related peptide (CGRP) from cultured sensory neurons, indicating that paclitaxel altered the function of the transient receptor potential vanilloid I (TRPV1) channels. Because protein kinase C (PKC) modulates the function of TRPV1, we questioned whether PKC mediated changes in neuronal sensitivity induced by chronic treatment with paclitaxel. We used the release of CGRP as an index of neuronal sensitivity. Our data show that paclitaxel decreased the activity and membrane localization of the conventional PKC isozymes, PKCα and PKCβI/II, to elicit a reduction in the release of CGRP from cultured sensory neurons. For our neurite morphology studies, we focused on the importance of the novel PKC isozyme, PKCε, in mediating the changes in neurite morphology induced by treatment with paclitaxel because studies have demonstrated that PKCε is important for enhancing neurite outgrowth. Since our preliminary data showed a correlative reduction in PKCε protein expression and neurite length and branching following treatment with paclitaxel, we questioned whether loss of PKCε mediated altered neurite morphology induced by paclitaxel. Unexpectedly, we found that downregulation of PKCε did not exacerbate the reduction in neurite length and branching induced by paclitaxel. Our work highlights the significance of PKCα and PKCβI/II as critical mediators of changes in neuronal sensitivity induced by paclitaxel and illuminates our understanding of the mechanisms underlying the neurotoxic effects of paclitaxel on sensory neuronal function.