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RATIONALE: Recreational and medical use of stimulants is increasing, and their use may increase susceptibility to aging and promote neurobehavioral impairments. The long-term consequences of these psychostimulants and how they interact with age have not been fully studied. OBJECTIVES: Our study investigated whether chronic exposure to the prototypical psychostimulant, methamphetamine (METH), at doses designed to emulate human therapeutic dosing, would confer a pro-oxidizing redox shift promoting long-lasting neurobehavioral impairments. METHODS: Groups of 4-month-old male and female C57BL/6J mice were administered non-contingent intraperitoneal injections of either saline or METH (1.4 mg/kg) twice a day for 4 weeks. Mice were randomly assigned to one experimental group: (i) short-term cognitive assessments (at 5 months), (ii) long-term cognitive assessments (at 9.5 months), and (ii) longitudinal motor assessments (at 5, 7 and 9 months). Brain regions were assessed for oxidative stress and markers of neurotoxicity after behavior testing. RESULTS: Chronic METH exposure induced short-term effects on associative memory, gait speed, dopamine (DA) signaling, astrogliosis in females and spatial learning and memory, balance, DA signaling, and excitotoxicity in males. There were no long-term effects of chronic METH on cognition, however, it decreased markers of excitotoxicity in the striatum and exacerbated age-associated motor impairments in males. CONCLUSION: In conclusion, cognitive and motor function were differentially and sex-dependently affected by METH exposure, and oxidative stress did not seem to play a role in the observed behavioral outcomes. Future studies are necessary to continue exploring the long-term neurobehavioral consequences of drug use in both sexes and the relationship between aging and drugs.

BACKGROUND: N-acetyl cysteine (NAC) is a thiolic antioxidant that is thought to increase cellular glutathione (GSH) by augmenting the concentration of available cysteine, an essential precursor to GSH production. Manipulating redox status can affect brain function, and NAC intake has been associated with improving brain function in models of neurodegenerative diseases. OBJECTIVES: The objective of the study was to determine if short-term dietary supplementation with NAC could ameliorate functional impairment associated with aging. METHODS: C57BL/6J male mice aged 6, 12, or 24 mo were fed a control diet or the control diet supplemented with 0.3% NAC for a total of 12 wk. After 4 wk of dietary supplementation, mice began a series of behavioral tests to measure spontaneous activity (locomotor activity test), psychomotor performance (bridge-walking and coordinated running), and cognitive capacity (Morris water maze and discriminated active avoidance). The performance of the mice on these tests was analyzed through the use of analyses of variance with Age and Diet as factors. RESULTS: Supplementation of NAC improved peak motor performance in a coordinated running task by 14% (P

Aging is known to slow the neurogenic capacity of the hippocampus, one of only two mammalian adult neurogenic niches. The reduction of adult-born neurons with age may initiate cognitive decline progression which is exacerbated in chronic neurodegenerative disorders, e.g., Alzheimer’s disease (AD). With physiologic neurogenesis diminished, but still viable in aging, non-invasive therapeutic modulation of this neuron regeneration process remains possible. The discovery of truly novel neuron regenerative therapies could be identified through phenotypic screening of small molecules that promote adult-born neurons from human neural progenitor cells (hNPCs). By identifying neuron-generating therapeutics and potentially novel mechanism of actions, therapeutic benefit could be confirmed through in vivo proof-of-concept studies. The key aging and longevity mTOR/p70S6 kinase axis, a commonly targeted pathway, is substrate for potential selective kinase modulators to promote new hippocampal neurons from NPCs. The highly regulated downstream substrate of mTOR, p70S6 kinase, directly controls pleiotropic cellular activities, including translation and cell growth. Stimulating this kinase, selectively in an adult neurogenic niche, should promote NPC proliferation, and cell growth and survival in the hippocampus. Studies of kinase profiling and immunocytochemistry of human progenitor neurogenesis suggest that the novel small molecule NNI-362 stimulates p70S6 kinase phosphorylation, which, in turn, promotes proliferation and differentiation of NPCs to neurons. NNI-362 promoted the associative reversal of age- and disease-related cognitive deficits in aged mice and Down syndrome-modeled mice. This oral, allosteric modulator may ultimately be beneficial for age-related neurodegenerative disorders involving hippocampal-dependent cognitive impairment, specifically AD, by promoting endogenous hippocampal regeneration. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-020-02126-3.

Introduction: An increasing number of middle-aged men are being screened for low testosterone levels and the number of prescriptions for various forms of testosterone replacement therapy (TRT) has increased dramatically over the last 10 years. However, the safety of TRT has come into question with some studies suggesting increased morbidity and mortality. Objective: Because the benefits of estrogen replacement in postmenopausal women and ovariectomized rodents are lost if there is an extended delay between estrogen loss and replacement, we hypothesized that TRT may also be sensitive to delayed replacement. Methods: We compared the effects of testosterone replacement after short-term (2 weeks) and long-term testosterone deprivation (LTTD; 10 weeks) in middle-aged male rats on cerebral ischemia, oxidative stress, and cognitive function. We hypothesized that LTTD would increase oxidative stress levels and abrogate the beneficial effects of TRT. Results: Hypogonadism itself and TRT after short-term castration did not affect stroke outcome compared to intact rats. However, after long-term hypogonadism in middle-aged male Fischer 344 rats, TRT exacerbated the detrimental behavioral effects of experimental focal cerebral ischemia, whereas this detrimental effect was prevented by administration of the free-radical scavenger tempol, suggesting that TRT exacerbates oxidative stress. In contrast, TRT improved cognitive performance in non-stroked rats regardless of the length of hypogonadism. In the Morris water maze, peripheral oxidative stress was highly associated with decreased cognitive ability. Conclusions: Taken together, these data suggest that TRT after long-term hypogonadism can exacerbate functional recovery after focal cerebral ischemia, but in the absence of injury can enhance cognition. Both of these effects are modulated by oxidative stress levels.

This study determined whether antioxidant supplementation is a viable complement to exercise regimens in improving cognitive and motor performance in a mouse model of Alzheimer’s disease risk. Starting at 12 months of age, separate groups of male and female mice expressing human Apolipoprotein E3 (GFAP-ApoE3) or E4 (GFAP-ApoE4) were fed either a control diet or a diet supplemented with vitamins E and C. The mice were further separated into a sedentary group or a group that followed a daily exercise regimen. After 8 weeks on the treatments, the mice were administered a battery of functional tests including tests to measure reflex and motor, cognitive, and affective function while remaining on their treatment. Subsequently, plasma inflammatory markers and catalase activity in brain regions were measured. Overall, the GFAP-ApoE4 mice exhibited poorer motor function and spatial learning and memory. The treatments improved balance, learning, and cognitive flexibility in the GFAP-ApoE3 mice and overall the GFAP-ApoE4 mice were not responsive. The addition of antioxidants to supplement a training regimen only provided further benefits to the active avoidance task, and there was no antagonistic interaction between the two interventions. These outcomes are indicative that there is a window of opportunity for treatment and that genotype plays an important role in response to interventions.

HIV infects the central nervous system and causes HIV/neuroAIDS, which is predominantly manifested in the form of mild cognitive and motor disorder in the era of combination antiretroviral therapy. HIV Tat protein is known to be a major pathogenic factor for HIV/neuroAIDS through a myriad of direct and indirect mechanisms. However, most, if not all of studies involve short-time exposure of recombinant Tat protein in vitro or short-term Tat expression in vivo. In this study, we took advantage of the doxycycline-inducible brain-specific HIV-1 Tat transgenic mouse model, fed the animals for 12 months, and assessed behavioral, pathological, and epigenetic changes in these mice. Long-term Tat expression led to poorer short-and long-term memory, lower locomotor activity and impaired coordination and balance ability, increased astrocyte activation and compromised neuronal integrity, and decreased global genomic DNA methylation. There were sex- and brain region-dependent differences in behaviors, pathologies, and epigenetic changes resulting from long-term Tat expression. All these changes are reminiscent of accelerated aging, raising the possibility that HIV Tat contributes, at least in part, to HIV infection-associated accelerated aging in HIV-infected individuals. These findings also suggest another utility of this model for HIV infection-associated accelerated aging studies.

Stroke leads to devastating outcomes including impairments of sensorimotor and cognitive function that may be long lasting. New intervention strategies are needed to overcome the long-lasting effects of ischemic injury. Previous studies determined that treatment with 5-methoxyindole-2-carboxylic acid (MICA) conferred chemical preconditioning and neuroprotection against stroke. The purpose of the current study was to determine whether the preconditioning can lead to functional improvements after stroke (done by transient middle cerebral artery occlusion). After 4 weeks of MICA feeding, half the rats underwent ischemic injury, while the other half remained intact. After one week recovery, all the rats were tested for motor and cognitive function (rotorod and water maze). At the time of euthanasia, measurements of long-term potentiation (LTP) were performed. While stroke injury led to motor and cognitive dysfunction, MICA supplementation did not reverse these impairments. However, MICA supplementation did improve stroke-related impairments in hippocampal LTP. The dichotomy of the outcomes suggest that more studies are needed to determine optimum duration and dosage for MICA to lead to substantial motor and cognitive improvements, along with LTP change and neuroprotection.

Purpose The purpose of this study was to determine if antioxidant supplementation, moderate exercise, and the combination of both treatments could ameliorate cognitive performance in adult mice and whether the apolipoprotein E ( APOE ) genotype as well as sex could influence the functional outcomes of the treatments. Methods For a period of 16 weeks, separate groups of male and female mice expressing either the human APOE3 or APOE4 isoforms were fed either a control diet (NIH-31) or the control diet supplemented with vitamins E and C (1.12 IU/g diet α-tocopheryl acetate and 1.65 mg/g ascorbic acid). The mice were further separated into a sedentary group or a group that followed a daily exercise regimen. After 8 weeks on the treatments, the mice were administered a battery of functional tests including tests to measure cognitive and affective function. Results There was no effect of genotype or treatment on the learning performance in the Morris water maze. In the discriminated avoidance task, APOE4 mice performed better in learning the discrimination component of the task. Overall, exercise improved performance of APOE4 and APOE3 mice on various aspects of the active avoidance task. Antioxidant supplementation improved performance only in the APOE4 mice. On the test for anxiety, APOE4 mice spent more time in the open arms and supplementation with antioxidant reversed that effect. Conclusion Exercise was the most effective treatment at improving cognitive function in both genotypes and sex, while antioxidants seemed to be effective only in the APOE4 . In young adult mice only non-spatial learning and memory were improved. The combination of the two treatments did not yield further improvement in cognition, and there was no antagonistic action of the antioxidant supplementation on the beneficial effects of exercise.

Highway workers in work zones are in close proximity to traveling vehicles, exposing them to injury risks when vehicles intrude into the work zone. The purpose of this research was to perform an analysis of injuries endured by highway workers due to intrusion accidents and to identify factors that would have a significant effect on injury severity.Ten years of California work zone injury data were collected and analyzed. The data were first used to determine trends in work zone injury. Statistical models were also created to evaluate variables influencing injury severity. Statistical models included multiple correspondence analysis, Cox proportional hazard regression, logistic regression, and Poisson regression.Statistical analysis of California injury data identified the 4 variables of accident/work zone location, work zone duration, time of day, and type of activity performed by the worker as having the most significant impact on injury severity. The results show that locations such as those on freeways/highways and stationary lane closures result in more severe injuries than work zones on city streets. Short-term stationary and short-duration work zones had increased odds of nonminor injuries compared to mobile work zones. For the time of day, the results indicate that the odds of more serious injuries are higher during nonpeak hours than during peak rush hours. Finally, workers on foot have greater odds of experiencing a more severe injury versus workers inside vehicles.This research has shown that considering the effects of work zone location, duration, time of day, and worker activity can have the most significant impact on risk of injury to workers. Understanding these factors can provide a basis for planning and design of work zones to improve worker safety.

Minor changes (~0.1 m/s) in human gait speed are predictive of various measures of decline and can be used to identify at-risk individuals prior to further decline. These associations are possible due to an abundance of human clinical research. However, age-related gait changes are not well defined in rodents, even though rodents are used as the primary pre-clinical model for many disease states as well as aging research. Our study investigated the usefulness of a novel automated system, the CatWalk™ XT, to measure age-related differences in gait. Furthermore, age-related functional declines have been associated with decreases in the reduced to oxidized glutathione ratio leading to a pro-oxidizing cellular shift. Therefore the secondary aim of this study was to determine whether chronic glutathione deficiency led to exacerbated age-associated impairments. Groups of male and female wild-type (gclm+/+) and knock-out (gclm-/-) mice aged 4, 10 and 17 months were tested on the CatWalk and gait measurements recorded. Similar age-related declines in all measures of gait were observed in both males and females, and chronic glutathione depletion was associated with some delays in age-related declines, which were further exacerbated. In conclusion, the CatWalk is a useful tool to assess gait changes with age, and further studies will be required to identify the potential compensating mechanisms underlying the effects observed with the chronic glutathione depletion.

Recent studies on military breachers in training environments suggest that there are neurocognitive risks from exposure to repeated low-level blasts. However, the dose accumulation effects from multiple low-level blast exposures and their relation to mild traumatic brain injury (mTBI) are not well understood. This paper presents a controlled neurobehavioral study of behavioral effects from repeated low-level blasts delivered at ten second intervals using a rat model. A custom designed shock tube was developed to deliver repeated low-level blasts to rats at short intervals on the order of seconds. A total of 192 rats were divided into three cohorts of 64 for testing. Each cohort was exposed to a different blast intensity (7.5, 15, or 25 psi reflective pressure with durations Behavioral testing results showed that repeated low-level blasts can affect PPI and contextual fear recall. PPI was not affected by repeated exposures to 7.5 psi blasts, but repeated 15 and 25 psi blasts disrupted PPI. All cohorts showed significant fear learning, but the highest blast group (25 psi, 15 repeats) had disruptions in spatial memory recall. None of the cohorts showed effects on cued fear recall or fear extinction and retention. The data collected are being used in continuous research to understand how the behavioral changes relate to mTBI, and how these animal tests can be scaled and modeled to interpret possible outcomes for humans.

Motor dysfunction has been found to be predictive of cognitive dysfunction in Alzheimer’s disease and to occur earlier than cognitive impairments. While apolipoprotein (Apo) E4 has been associated with cognitive impairments, it remains unclear whether it also increases risk for motor dysfunction. Exercise and antioxidants are often recommended to reduce cognitive declines, however it is unclear whether they can successfully improve motor impairments. This study was designed to determine the extent of the impact of apolipoprotein genotype on motor function, and whether interventions such as exercise and antioxidant intake can improve motor function. This study is the first to identify the nature of the interaction between antioxidant intake and exercise using a mouse model expressing either the human ApoE3 or ApoE4 isoforms under glial fibrillary acid protein promoter (GFAP-ApoE3 and GFAP-ApoE4 mice). The mice were fed either a control diet or the control diet supplemented with vitamins E and C (1.12 IU/g diet α-tocopheryl acetate and 1.65 mg/g ascorbic acid). Each genotype/diet group was further divided into a sedentary group or a group that followed a 6 days a week exercise regimen. After 8 weeks on their respective treatment, the mice were administered a battery of motor tests to measure reflexes, strength, coordination and balance. GFAP-ApoE4 mice exhibited impaired motor learning and diminished strength compared to the GFAP-ApoE3 mice. Exercise alone was more efficient at improving motor function and reversing ApoE4-associated impairments than antioxidants alone, even though improvements were rather subtle. Contrarily to expected outcomes, combination of antioxidants and exercise did not yield further improvements of motor function. Interestingly, antioxidants antagonized the beneficial effects of exercise on strength. These data suggest that environmental and genetic factors influence the outcome of interventions on motor function and should be investigated more thoroughly and taken into consideration when implementing changes in lifestyles.

Metformin is an oral anti-diabetic used as first-line therapy for type 2 diabetes. Because benefits of metformin extend beyond diabetes to other age-related pathology, and because its effect on gene expression profiles resembles that of caloric restriction, metformin has a potential as an anti-aging intervention and may soon be assessed as an intervention to extend healthspan. However, beneficial actions of metformin in the central nervous system have not been clearly established. The current study examined the effect of chronic oral metformin treatment on motor and cognitive function when initiated in young, middle-aged, or old male mice. C57BL/6 mice aged 4, 11, or 22 months were randomly assigned to either a metformin group (2 mg/ml in drinking water) or a control group. The mice were monitored weekly for body weight, as well as food and water intake and a battery of behavioral tests for motor, cognitive and visual function was initiated after the first month of treatment. Liver, hippocampus and cortex were collected at the end of the study to assess redox homeostasis. Overall, metformin supplementation in male mice failed to affect blood glucose, body weights and redox homeostasis at any age. It also had no beneficial effect on age-related declines in psychomotor, cognitive or sensory functions. However, metformin treatment had a deleterious effect on spatial memory and visual acuity, and reduced SOD activity in brain regions. These data confirm that metformin treatment may be associated with deleterious effect resulting from the action of metformin on the central nervous system.

The number of sensors placed on warfighters’ personal protective equipment (PPE) continues to increase each year. It is important to be able to accurately measure the dynamic response of PPE in order to characterize new sensors that are meant to track warfighter movement. In an effort to help predict head motion, a method has been developed to accurately measure the angular and linear acceleration of a semi-rigid helmet using four triaxial linear accelerometers. This four-accelerometer array configuration is based on the 3-2-2-2 nine accelerometer package (NAP) method and was tailored to accurately measure the helmet response during impact and blast overpressure events. Method development and testing were performed using U.S. Army Advanced Combat Helmets. Since angular motion calculation using the NAP method requires orthogonal sensor placement, it was necessary to revise the standard NAP sensor configuration to account for the geometric constraints of a helmet. Modal analysis was performed to determine the locations of least vibration, and shock tube and drop tests were conducted to investigate helmet flex during impacts. Knowledge concerning the dominant vibration modes of the helmet guided accelerometer placement and helped mitigate the effects of sensor data oscillation on the calculated angular motion. Local helmet deformation strongly depends on the impact site; several accelerometer array configurations were developed to account for various impact directions. Linear accelerations were measured and angular accelerations were calculated for guided free drop and shock tube tests in the laboratory. In guided free drop tests, the helmet and headform were dropped onto an anvil at various velocities and were allowed to freely bounce after impact. In shock tube tests, the helmet and headform were allowed to swing freely when subjected to a high shock wave simulating an IED blast. The modified NAP method was able to accurately measure the linear and angular acceleration of the helmet for both types of tests. The angular motion calculation was validated using a high-speed video camera recording the helmet response at 10,000 frames per second. Results were also compared to angular rate sensors available on the market. It was determined that with a detailed understanding of a semi-rigid body’s vibration and proper placement of linear accelerometers, angular acceleration during high-shock impacts can be accurately calculated for semi-rigid, irregular shaped objects. This accelerometer placement method has been applied to several other military grade helmets and been used in models predicting head motion from helmet motion data.Copyright © 2013 by ASME

There is significant concern that blast overpressure can cause mild traumatic brain injury (mTBI). An accurate understanding of the blast flow and overpressure event as well as it’s interaction with the head and helmet system is a necessary first step in establishing loading conditions to the head. It also provides a means for model validation and other predictive capabilities. A custom-designed Blast Overpressure Bust (BOB) containing 22 surface pressure sensors was rigidly mounted in a live-fire blast event. The blast field tests were conducted in an open field using 4 lbs. of cylindrical C4 charges suspended 48″ above the pad. The BOB was mounted to a torso surrogate and positioned 92″ from the hanging charge. The BOB was oriented at blast impact angles of 0 (front-facing), 45, 90, and 180 degrees. The BOB was tested in both bare and helmeted configurations. Data recorded across a bare headform at each angle established a baseline for the pressure trace at each sensor location. Two helmeted cases were investigated: Advanced Combat Helmet (ACH) with the sling suspension system and ACH with Team Wendy pads. Results showed peak pressures on exposed surfaces normal to the blast were ∼1200kPa with side-on pressures of ∼400kPa. The addition of a helmet did not alter the peak normal pressures, but showed slight to moderate increases in pressure beneath the helmet based on the amount of cushioning present. The sling suspension, which leaves an open gap between the head and helmet, resulted in several recorded amplification points beneath the helmet with the peaks reaching ∼800kPa. The Team Wendy pads trials, which effectively fill the gap between the head and helmet, showed amplifications with peaks of ∼500kPa. An additional set of tests was conducted using an ingress barrier positioned between the head and helmet at the brim. Results showed pressures under the helmet that were lower than the bare headform trials. While it was shown that adding a helmet did in fact increase pressures relative to the bare headform case, these amplifications were still far less than the peak pressure exerted on the exposed surfaces of the headform. The data presented herein is the most robust data set to date for pressures exerted on a helmeted headform and is considered applicable to the first 3–5ms of an unconstrained system, during which time motion is minimal.Copyright © 2013 by ASME