Traumatic brain injury (TBI) and drug addiction are common comorbidities, but it is unknown if the neurological sequelae of TBI contribute to this relationship. We have previously reported elevated ...oxycodone seeking after drug self‐administration in rats that received repeated blast TBI (rbTBI). TBI and exposure to drugs of abuse can each change structural and functional neuroimaging outcomes, but it is unknown if there are interactive effects of injury and drug exposure. To determine the effects of TBI and oxycodone exposure, we subjected rats to rbTBI and oxycodone self‐administration and measured drug seeking and several neuroimaging measures. We found interactive effects of rbTBI and oxycodone on fractional anisotropy (FA) in the nucleus accumbens (NAc) and that FA in the medial prefrontal cortex (mPFC) was correlated with drug seeking. We also found an interactive effect of injury and drug on widespread functional connectivity and regional homogeneity of the blood oxygen level dependent (BOLD) response, and that intra‐hemispheric functional connectivity in the infralimbic medial prefrontal cortex positively correlated with drug seeking. In conclusion, rbTBI and oxycodone self‐administration had interactive effects on structural and functional magnetic resonance imaging (MRI) measures, and correlational effects were found between some of these measures and drug seeking. These data support the hypothesis that TBI and opioid exposure produce neuroadaptations that contribute to addiction liability.
We previously found that repeated blast traumatic brain injury (rbTBI) increases oxycodone seeking after self‐administration. Here, we report that rbTBI and oxycodone self‐administration have interactive effects on structural and functional neuroimaging measures. Fractional anisotropy negatively correlated with drug seeking in the prelimbic and infralimbic prefrontal cortex and interhemispheric connectivity of the infralimbic prefrontal cortex positively correlated with drug seeking.
Olfactory receptor (OR) choice provides an extreme example of allelic competition for transcriptional dominance, where every olfactory neuron stably transcribes one of approximately 2,000 or more OR ...alleles
. OR gene choice is mediated by a multichromosomal enhancer hub that activates transcription at a single OR
, followed by OR-translation-dependent feedback that stabilizes this choice
. Here, using single-cell genomics, we show formation of many competing hubs with variable enhancer composition, only one of which retains euchromatic features and transcriptional competence. Furthermore, we provide evidence that OR transcription recruits enhancers and reinforces enhancer hub activity locally, whereas OR RNA inhibits transcription of competing ORs over distance, promoting transition to transcriptional singularity. Whereas OR transcription is sufficient to break the symmetry between equipotent enhancer hubs, OR translation stabilizes transcription at the prevailing hub, indicating that there may be sequential non-coding and coding mechanisms that are implemented by OR alleles for transcriptional prevalence. We propose that coding OR mRNAs possess non-coding functions that influence nuclear architecture, enhance their own transcription and inhibit transcription from their competitors, with generalizable implications for probabilistic cell fate decisions.
Each year, traumatic brain injuries (TBI) affect millions worldwide. Mild TBIs (mTBI) are the most prevalent and can lead to a range of neurobehavioral problems, including substance abuse. A single ...blast exposure, inducing mTBI alters the medial prefrontal cortex, an area implicated in addiction, for at least 30 days post injury in rats. Repeated blast exposures result in greater physiological and behavioral dysfunction than single exposure; however, the impact of repeated mTBI on addiction is unknown. In this study, the effect of mTBI on various stages of oxycodone use was examined. Male Sprague Dawley rats were exposed to a blast model of mTBI once per day for 3 days. Rats were trained to self‐administer oxycodone during short (2 h) and long (6 h) access sessions. Following abstinence, rats underwent extinction and two cued reinstatement sessions. Sham and rbTBI rats had similar oxycodone intake, extinction responding and cued reinstatement of drug seeking. A second group of rats were trained to self‐administer oxycodone with varying reinforcement schedules (fixed ratio (FR)‐2 and FR‐4). Under an FR‐2 schedule, rbTBI‐exposed rats earned fewer reinforcers than sham‐exposed rats. During 10 extinction sessions, the rbTBI‐exposed rats exhibited significantly more seeking for oxycodone than the sham‐injured rats. There was a positive correlation between total oxycodone intake and day 1 extinction drug seeking in sham, but not in rbTBI‐exposed rats. Together, this suggests that rbTBI‐exposed rats are more sensitive to oxycodone‐associated cues during reinstatement than sham‐exposed rats and that rbTBI may disrupt the relationship between oxycodone intake and seeking.
Rats were exposed to repeated blast mild traumatic brain injury, then underwent oxycodone self‐administration and seeking. Injured rats self‐administered less oxycodone under an FR‐2 schedule but were no different under an FR‐4 schedule. Despite lower intake, injured rats had significantly greater responding during extinction, and the relationship between prior drug intake and drug seeking observed in sham‐injured animals was lost in injured rats.
Repetitive subconcussive head impact exposure has been associated with clinical and MRI changes in some non-concussed contact sport athletes over the course of a season. However, analysis of human ...tolerance for repeated head impacts is complicated by concussion and head impact exposure history, genetics, and other personal factors. Therefore, the objective of the current study was to develop a rodent model for repetitive subconcussive head impact exposure that can be used to understand injury mechanisms and tolerance in the human. This study incorporated the Medical College of Wisconsin Rotational Injury Model to expose rats to multiple low-level head accelerations per day over a 4-week period. The peak magnitude of head accelerations were scaled from our prior human studies of contact sport athletes and the number of exposures per day were based on the median (moderate exposure) and 95th percentile (high exposure) number of exposures per day across the human sample. Following the exposure protocol, rats were assessed for cognitive deficits, emotional changes, blood serum levels of axonal injury biomarkers, and histopathological evidence of injury. High exposure rats demonstrated cognitive deficits and evidence of anxiety-like behaviors relative to shams. Moderate exposure rats did not demonstrate either of those behaviors. Similarly, high exposure rats had histopathological evidence of gliosis i.e., elevated Iba1 intensity and glial fibrillary acidic protein (GFAP) volume relative to shams in the basolateral amygdala and other areas. Blood serum levels of neurofilament light (NFL) demonstrated a dose response relationship with increasing numbers of low-level head acceleration exposures with a higher week-to-week rate of NFL increase for the high exposure group compared to the moderate exposure group. These findings demonstrate a cumulative effect of repeated low-level head accelerations and provide a model that can be used in future studies to better understand mechanisms and tolerance for brain injury resulting from repeated low-level head accelerations, with scalable biomechanics between the rat and human.
Numerous epidemiological studies have found co-morbidity between non-severe traumatic brain injury (TBI) and substance misuse in both civilian and military populations. Preclinical studies have also ...identified this relationship for some misused substances. We have previously demonstrated that repeated blast traumatic brain injury (rbTBI) increased oxycodone seeking without increasing oxycodone self-administration, suggesting that the neurological sequelae of traumatic brain injury can elevate opioid misuse liability. Here, we determined the chronicity of this effect by testing different durations of time between injury and oxycodone self-administration and durations of abstinence. We found that the subchronic (four weeks), but not the acute (three days) or chronic (four months) duration between injury and oxycodone self-administration was associated with increased drug seeking and re-acquisition of self-administration following a 10-day abstinence. Examination of other abstinence durations (two days, four weeks, or four months) revealed no effect of rbTBI on drug seeking at any of the abstinence durations tested. Together, these data indicate that there is a window of vulnerability after TBI when oxycodone self-administration is associated with elevated drug seeking and relapse-related behaviors.
•Oxycodone seeking was higher in TBI rats in the subchronic time after injury.•Oxycodone re-acquisition was also higher in subchronic TBI rats.•No effect of TBI on drug seeking when oxycodone abstinence was > or < 10 days.
Quantifying injury tolerance for concussion is complicated by variability in the type, severity, and time course of post-injury physiological and behavioral changes. The current study outlined acute ...and chronic changes in behavioral metrics following rotational acceleration-induced concussion in rats. The Medical College of Wisconsin (MCW) rotational injury model independently controlled magnitude and duration of the rotational acceleration pulse. Increasing rotational acceleration magnitude produced longer recovery times, which were used in this study and our prior work as an assessment of acute injury severity. However, longer duration rotational accelerations produced changes in emotionality as measured using the elevated plus maze. Cognitive deficits were for the most part not apparent in the Morris water maze assessment, possibly due to the lower severity of rotational acceleration pulses incorporated in this study. Changes in emotionality evolved between acute and chronic assessments, in some cases increasing in severity and in others reversing polarity. These findings highlight the complexity of quantifying injury tolerance for concussion and demonstrate a need to incorporate rotational acceleration magnitude and duration in proposed injury tolerance metrics. Rotational velocity on its own was not a strong predictor of the magnitude or type of acute behavioral changes following concussion, although its combination with rotational acceleration magnitude using multivariate analysis was the strongest predictor for acute recovery time and some chronic emotional-type behavioral changes.
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