Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Objective: Exposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long-term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of mTBI in these models. This study provides the first account of lifelong neurobehavioral and histological consequences of repetitive mTBI providing unique insight into the constellation of evolving and ongoing pathologies with late survival. Methods: Male C57BL/6J mice (aged 2–3 months) were exposed to either single or repetitive mild TBI or sham procedure. Thereafter, animals were monitored and assessed at 24 months post last injury for measures of motor coordination, learning deficits, cognitive function, and anxiety-like behavior prior to euthanasia and preparation of the brains for detailed neuropathological and protein biochemical studies. Results: At 24 months survival animals exposed to r-mTBI showed clear evidence of learning and working memory impairment with a lack of spatial memory and vestibule-motor vestibulomotor deficits compared to sham animals. Associated with these late behavioral deficits there was evidence of ongoing axonal degeneration and neuroinflammation in subcortical white matter tracts. Notably, these changes were also observed after a single mTBI, albeit to a lesser degree than repetitive mTBI. Interpretation: In this context, our current data demonstrate, for the first time, that rather than an acute, time limited event, mild TBI can precipitate a lifelong degenerative process. These data therefore suggest that successful treatment strategies should consider both the acute and chronic nature of mTBI

Negative impact of female sex on outcomes from repetitive mild traumatic brain injury in hTau mice is age dependent: a Chronic Effects of Neurotrauma Consortium study

Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI. This study examined the neurobehavioral and neuropathological effects of age and sex on the outcome 15 days following repetitive mild traumatic brain injury (r-mTBI) in mice transgenic for human tau (hTau). These mice express the six human isoforms of tau but do not express endogenous murine tau and they develop tau pathology and memory impairment in an age-dependent manner. After 5 mild impacts, aged female mice showed motor impairments that were absent in aged male mice, as well as younger animals. Conversely, aged female sham mice outperformed all other groups of aged mice in a Barnes maze spatial memory test. Pathologically, increases in IBA-1 and GFAP staining typically seen in this model of r-mTBI showed the expected increases with both injury and age, but phosphorylated tau stained with CP13 in the hippocampus (reduced in female sham mice compared to males) and PHF1 in the cortex (reduced in female TBI mice compared to male TBI mice) showed the only histological signs of sex-dependent differences in these mice

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

Ultrastructural Changes in the White and Gray Matter of Mice at Chronic Time Points After Repeated Concussive Head Injury

Mild traumatic brain injury is a risk factor for neurodegenerative disease. We recently developed a model of repetitive concussive injury in mice that we have extensively characterized from 24 hours to 24 months after injury. Animals show evidence of progressive spatial memory deficits, thinning of the corpus callosum, axonal injury, and neuroglial activation. Here, we extended our neuropathologic characterization to the ultrastructural level in both a qualitative and a quantitative study. We focused on chronic (3 and 6 months) postinjury time points when the earliest stages of degenerative secondary changes were previously observed. In both C57BL/6 and hTau mice, we found white matter damage typified by axonal degeneration, microglial phagocytosis, and increased neuroglial cell density. In the cerebral cortex, we observed evidence of synaptic degeneration, dark neurons, altered dendritic microfilaments, subtle changes to the microvasculature, a mild augmentation of age-related features such as lipofuscin deposition, and electron-dense inclusions in microglial and perivascular cells. The majority of these ultrastructural features seemed to be more prominent at 3 versus 6 months after injury. Similar patterns were observed in C57BL/6 and hTau mice. These findings further support the relevance of our concussive injury model to the consequences of repetitive mild traumatic brain injury in humans

Negative Impact of Female Sex on Outcomes from Repetitive Mild Traumatic Brain Injury in hTau Mice Is Age Dependent: A Chronic Effects of Neurotrauma Consortium Study

Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI. This study examined the neurobehavioral and neuropathological effects of age and sex on the outcome 15 days following repetitive mild traumatic brain injury (r-mTBI) in mice transgenic for human tau (hTau). These mice express the six human isoforms of tau but do not express endogenous murine tau and they develop tau pathology and memory impairment in an age-dependent manner. After 5 mild impacts, aged female mice showed motor impairments that were absent in aged male mice, as well as younger animals. Conversely, aged female sham mice outperformed all other groups of aged mice in a Barnes maze spatial memory test. Pathologically, increases in IBA-1 and GFAP staining typically seen in this model of r-mTBI showed the expected increases with both injury and age, but phosphorylated tau stained with CP13 in the hippocampus (reduced in female sham mice compared to males) and PHF1 in the cortex (reduced in female TBI mice compared to male TBI mice) showed the only histological signs of sex-dependent differences in these mice

Chronic Hippocampal Abnormalities and Blunted HPA Axis in an Animal Model of Repeated Unpredictable Stress

Incidence of post-traumatic stress disorder (PTSD) ranges from 3 to 30% in individuals exposed to traumatic events, with the highest prevalence in groups exposed to combat, torture, or rape. To date, only a few FDA approved drugs are available to treat PTSD, which only offer symptomatic relief and variable efficacy. There is, therefore, an urgent need to explore new concepts regarding the biological responses causing PTSD. Animal models are an appropriate platform for conducting such studies. Herein, we examined the chronic behavioral and neurobiological effects of repeated unpredictable stress (RUS) in a mouse model. 12 weeks-old C57BL/6J male mice were exposed to a 21-day RUS paradigm consisting of exposures to a predator odor (TMT) whilst under restraint, unstable social housing, inescapable footshocks and social isolation. Validity of the model was assessed by comprehensive examination of behavioral outcomes at an acute timepoint, 3 and 6 months post-RUS; and molecular profiling was also conducted on brain and plasma samples at the acute and 6 months timepoints. Stressed mice demonstrated recall of traumatic memories, passive stress coping behavior, acute anxiety, and weight gain deficits when compared to control mice. Immunoblotting of amygdala lysates showed a dysregulation in the p75NTR/ProBDNF, and glutamatergic signaling in stressed mice at the acute timepoint. At 6 months after RUS, stressed mice had lower plasma corticosterone, reduced hippocampal CA1 volume and reduced brain-derived neurotrophic factor levels. In addition, glucocorticoid regulatory protein FKBP5 was downregulated in the hypothalamus of stressed mice at the same timepoint, together implicating an impaired hypothalamus-pituitary-adrenal-axis. Our model demonstrates chronic behavioral and neurobiological outcomes consistent with those reported in human PTSD cases and thus presents a platform through which to understand the neurobiology of stress and explore new therapeutic interventions

Data_Sheet_1_Chronic Hippocampal Abnormalities and Blunted HPA Axis in an Animal Model of Repeated Unpredictable Stress.DOCX

<p>Incidence of post-traumatic stress disorder (PTSD) ranges from 3 to 30% in individuals exposed to traumatic events, with the highest prevalence in groups exposed to combat, torture, or rape. To date, only a few FDA approved drugs are available to treat PTSD, which only offer symptomatic relief and variable efficacy. There is, therefore, an urgent need to explore new concepts regarding the biological responses causing PTSD. Animal models are an appropriate platform for conducting such studies. Herein, we examined the chronic behavioral and neurobiological effects of repeated unpredictable stress (RUS) in a mouse model. 12 weeks-old C57BL/6J male mice were exposed to a 21-day RUS paradigm consisting of exposures to a predator odor (TMT) whilst under restraint, unstable social housing, inescapable footshocks and social isolation. Validity of the model was assessed by comprehensive examination of behavioral outcomes at an acute timepoint, 3 and 6 months post-RUS; and molecular profiling was also conducted on brain and plasma samples at the acute and 6 months timepoints. Stressed mice demonstrated recall of traumatic memories, passive stress coping behavior, acute anxiety, and weight gain deficits when compared to control mice. Immunoblotting of amygdala lysates showed a dysregulation in the p75NTR/ProBDNF, and glutamatergic signaling in stressed mice at the acute timepoint. At 6 months after RUS, stressed mice had lower plasma corticosterone, reduced hippocampal CA1 volume and reduced brain-derived neurotrophic factor levels. In addition, glucocorticoid regulatory protein FKBP5 was downregulated in the hypothalamus of stressed mice at the same timepoint, together implicating an impaired hypothalamus-pituitary-adrenal-axis. Our model demonstrates chronic behavioral and neurobiological outcomes consistent with those reported in human PTSD cases and thus presents a platform through which to understand the neurobiology of stress and explore new therapeutic interventions.</p

High serum Abeta and vascular risk factors in first-degree relatives of Alzheimer's disease patients.

The main objective of this study was to determine whether elevated blood beta-amyloid (Abeta) levels among the first-degree relatives of patients with Alzheimer's Disease (AD) are associated with vascular risk factors of AD. Serum Abeta was measured in samples from 197 cognitively normal first-degree relatives of patients with AD-like dementia. Study participants were recruited as part of an ancillary study of the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT subpopulation). The ADAPT subpopulation was found to be similar in age, sex, and ethnicity to another cognitively normal cohort (n = 98). Using cross-sectional analyses, we examined the association of Abeta with blood pressure, lipid levels, apolipoprotein E genotypes, and the use of prescribed medication to treat vascular risk factors in the ADAPT subpopulation. Abeta(1-40) was positively associated with age, use of antihypertensives, and serum creatinine, and we observed a marginal negative interaction on Abeta(1-40) associated with systolic blood pressure and use of antihypertensives. Serum Abeta(1-42) was associated with statin use and a positive correlation of Abeta (1-42) with HDL was observed among statin nonusers. These findings suggest that high Abeta in the periphery among the family history-enriched cohorts may be due to enrichment of vascular risk factors and may reflect presymptomatic AD pathology. It remains to be determined whether the association of Abeta with medications used for treating vascular risk factors indicates prevention of AD. Longitudinal evaluation of blood Abeta in this cohort will provide a better understanding of the significance of this association in AD etiology

Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area

International audienceBrain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VIA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VIA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations