Acute or delayed treatment with anatabine improves spatial memory and reduces pathological sequelae at late time-points after repetitive mild traumatic brain injury

Traumatic brain injury (TBI) has chronic and long-term consequences for which there are currently no approved pharmacological treatments. We have previously characterized the chronic neurobehavioral and pathological sequelae of a mouse model of repetitive mild TBI (r-mTBI) through to 2 years post-TBI. Despite the mild nature of the initial insult, secondary injury processes are initiated that involve neuroinflammatory and neurodegenerative pathways persisting and progressing for weeks and months post-injury and providing a potential window of opportunity for therapeutic intervention. In this study we examined the efficacy of a novel anti-inflammatory compound, anatabine, in modifying outcome after TBI. Our model of r-mTBI involves a series of five mild impacts (midline impact at 5 m/sec, 1 mm strike depth, 200 msec dwell time) with an interval of 48 h. Anatabine treatment was administered starting 30 min after injury and was delivered continuously through drinking water. At 6 months after TBI, anatabine treatment improved spatial memory in injured mice. Nine months after TBI, a cohort of mice was euthanized for pathological analysis that revealed reductions in astroglial (glial fibrillary acid protein, GFAP) and microglial (ionized calcium-binding adapter molecule 1, IBA1) responses in treated, injured animals. Treatments for the remaining mice were then crossed-over to assess the effects of late treatment administration and the effects of treatment termination. Nine months following crossover the remaining mice showed no effect of injury on their spatial memory, and whereas pathological analysis showed improvements in mice that had received delayed treatment, corpus callosum IBA1 increased in post-crossover placebo r-mTBI mice. These data demonstrate efficacy of both early and late initiation of treatment with anatabine in improving long term behavioral and pathology outcomes after mild TBI. Future studies will characterize the treatment window, the time course of treatment needed, and the dose needed to achieve therapeutic levels of anatabine in humans after injury

Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury

Traumatic brain injury (TBI) has chronic and long-term consequences for which there are currently no approved pharmacological treatments. We have previously characterized the chronic neurobehavioral and pathological sequelae of a mouse model of repetitive mild TBI (r-mTBI) through to 2 years post-TBI. Despite the mild nature of the initial insult, secondary injury processes are initiated that involve neuroinflammatory and neurodegenerative pathways persisting and progressing for weeks and months post-injury and providing a potential window of opportunity for therapeutic intervention. In this study we examined the efficacy of a novel anti-inflammatory compound, anatabine, in modifying outcome after TBI. Our model of r-mTBI involves a series of five mild impacts (midline impact at 5 m/sec, 1 mm strike depth, 200 msec dwell time) with an interval of 48 h. Anatabine treatment was administered starting 30 min after injury and was delivered continuously through drinking water. At 6 months after TBI, anatabine treatment improved spatial memory in injured mice. Nine months after TBI, a cohort of mice was euthanized for pathological analysis that revealed reductions in astroglial (glial fibrillary acid protein, GFAP) and microglial (ionized calcium-binding adapter molecule 1, IBA1) responses in treated, injured animals. Treatments for the remaining mice were then crossed-over to assess the effects of late treatment administration and the effects of treatment termination. Nine months following crossover the remaining mice showed no effect of injury on their spatial memory, and whereas pathological analysis showed improvements in mice that had received delayed treatment, corpus callosum IBA1 increased in post-crossover placebo r-mTBI mice. These data demonstrate efficacy of both early and late initiation of treatment with anatabine in improving long term behavioral and pathology outcomes after mild TBI. Future studies will characterize the treatment window, the time course of treatment needed, and the dose needed to achieve therapeutic levels of anatabine in humans after injury

VISUAL DYSFUNCTION SCREENING ON rmTBI MOUSE MODELS USING AN OPTOMOTOR ASSESSMENT

(Statement of Responsibility) by Destinee Aponte(Thesis) Thesis (B.A.) -- New College of Florida, 2016RESTRICTED TO NCF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USEOnline version not currently available.(Bibliography) Includes bibliographical references.This bibliographic record is available under the Creative Commons CC0 public domain dedication. The New College of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.Faculty Sponsor: Bauer, Gordo

Distinct nonlinear spectrotemporal integration in primary and secondary auditory cortices

Abstract Animals sense sounds through hierarchical neural pathways that ultimately reach higher-order cortices to extract complex acoustic features, such as vocalizations. Elucidating how spectrotemporal integration varies along the hierarchy from primary to higher-order auditory cortices is a crucial step in understanding this elaborate sensory computation. Here we used two-photon calcium imaging and two-tone stimuli with various frequency-timing combinations to compare spectrotemporal integration between primary (A1) and secondary (A2) auditory cortices in mice. Individual neurons showed mixed supralinear and sublinear integration in a frequency-timing combination-specific manner, and we found unique integration patterns in these two areas. Temporally asymmetric spectrotemporal integration in A1 neurons suggested their roles in discriminating frequency-modulated sweep directions. In contrast, temporally symmetric and coincidence-preferring integration in A2 neurons made them ideal spectral integrators of concurrent multifrequency sounds. Moreover, the ensemble neural activity in A2 was sensitive to two-tone timings, and coincident two-tones evoked distinct ensemble activity patterns from the linear sum of component tones. Together, these results demonstrate distinct roles of A1 and A2 in encoding complex acoustic features, potentially suggesting parallel rather than sequential information extraction between these regions