Search

Abstract: Given the high rates of physical trauma and pain among service members, opioid-prescribing practices and use patterns have significant implications for the well-being of service members and can affect military medicine and personnel readiness. This study measured the association between prescribed opioid and benzodiazepine medications and subsequently reported injuries (accidental, alcohol and drug related, self-inflicted, and violence related) among active duty military members. Participants were service members who entered the military between January 1, 2005, and June 30, 2010. In a nested case-control design, we compared individuals with injuries to individuals without injuries with respect to their opioid and benzodiazepine prescriptions in the 30 days before the injury of an index case. We used a multiintercept, logistic regression model to compare coefficient estimates by injury type. Overall, approximately 17% of individuals with an injury and 4% of individuals without an injury had a recorded opioid prescription. Individuals with an injury of any type had greater odds of prior exposure to opioid prescriptions than controls. Although a dose-response effect was observed for all injury types, it reached a plateau sooner for natural or environmental accidents and self-inflicted injuries relative to alcohol-related and drug-related injuries, violence-related injuries, vehicle accidents, accidental falls, and other accidents. Benzodiazepine prescriptions were found in 3.5% of individuals with an injury and 0.5% of individuals without an injury. The association between benzodiazepine prescriptions and injuries was strongest for natural and environmental accidents., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Recent expansions in the roles of women in combat have prompted increased interest in the psychological toll combat exposure may have on female service members as compared to males. This study examined the interactive effects of gender and combat exposure on transitions in posttraumatic stress disorder (PTSD) diagnostic status (presence or absence of PTSD diagnosis). We used administrative data of 20,000 U.S. Army soldiers whose combat exposure was assessed after return from deployment between January 1, 2008 and June 30, 2014; soldiers' PTSD diagnostic status was determined using International Classification of Diseases-9 diagnoses at four time points separated by 12 months. We used a mixed-effects logit transition model to examine the effects of combat and gender on incidence, persistence, and prevalence of PTSD diagnosis. Incidence and prevalence of PTSD diagnosis were higher among women, but persistence of PTSD diagnosis was higher in men. Higher rates of new PTSD diagnosis among women were not dependent on combat exposure, suggesting that other types of trauma may be responsible for increased rates among women. Gender differences in prevalence and persistence of PTSD diagnosis were greater among combat-exposed soldiers than among those not exposed to combat. Men maintained a PTSD diagnosis over longer periods of time than women suggesting greater PTSD persistence, and this pattern was particularly pronounced among soldiers exposed to combat. These results have implications for the recent policy changes and gender-based prevention strategies, and suggest that women in combat roles may be no more vulnerable to PTSD than are their male counterparts. Though the gender differences were small, they are indicative of healthcare utilization patterns that may be important for prevention and that warrant further exploration., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

O-GlcNAcylation, a post-translational modification involving O-linkage of β-N-acetylglucosamine to Ser/Thr residues on target proteins, is increasingly recognized as a critical regulator of synaptic function. Enzymes that catalyze O-GlcNAcylation are found at both presynaptic and postsynaptic sites, and O-GlcNAcylated proteins localize to synaptosomes. An acute increase in O-GlcNAcylation can affect neuronal communication by inducing long-term depression (LTD) of excitatory transmission at hippocampal CA3-CA1 synapses, as well as suppressing hyperexcitable circuits in vitro and in vivo. Despite these findings, to date, no studies have directly examined how O-GlcNAcylation modulates the efficacy of inhibitory neurotransmission. Here we show an acute increase in O-GlcNAc dampens GABAergic currents onto principal cells in rodent hippocampus likely through a postsynaptic mechanism, and has a variable effect on the excitation/inhibition balance. The overall effect of increased O-GlcNAc is reduced synaptically-driven spike probability via synaptic depression and decreased intrinsic excitability. Our results position O-GlcNAcylation as a novel regulator of the overall excitation/inhibition balance and neuronal output.

Optogenetics is widely used in neuroscience to control neural circuits. However, non-invasive methods for light delivery in brain are needed to avoid physical damage caused by current methods. One potential strategy could employ x-ray activation of radioluminescent particles (RPLs), enabling localized light generation within the brain. RPLs composed of inorganic scintillators can emit light at various wavelengths depending upon composition. Cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light in response to x-ray or ultraviolet (UV) stimulation, could potentially be used to control neural circuits through activation of channelrhodopsin-2 (ChR2), a light-gated cation channel. Whether inorganic scintillators themselves negatively impact neuronal processes and synaptic function is unknown, and was investigated here using cellular, molecular, and electrophysiological approaches. As proof of principle, we applied UV stimulation to 4 μm LSO:Ce particles during whole-cell recording of CA1 pyramidal cells in acute hippocampal slices from mice that expressed ChR2 in glutamatergic neurons. We observed an increase in frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), indicating activation of ChR2 and excitation of neurons. Importantly, LSO:Ce particles did not affect survival of primary mouse cortical neurons, even after 24 h of exposure. In extracellular dendritic field potential recordings, no change in the strength of basal glutamatergic transmission was observed during exposure to LSO:Ce microparticles. However, the amplitude of the fiber volley was slightly reduced with high stimulation. Additionally, there was a slight decrease in the frequency of sEPSCs in whole-cell voltage-clamp recordings from CA1 pyramidal cells, with no change in current amplitudes. The amplitude and frequency of spontaneous inhibitory postsynaptic currents were unchanged. Finally, long term potentiation (LTP), a synaptic modification believed to underlie learning and memory and a robust measure of synaptic integrity, was successfully induced, although the magnitude was slightly reduced. Together, these results show LSO:Ce particles are biocompatible even though there are modest effects on baseline synaptic function and long-term synaptic plasticity. Importantly, we show that light emitted from LSO:Ce particles is able to activate ChR2 and modify synaptic function. Therefore, LSO:Ce inorganic scintillators are potentially viable for use as a new light delivery system for optogenetics.

The etiology of late-onset Alzheimer's disease is unknown. Recent epidemiological studies suggest that exposure to high levels of ozone (O 3 ) may be a risk factor for late-onset Alzheimer's disease. Nonetheless, whether and how O 3 exposure contributes to AD development remains to be determined. In this study, we tested the hypothesis that O 3 exposure synergizes with the genetic risk factor APOE ε4 and aging leading to AD, using male apolipoprotein E (apoE)4 and apoE3 targeted replacement mice as men have increased risk exposure to high levels of O 3 via working environments and few studies have addressed APOE ε4 effects on males. Surprisingly, our results show that O 3 exposure impairs memory in old apoE3, but not old apoE4 or young apoE3 and apoE4, male mice. Further studies show that old apoE4 mice have increased hippocampal activities or expression of some enzymes involved in antioxidant defense, diminished protein oxidative modification, and neuroinflammation following O 3 exposure compared with old apoE3 mice. These novel findings highlight the complexity of interactions between APOE genotype, age, and environmental exposure in AD development., (Published by Elsevier Inc.)

Optical stimulation and imaging of neurons deep in the brain require implantable optical neural probes. External optical access to deeper regions of the brain is limited by scattering and absorption of light as it propagates through tissue. Implantable optoelectronic probes capable of high-resolution light delivery and high-density neural recording are needed for closed-loop manipulation of neural circuits. Micro-light-emitting diodes (μLEDs) have been used for optical stimulation, but predominantly on rigid silicon or sapphire substrates. Flexible polymer neural probes would be preferable for chronic applications since they cause less damage to brain tissue. Flexible μLED neural probes have been recently implemented by flip-chip bonding of commercially available μLED chips onto flexible substrates. Here, we demonstrate a monolithic design for flexible optoelectronic neural interfaces with embedded gallium nitride μLEDs that can be microfabricated at wafer-scale. Parylene C is used as the substrate and insulator due to its biocompatibility, compliance, and optical transparency. We demonstrate one-dimensional and two-dimensional individually-addressable μLED arrays. Our μLEDs have sizes as small as 22 × 22 μm in arrays of up to 32 μLEDs per probe shank. These devices emit blue light at a wavelength of 445 nm, suitable for stimulation of channelrhodopsin-2, with output powers greater than 200 μW at 2 mA. Our flexible optoelectronic probes are double-sided and can illuminate brain tissue from both sides. Recording electrodes are co-fabricated with μLEDs on the front- and backside of the optoelectronic probes for electrophysiology recording of neuronal activity from the volumes of tissue on the front- and backside simultaneously with bi-directional optical stimulation.

Neocortical circuits are sensitive to experience, showing both anatomical and electrophysiological changes in response to altered sensory input. We examined input- and cell-type-specific changes in thalamo- and intracortical pathways during learning using an automated, home-cage sensory association training (SAT) paradigm coupling multi-whisker stimulation to a water reward. We found that the posterior medial nucleus (POm) but not the ventral posterior medial (VPM) nucleus of the thalamus drives increased cortical activity after 24 h of SAT, when behavioral evidence of learning first emerges. Synaptic strengthening within the POm thalamocortical pathway was first observed at thalamic inputs to L5 and was not generated by sensory stimulation alone. Synaptic changes in L2 were delayed relative to L5, requiring 48 h of SAT to drive synaptic plasticity at thalamic and intracortical inputs onto L2 Pyr neurons. These data identify the POm thalamocortical circuit as a site of rapid synaptic plasticity during learning and suggest a temporal sequence to learning-evoked synaptic changes in the sensory cortex., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: This study's purpose is to inform future research decisions about optimal measures for identifying combat deployments. We aim to evaluate four commonly utilized measures available in population-level administrative data to identify combat deployments in recent military operations among active duty Army personnel., Methods: We compare these measures in three ways: (1) agreement (assessing the extent to which soldiers were differentially identified as combat deployed via each measure); (2) validity (calculating the sensitivity of each measure against a criterion measure); and (3) corroboration (examining how each measure predicted subsequent incidence of traumatic brain injury and post-traumatic stress disorder)., Results: We found that using personnel records to identify deployments to Iraq, Afghanistan, and/or Kuwait captured over 98% of combat-related deployments identified via self-reported measures. The addition of Kuwait allowed for detection of nearly 100% of battle injuries, improving sensitivity from 94.5% to 99.8%. However, self-reported combat exposure measures showed the largest differential in subsequent incidence of traumatic brain injury and post-traumatic stress disorder. Completeness and accuracy of different combat deployment measures varied significantly., Conclusions: Using personnel records to identify deployment to Iraq, Afghanistan, and/or Kuwait was the most valid and comprehensive measure of combat deployment. However, self-reported combat exposure measures were more predictive of combat-related outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

O-GlcNAcylation is a ubiquitous and dynamic post-translational modification involving the O-linkage of β- N -acetylglucosamine to serine/threonine residues of membrane, cytosolic, and nuclear proteins. This modification is similar to phosphorylation and regarded as a key regulator of cell survival and homeostasis. Previous studies have shown that phosphorylation of serine residues on synaptic proteins is a major regulator of synaptic strength and long-term plasticity, suggesting that O-GlcNAcylation of synaptic proteins is likely as important as phosphorylation; however, few studies have investigated its role in synaptic efficacy. We recently demonstrated that acutely increasing O-GlcNAcylation induces a novel form of LTD at CA3-CA1 synapses, O-GlcNAc LTD. Here, using hippocampal slices from young adult male rats and mice, we report that epileptiform activity at CA3-CA1 synapses, generated by GABA A R inhibition, is significantly attenuated when protein O-GlcNAcylation is pharmacologically increased. This dampening effect is lost in slices from GluA2 KO mice, indicating a requirement of GluA2-containing AMPARs, similar to expression of O-GlcNAc LTD. Furthermore, we find that increasing O-GlcNAcylation decreases spontaneous CA3 pyramidal cell activity under basal and hyperexcitable conditions. This dampening effect was also observed on cortical hyperexcitability during in vivo EEG recordings in awake mice where the effects of the proconvulsant pentylenetetrazole are attenuated by acutely increasing O-GlcNAcylation. Collectively, these data demonstrate that the post-translational modification, O-GlcNAcylation, is a novel mechanism by which neuronal and synaptic excitability can be regulated, and suggest the possibility that increasing O-GlcNAcylation could be a novel therapeutic target to treat seizure disorders and epilepsy. SIGNIFICANCE STATEMENT We recently reported that an acute pharmacological increase in protein O-GlcNAcylation induces a novel form of long-term synaptic depression at hippocampal CA3-CA1 synapses (O-GlcNAc LTD). This synaptic dampening effect on glutamatergic networks suggests that increasing O-GlcNAcylation will depress pathological hyperexcitability. Using in vitro and in vivo models of epileptiform activity, we show that acutely increasing O-GlcNAc levels can significantly attenuate ongoing epileptiform activity and prophylactically dampen subsequent seizure activity. Together, our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics., (Copyright © 2017 the authors 0270-6474/17/378207-09$15.00/0.)

There is growing evidence that metabolic stressors increase an organism's risk of depression. Chronic mild stress is a popular animal model of depression and several serendipitous findings have suggested that food deprivation prior to sucrose testing in this model is necessary to observe anhedonic behaviors. Here, we directly tested this hypothesis by exposing animals to chronic mild stress and used an overnight 2-bottle sucrose test (food ad libitum) on Day 5 and 10, then food and water deprive animals overnight and tested their sucrose consumption and preference in a 1-hr sucrose test the following morning. Approximately 65% of stressed animals consumed sucrose and showed a sucrose preference similar to nonstressed controls in an overnight sucrose test, and 35% showed a decrease in sucrose intake and preference. Following overnight food and water deprivation the previously "resilient" animals showed a significant decrease in sucrose preference and greatly reduced sucrose intake. In addition, we evaluated whether the onset of anhedonia following food and water deprivation corresponds to alterations in corticosterone, epinephrine, circulating glucose, or interleukin-1 beta (IL-1β) expression in limbic brain areas. Although all stressed animals showed adrenal hypertrophy and elevated circulating epinephrine, only stressed animals that were food deprived were hypoglycemic compared with food-deprived controls. Additionally, food and water deprivation significantly increased hippocampus IL-1β while food and water deprivation only increased hypothalamus IL-1β in stress-susceptible animals. These data demonstrate that metabolic stress of food and water deprivation interacts with chronic stressor exposure to induce physiological and anhedonic responses., ((c) 2015 APA, all rights reserved).)

Current theories on the pathogenesis of autism spectrum disorders (ASD) maintain that the associated cognitive and behavioral symptoms are caused by aberrant synaptic transmission affecting specific brain circuits. Transgenic mouse models have implicated the involvement of cell adhesion proteins in synaptic dysfunction and ASD pathogenesis. Recently, Aoto et al. (Cell 154: 75-88, 2013) has shown that alternatively spliced neurexin proteins affect the efficacy of AMPA receptor-mediated excitatory currents in both cultured neuronal networks and acute hippocampal slices constituting a potential ASD-related electrophysiological phenotype., (Copyright © 2015 the American Physiological Society.)

Exaggerated pro-inflammatory cytokine production by primed microglia is thought to mediate pathology during stress, aging, and neurodegeneration. Recently, it was demonstrated that beta-adrenergic receptor (β-AR) antagonism prevents priming of microglia in mice exposed to chronic stress. To determine if β-AR stimulation is sufficient to prime microglia, rats were intra-cerebroventricularly administered isoproterenol (β-AR agonist) or vehicle and 24 h later hippocampal microglia were placed in culture with media or LPS. Prior isoproterenol treatment significantly enhanced IL-1β and IL-6, but not TNF-α production following LPS stimulation. These data suggest that central β-AR stimulation is sufficient to prime microglia cytokine responses., (Copyright © 2012 Elsevier B.V. All rights reserved.)