Study Objectives Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) commonly cooccur. Approaches to research and treatment of these disorders have been segregated, despite overlapping symptomology. We and others have hypothesized that comorbid TBI + PTSD generates worse symptoms than either condition alone. We present a mouse model of comorbid TBI + PTSD to further explore this condition. Methods A mouse model of TBI + PTSD was generated using the single prolonged stress (SPS) protocol in combination with the controlled cortical impact (CCI) protocol. This resulted in four experimental groups: control, TBI, PTSD, and TBI + PTSD. Behavioral phenotyping included gait analysis, contextual fear conditioning, acoustic startle response, and prepulse inhibition. Results Mice in the TBI + PTSD group showed a significantly impaired gait compared to their counterparts with TBI alone as well as control mice. Mice in the TBI + PTSD group showed significantly impaired contextual fear recall compared to controls. Prepulse inhibition testing revealed intact acoustic startle and auditory sensory gating. Conclusions These results indicate that SPS paired with CCI in mice produces unique behavioral impairments in gait and fear recall that are not present in either condition alone. Further studies are underway to examine additional behavioral, physiological, and pathological phenotypes in this combined model of TBI + PTSD.
Sensory gating, the ability to suppress sensory information of irrelevant stimuli, is affected in several neuropsychiatric diseases, notably schizophrenia and autism. It is currently unclear how these deficits interact with other hallmark symptoms of these disorders, such as social withdrawal and difficulty with interpersonal relationships. The highly affiliative prairie vole (Microtus ochrogaster) may be an ideal model organism to study the neurobiology underlying social behavior. In this study, we assessed unimodal acoustic sensory gating in male and female prairie voles using the prepulse inhibition (PPI) paradigm, whereby a lower amplitude sound (prepulse) decreases the startle response to a high amplitude sound (pulse) compared to the high amplitude sound alone. Prairie voles showed evidence of PPI at all prepulse levels compared to pulse alone, with both males and females showing similar levels of inhibition. However, unlike what has been reported in other rodent species, prairie voles did not show a within-session decrease in startle response to the pulse alone, nor did they show a decrease in startle response to the pulse over multiple days, highlighting their inability to habituate to startling stimuli (short-and long-term). When contrasted with a cohort of male wildtype C57Bl/6J mice that underwent a comparable PPI protocol, individual voles showed significantly higher trial-by-trial variability as well as longer latency to startle than mice. The benefits and caveats to using prairie voles in future sensory gating experiments are discussed.
Results: The PTSD+ group demonstrated less SWA [F 1, 113 =5.11, p=.03] than the PTSD-group, but no group differences were observed in sigma. In the PTSD+ group, SWA positively correlated with overall PTSD severity determined by the CAPS (r=.21, p=.05) and sigma negatively correlated with CAPS cognitive items (r=-.21, p=.05). Adjusting for age did not impact the significance of relationships tested. However, age correlated with overall PTSD severity (r=-.50, p< .001) CAPS cognitive items (r=-.26, p=.01) and SWA (r=-.48, p< .001), but not with sigma. Conclusion: SWA is associated with overall PTSD severity and age, while sigma is related to CAPS cognitive items. Although sigma did not differ between groups, other related features, such as sleep spindles, may be related to cognitive functioning in PTSD, and age may uniquely contribute to relationships involving SWA. More precise and objective measures are necessary to fully assess the relationships between SWA, sigma, PTSD, and cognitive functioning in military veterans. Support (If Any): Department of Defense Congressionally Directed Medical Research Programs (Germain-W81XWH-06-1-0257, W81XWH-08-1-0637, W81XWH-12-2-0024; Reifman-W81XWH-14-2-0145) National Institutes of Health (Germain-MH083035; PI: Buysse-4T32HL082610-10). Disclaimer: The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Army or of the US Department of Defense. This abstract has been approved for public release with unlimited distribution. TRAUMA EXPOSURE POTENTIATES THE RELATIONSHIP BETWEEN SLEEP AND CHRONIC PAIN IN VETERANS WITH TBI AND PTSD Introduction:One of the main sequelae of mild traumatic brain injury (mTBI) is sleep-wake disturbances (e.g., excessive daytime sleepiness, insomnia and circadian rhythm disorders), which is present in 50-70% of civilians and Veterans with mTBI. In addition to sleep-wake disturbances, mTBI is commonly associated with headache and chronic pain. As the relationship between sleep-wake disturbances and chronic pain/headache may be potentiated by the co-existence of trauma, the purpose of this study is to describe the association between sleep-wake disturbances and pain in a large sample of Veterans without trauma exposure, with mTBI, with post-traumatic stress disorder (PTSD), and with co-morbid mTBI+PTSD. Methods: Veterans without trauma exposure (Control; n=309), with mTBI (n=117), with PTSD (n=130), and with comorbid mTBI and PTSD (mTBI+PTSD; n=96) were consented and enrolled from the VA Portland Health Care System Sleep Disorders Laboratory. Data collected included overnight in-lab polysomnography, self-reported sleep-wake disturbances assessed via the insomnia severity index (ISI), and the presence/severity of headache/pain as assessed via the NIH PROMIS Global Health scale. TBI and PTSD symptom severity was assessed using the Rivermead Post-Concussive Questionnaire (RPQ) and the PTSD Checklist (PCL-5), respectively.
including bradykinesia, tremor, rigidity and sleep-wake disturbances (SWD). SWDs are one of the most frequent non-motor symptoms of PD, often preceding the onset of other symptoms and, despite growing interest in studying SWD in the context of PD, there is a lack of appropriate murine models. Some lines of evidence recently suggested that sleep deficits correlate with increased burden in neurodegenerative disease and that sleep might alleviate disease severity by increasing clearance of metabolites and proteins from interstitial space, which could prove beneficial in diseases with protein accumulation/aggregation as primary pathology. Methods: We performed EEG/EMG recordings in vesicular monoamine transporter 2 (VMAT2) deficient mice at age of 5 months. Afterwards, at age of 14 months we investigated whether sleep modulation by means of pharmacological sleep induction and chronic REM sleep restriction had an effect on alpha-synuclein accumulation in the brain of VMAT2 deficient mice and behavioral symptoms. Results: EEG/EMG recordings in VMAT2 deficient mice (n=6) and wild type (WT) littermates (n=7) at age of 5 months shows that VMAT2 deficient animals present SWD and EEG changes similar to those seen in PD, namely: increased arousal, decreased time spent in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep and lower sleep efficiency. Furthermore, our results suggest that alpha-synuclein burden was reduced in the sleep-induced (SI) group as compared to the untreated (Ctrl) group. However, we found sleep modulation not associated with improved motor ability, which probably indicates hypodopaminergia as the primary cause of the phenotype as opposed to synucleopathy. Conclusion: Overall, our results suggest that VMAT2 deficient mice present increased arousal and reduced sleep efficiency and that revers- We therefore evaluated longitudinal changes in sleep and drug response. Methods: Adult male mice (n=9 each genotype) underwent surgery for EEG/EMG electrodes and E-mitters. Baseline was recorded at 10 (absent from motor symptoms), 15 (mild), 20 (moderate), and 25 (severe) weeks of age. Sleep deprivation was performed for 6 hours after baseline. Three doses of ropinirole, a dopamine D2-like receptor agonist, were intraperitoneally administered before the light off at 13, 17, 21, and 25 week olds. Results: MitoPark mice showed an age-dependent decline of up to 40% in locomotion following a new environment, while there was no difference between control and MitoPark mice in spontaneous locomotion through 24 hours on baseline in all ages examined. MitoPark mice had normal amounts, and natural diurnal distributions, of wakefulness and sleep in the baseline by 20 weeks. Once motor symptoms severely exacerbated at 25 weeks, sleep fragmentation and a decrease in NREM sleep amount occurred during light period. There was no difference in the occurrence of REM without atonia at 25 weeks. MitoPark mice age-dependently showed more enhanced increases in locomotion at middle and high doses than controls for 3 hours...
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