Browsing by Subject "locomotor activity"
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Item Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice(Frontiers Media S.A., 2020-12-15) Joshi, Chaitanya R.; Stacy, Satomi; Sumien, Nathalie; Ghorpade, Anuja; Borgmann, KathleenDespite effective antiretroviral therapy (ART), mild forms of HIV-associated neurocognitive disorders (HAND) continue to afflict approximately half of all people living with HIV (PLWH). As PLWH age, HIV-associated inflammation perturbs the balance between brain matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), likely contributing to neuropathogenesis. The MMP/TIMP balance is associated with cognition, learning, and memory, with TIMPs eliciting neuroprotective effects. Dysregulation of the MMP/TIMP balance was evident in the brains of PLWH where levels of TIMP-1, the inducible family member, were significantly lower than non-infected controls, and MMPs were elevated. Here, we evaluated the MMP/TIMP levels in the doxycycline (DOX)-induced glial fibrillary acidic protein promoter-driven HIV-1 transactivator of transcription (Tat) transgenic mouse model. The HIV-1 protein Tat is constitutively expressed by most infected cells, even during ART suppression of viral replication. Many studies have demonstrated indirect and direct mechanisms of short-term Tat-associated neurodegeneration, including gliosis, blood-brain barrier disruption, elevated inflammatory mediators and neurotoxicity. However, the effects of acute vs. prolonged exposure on Tat-induced dysregulation remain to be seen. This is especially relevant for TIMP-1 as expression was previously shown to be differentially regulated in human astrocytes during acute vs. chronic inflammation. In this context, acute Tat expression was induced with DOX intraperitoneal injections over 3 weeks, while DOX-containing diet was used to achieve long-term Tat expression over 6 months. First, a series of behavior tests evaluating arousal, ambulation, anxiety, and cognition was performed to examine impairments analogous to those observed in HAND. Next, gene expression of components of the MMP/TIMP axis and known HAND-relevant inflammatory mediators were assessed. Altered anxiety-like, motor and/or cognitive behaviors were observed in Tat-induced (iTat) mice. Gene expression of MMPs and TIMPs was altered depending on the duration of Tat expression, which was independent of the HIV-associated neuroinflammation typically implicated in MMP/TIMP regulation. Collectively, we infer that HIV-1 Tat-mediated dysregulation of MMP/TIMP axis and behavioral changes are dependent on duration of exposure. Further, prolonged Tat expression demonstrates a phenotype comparable to asymptomatic to mild HAND manifestation in patients.Item CHARACTERIZATION OF COCAINE-CONDITIONED LOCOMOTOR RESPONSES BY MODULATION OF ENVIRONMENTAL CONTEXT AND NEURAL PLASTICITY-SIGNALING PATHWAYS(2014-03) Nguyen, Jacques D.; Forster, Michael J.Rodent models are commonly used for the study of substance abuse and addiction. The objective of this study was to characterize the cocaine-conditioned locomotor response, a behavioral phenomenon observed in mice, following an acute injection of cocaine, and to determine its mechanism of action for potential therapeutic targeting. Compounds known to modulate neural plasticity were evaluated for their ability to affect the acquisition and expression of the conditioned behavior. Purpose (a): In rodents, increase in locomotion is a hallmark effect of psychostimulant exposure and conditioning that is associated with activation of mesocorticolimbic dopamine signals mediating reinforcing/rewarding actions. The objective of this study was to characterize the cocaine-conditioned locomotor response following an acute injection of cocaine, specifically the modulating roles of environmental context and plasticity-associated signals. Methods (b): Cocaine (40mg/kg) was administered to different groups of Swiss-Webster, C57Bl/6, or DBA2 mice via intraperitoneal injection (i.p.), in either a locomotor activity testing apparatus or the home cage, 2 hours following an activity test under saline. Mice placed in the testing chambers were given 30 minutes to explore freely and locomotion was monitored using a Digiscan photocell apparatus. A conditioned effect of cocaine was inferred by an increase in horizontal activity counts relative to home cage cocaine controls during a test in the same apparatus on the following day. Compounds known to modulate neural plasticity-associated signaling cascades were evaluated for their ability to affect the acquisition and expression of cocaine-conditioned locomotor response, using a two-day protocol. Mice were administered haloperidol (0.05-1 mg/kg), dizocilpine (0.01-0.25mg/kg), nifedipine (0.1-10 mg/kg), cycloheximide (2.5-10mg/kg), or vehicle, prior to placement into the activity chambers on the test day for expression or prior to acquisition day. Results (c): Haloperidol (0.25-1 mg/kg) inhibited expression of the cocaine-conditioned locomotion, though failed to alter acquisition of the behavioral response. Dizocilpine (0.05-0.25 mg/kg) attenuated acquisition and exacerbated expression. Nifedipine had no effect on the conditioned locomotor response. Cycloheximide (2.5-10 mg/kg) attenuated acquisition of the conditioned response. Conclusions (d): These findings suggest that plasticity-dependent signaling pathways mediate associations of context following acute cocaine exposure and are necessary for the acquisition and expression of the cocaine-conditioned locomotor response.