Behavioral Characterization of an Angelman Syndrome Mouse Model.

This manuscript describes a battery of behavioral tests available to characterize Angelman syndrome (AS)-like phenotypes in an established murine model of AS. We use the rotarod learning paradigm, detailed gait analysis, and nest building test to detect and characterize animal motor impairments. We test animal emotionality in the open field and elevated plus maze tests, as well as the affect in the tail suspension test. When AS mice are tested in the open field test, the results should be interpreted with care, since motor dysfunctions influence mouse behavior in the maze and alter activity scores. The reproducibility and effectiveness of the presented behavioral tests has already been validated in several independent Uba3a mouse lines with different knockout variants, establishing this set of tests as an excellent validation tool in AS research. Models with the relevant construct and face validity will warrant further investigations to elucidate the pathophysiology of the disease and grant the development of causal treatments.

Intensity of 40K Decay Fluctuations an Indicator of an Environmental Factor Determining Infradian Rhythms of Mouse Motor Activity, Circulating Cortisol in Rabbits, and Proliferation of L-929 Cultured Cells.

The multi-day dynamics of the intensity of 40K decay fluctuations was compared with motor activity of laboratory mice, circulating cortisol in rabbits, and proliferation of fibroblast-like cultured cells L-929. A positive correlation was established between the intensity of decay fluctuations on the one hand, and total daily motor activity in mice and plasma cortisol level in rabbits, on the other hand. In addition, a negative correlation was observed between 40K decay fluctuations and proliferative activity of the cultured cells. Interestingly, these close correlations were observed not only against the background 4-day rhythm, but also in the time when any rhythmicity was absent. Thus, the intensity of 40K decay fluctuations is an indicator of a biotropic environmental factor that augments motor activity and raises the circulating cortisol in animals and down-regulates proliferation of cultured cells.

The Head Control Scale: Responsiveness and Concurrent Validity With the Alberta Infant Motor Scale.

PURPOSE: The purpose of this study was to investigate the Head Control Scale's (HCS's) responsiveness and concurrent validity with the Alberta Infant Motor Scale (AIMS). METHODS: The HCS and the AIMS were administered to 50 infants and young children. Thirty children were reevaluated at hospital discharge or at 18 months of age. RESULTS: A statistically significant positive change was noted in mean score from the initial HCS assessment to the second assessment for total score and all position scores. Concurrent validity between HCS and AIMS total scores was excellent. CONCLUSION: Responsiveness to changes in head control and concurrent validity with the AIMS were established, supporting HCS use in clinical practice.

Resistance wheel running improves contractile strength, but not metabolic capacity, in a murine model of volumetric muscle loss injury.

The primary objective of this study was to determine if low- or high-resistance voluntary wheel running leads to functional improvements in muscle strength (i.e., isometric and isokinetic torque) and metabolic function (i.e., permeabilized fibre bundle mitochondrial respiration) after a volumetric muscle loss (VML) injury. C57BL/6J mice were randomized into one of four experimental groups at age 12 weeks: uninjured control, VML untreated (VML), low-resistance wheel running (VML-LR) and high-resistance wheel running (VML-HR). All mice, excluding the uninjured, were subject to a unilateral VML injury to the plantar flexor muscles and wheel running began 3 days post-VML. At 8 weeks post-VML, peak isometric torque was greater in uninjured compared to all VML-injured groups, but both VML-LR and VML-HR had greater (∼32%) peak isometric torque compared to VML. All VML-injured groups had less isokinetic torque compared to uninjured, and there was no statistical difference among VML, VML-LR and VML-HR. No differences in cumulative running distance were observed between VML-LR and VML-HR groups. Because adaptations in VML-HR peak isometric torque were attributed to greater gastrocnemius muscle mass, atrophy- and hypertrophy-related protein content and post-translational modifications were explored via immunoblot; however, results were inconclusive. Permeabilized fibre bundle mitochondrial oxygen consumption was 22% greater in uninjured compared to VML, but there was no statistical difference among VML, VML-LR and VML-HR. Furthermore, neither wheel running group demonstrated a change in the relative protein content of the mitochondrial biogenesis transcription factor, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). These results indicate that resistance wheel running alone only has modest benefits in the VML-injured muscle. NEW FINDINGS: What is the central question of the study? Does initiation of a resistance wheel running regimen following volumetric muscle loss (VML) improve the functional capacity of skeletal muscle? What is the main finding and its importance? Resistance wheel running led to greater muscle mass and strength in mice with a VML injury but did not result in a full recovery. Neither low- nor high-resistance wheel running was associated with a change in permeabilized muscle fibre respiration despite runners having greater whole-body treadmill endurance capacity, suggesting resilience to metabolic adaptations in VML-injured muscle. Resistance wheel running may be a suitable adjuvant rehabilitation strategy, but alone does not fully mitigate VML pathology.

Spatial distribution of hand-grasp motor task activity in spinal cord functional magnetic resonance imaging.

Upper extremity motor paradigms during spinal cord functional magnetic resonance imaging (fMRI) can provide insight into the functional organization of the cord. Hand-grasping is an important daily function with clinical significance, but previous studies of similar squeezing movements have not reported consistent areas of activity and are limited by sample size and simplistic analysis methods. Here, we study spinal cord fMRI activation using a unimanual isometric hand-grasping task that is calibrated to participant maximum voluntary contraction (MVC). Two task modeling methods were considered: (1) a task regressor derived from an idealized block design (Ideal) and (2) a task regressor based on the recorded force trace normalized to individual MVC (%MVC). Across these two methods, group motor activity was highly lateralized to the hemicord ipsilateral to the side of the task. Activation spanned C5-C8 and was primarily localized to the C7 spinal cord segment. Specific differences in spatial distribution are also observed, such as an increase in C8 and dorsal cord activity when using the %MVC regressor. Furthermore, we explored the impact of data quantity and spatial smoothing on sensitivity to hand-grasp motor task activation. This analysis shows a large increase in number of active voxels associated with the number of fMRI runs, sample size, and spatial smoothing, demonstrating the impact of experimental design choices on motor activation.

Juvenile physical activity protects against isoproterenol-induced cardiac dysfunction later in life.

Cardiovascular disease is an enormous public health problem, particularly in older populations. Exercise is the most potent cardioprotective intervention identified to date, with exercise in the juvenile period potentially imparting greater protection, given the plasticity of the developing heart. To test the hypothesis that voluntary wheel running early in life would be cardioprotective later in life when risk for disease is high, we provided male and female juvenile (3 wk old) mice access to a running wheel for 2 wk. Mice then returned to a home cage to age to adulthood (4-6 mo) before exposure to isoproterenol (ISO) to induce cardiac stress. Cardiac function and remodeling were compared with sedentary control mice, sedentary mice exposed to ISO, and mice that exercised in adulthood immediately before ISO. Early in life activity protected against ISO-induced stress as evidenced by attenuated cardiac mass, myocyte size, and fibrosis compared with sedentary mice exposed to ISO. ISO-induced changes in cardiac function were ameliorated in male mice that engaged in wheel running, with ejection fraction and fractional shortening reversed to control values. Adrenergic receptor expression was downregulated in juvenile male runners. This suppression persisted in adulthood following ISO, providing a putative mechanism by which exercise in the young male heart provides resilience to cardiac stress later in life. Together, we show that activity early in life induces persistent cardiac changes that attenuate ISO-induced stress in adulthood. Identification of the mechanisms by which early in life exercise is protective will yield valuable insights into how exercise is medicine across the life course.NEW & NOTEWORTHY Voluntary wheel running activity early in life induces persistent changes in the heart that attenuate isoproterenol-induced hypertrophy and fibrosis in adulthood. Though the mechanisms of this protection remain incompletely understood, activity-induced downregulation of adrenergic receptor expression early in life may contribute to later protection against adrenergic stress. Together these data suggest that efforts to maintain an active lifestyle early in life may have long-lasting cardioprotective benefits.

Lipopolysaccharide-induced sickness behavior is not altered in male Fmr1-deficient mice.

OBJECTIVES: Fragile X syndrome is the main monogenetic cause of intellectual disability and autism. Alterations in the immune system are commonly found in these developmental disorders. We and others have demonstrated that Fmr1 mutant mice present an altered response to immune stimuli. However, whether this altered immune response can influence the Fmr1 mutant behavioral outcomes in response to inflammation has not been fully investigated. MATERIALS AND METHODS: In the current study, we examine the behavioral sickness response of male wildtype and knockout  mice to the innate immune stimulus lipopolysaccharide (LPS) (0.1 mg/kg) to determine if Fmr1 mutants have altered sickness behavior. We used an enzyme-linked immunosorbent assay (ELISA) to measure changes in the cytokine interleukin-6 (IL-6) to determine that inflammation was induced in the mice. Sickness behavior was assessed in a wheel-running paradigm, and a tail suspension test was used to assess the depressive-like phenotype that follows sickness behavior in response to LPS. RESULTS: The ELISA using blood serum confirmed a significant increase in IL-6 in mice that were treated with LPS. Treated Fmr1 mutants exhibited decreased distance traveled in the wheel running after LPS administration, similar to treated controls. Another cohort of animals treated with LPS were tested in the tail suspension test and exhibited no alterations in immobility time in response to LPS. CONCLUSION: Together, our data suggest that Fmr1 mutant mice do not have altered sickness behavior in response to a low dose of LPS.

Tracking de 10 anos da aptidão física e capacidade funcional de mulheres adultas praticantes de atividade física / 10-Year tracking of fitness and functional capacity of adult women practicing physical activity of physical activity

Contexto e objetivo: Diversos benefícios são advindos da prática da atividade física durante o envelhecimento, porém poucos são os achados que apresentem os dados ao longo do tempo. Assim, o objetivo deste estudo foi verificar a estabilidade das variáveis da aptidão física e capacidade funcional de mulheres adultas praticantes de atividade física em um período de 10 anos. Desenho e local: Estudo longitudinal com mulheres de São Caetano do Sul. Métodos: A amostra foi composta por 157 mulheres com idade entre 45 e 86 anos (65,7 ± 6,7), analisadas em quatro intervalos de tempo: baseline, 6, 8 e 10 anos, todas praticantes de atividade física. A avaliação incluiu variáveis antropométricas, neuromotoras e de capacidade funcional. A análise estatística utilizada foi o teste t de Student, correlação de Spearman Rho e delta percentual. O nível de significância adotado foi de P < 0,01. Resultados: Os resultados apresentaram correlações de estabilidade alta e significante (rho = 0,64 a 0,87) nos três grupos nas variáveis índice de massa corporal, adiposidade, força de membros superiores, flexibilidade e agilidade. O acompanhamento de 6 a 10 anos evidenciou diferenças significantes de força de membros superiores, inferiores, agilidade e equilíbrio, sendo expressa pela redução da força de membros superiores de 8% a 13%, força de membros inferiores de 18% a 21%, agilidade de 18% a 19% e equilíbrio de 28% a 34%. Conclusão: Houve estabilidade das variáveis antropométricas, neuromotoras, capacidade funcional e equilíbrio de mulheres adultas praticantes de atividade física, mesmo apresentando redução significativa nas variáveis citadas anteriormente.

Effect of 40 Hz light flicker on behaviors of adult C57BL/6J mice.

40 Hz light flicker can activate multiple brain regions of wild-type mice. However, there are no systematic studies on the behavioral effects of 40 Hz light flicker on wild-type mice. Adult wild-type C57BL/6J mice were treated with 40 Hz light flicker (200 lx, 40 Hz, 1 h/day for 3 weeks) to evaluate its effects on several behaviors, including mood, locomotor activity, memory, social interaction, mechanical pain, and sense of smell. In the open field test, the elevated zero-maze test, forced swimming test, and tail suspension test, 40 Hz mice showed no anxiety and depression-like behaviors. In the rotarod test, no differences were found between the anti-fatigue ability and motor coordination ability. In memory-related tests, 40 Hz mice showed the short-term cognitive enhancement in the novel object recognition test. Interestingly, 40 Hz mice showed no enhanced the long-term memory performance in the contextual fear conditioning test, and tone-cued fear conditioning test. Besides, 40 Hz mice increased their exploration of social cues that were unfamiliar to them and differed significantly from their own experiences. In terms of sensory abilities, 40 Hz mice had unchanged pain sensitivity in the von Frey fiber test and significant enhancement in the olfactory ability in the food-seeking test. In conclusion, this 40 Hz light stimulation paradigm has high safety and can improve the specific behavioral ability, which provides a theoretical basis for the future use of 40 Hz light flicker as a disease prevention or treatment method.

Effects of high-resistance wheel running on hallmarks of endurance and resistance training adaptations in mice.

Exercise effectively promotes and preserves cardiorespiratory, neuromuscular, metabolic, and cognitive functions throughout life. The molecular mechanisms underlying the beneficial adaptations to exercise training are, however, still poorly understood. To improve the mechanistic study of specific exercise training adaptations, standardized, physiological, and well-characterized training interventions are required. Therefore, we performed a comprehensive interrogation of systemic changes and muscle-specific cellular and molecular adaptations to voluntary low-resistance wheel running (Run) and progressive high-resistance wheel running (RR) in young male mice. Following 10 weeks of training, both groups showed similar improvements in body composition and peak oxygen uptake (V̇O2peak ), as well as elevated mitochondrial proteins and capillarization markers in the M. plantaris. Run mice clearly outperformed RR mice in a forced treadmill running capacity test, while RR mice displayed increased grip strength as well as superior mass gains in the M. soleus, associated with distinct proteomic changes specifying the two paradigms. Thus, even though both training modalities induce overlapping adaptations, Run interventions preferably improve submaximal running performance, while progressive RR is a valid model to study training-induced gains in grip strength and plantar flexor hypertrophy.

Chronic food restriction in mice and increased systemic ghrelin induce preference for running wheel activity.

OBJECTIVES: In eating disorders, particularly anorexia nervosa (AN), patients exhibit intense physical activity which is inappropriate regarding food restriction and chronic undernutrition, and exacerbates weight loss and energy deprivation. Rodent models of food restriction exhibit increased running wheel activity in the food anticipation period, also known as Food Anticipatory Activity (FAA). FAA probably has various physiological and/or neurobiological origins. Plasma concentrations of the orexigenic hormone ghrelin are, for example, increased during FAA. We hypothesize that the drive for physical activity in chronic food restriction is triggered by metabolic factors but also relies on motivational aspects that we aim to decipher in this study. METHODS: Young female C57Bl6/J mice were exposed to a paradigm based on a progressive 50% quantitative food restriction alone (FR) or associated with running wheel activity (Food Restriction Wheel: FRW) in their home-cage during 15 days. We measured preference for running wheel in a three-chamber apparatus in which animals could choose to explore either a known running wheel or a novel object. Testing took place either during resting or during FAA. We calculated the time spent in each compartment and the activity in running wheels. After progressive refeeding over 10 days, mice were tested again when refed. Plasma levels of both ghrelin isoforms were measured with selective immunoassays. RESULTS: When tested during FAA period, food restricted mice displayed increased preference for the running wheel compared to ad libitum fed controls. Both FR and FRW mice exhibited increased running time and distance in the wheel and running distance was correlated with ghrelin levels. Similar preference and behavior were found when testing took place during the resting period. Animals housed without an active wheel also exhibited active running. Progressive refeeding resulted in body weight restoration, a decrease in FAA and completely abolished preference for the running wheel. Refed animals displayed similar behavior as ad libitum fed controls. CONCLUSIONS: These data provide evidence that food restriction-induced physical activity is closely correlated with metabolic adaptations to nutritional status implicating ghrelin in the quantity of physical activity.

Quantitative measurement of motor activity during sleep in isolated REM sleep behavior disorder patients using actigraphy before and after treatment with clonazepam.

STUDY OBJECTIVES: We conducted a prospective study to quantify motor activity during sleep measured by actigraphy before and after 3 months of treatment with clonazepam in patients with video-polysomnography (vPSG) confirmed isolated rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: The motor activity amount (MAA) and the motor activity block (MAB) during sleep were obtained from actigraphy. Then, we compared quantitative actigraphic measures with the results of the REM sleep behavior disorder questionnaire for the previous 3-month period (RBDQ-3M) and of the Clinical Global Impression-Improvement scale (CGI-I), and analyzed correlations between baseline vPSG measures and actigraphic measures. RESULTS: Twenty-three iRBD patients were included in the study. After medication treatment, large activity MAA dropped in 39% of patients, and the number of MABs decreased in 30% of patients when applying 50% reduction criteria. 52% of patients showed more than 50% improvement in either one. On the other hand, 43% of patients answered "much or very much improved" on the CGI-I, and RBDQ-3M was reduced by more than half in 35% of patients. However, there was no significant association between the subjective and objective measures. Phasic submental muscle activity during REM sleep was highly correlated with small activity MAA (Spearman's rho = 0.78, p < .001) while proximal and axial movements during REM sleep correlated with large activity MAA (rho = 0.47, p = .030 for proximal movements, rho = 0.47, p = .032 for axial movements). CONCLUSIONS: Our findings imply that quantifying motor activity during sleep using actigraphy can objectively assess therapeutic response in drug trials in patients with iRBD.

Voluntary wheel running promotes resilience to the behavioral effects of unpredictable chronic mild stress in male and female mice.

Besides significant benefits to physical health, exercise promotes mental health, reduces symptoms of mental illness, and enhances psychological development. Exercise can offset the impact of chronic stress, which is a major precursor to the development of mental disorders. The effects of exercise on chronic stress-induced behaviors are contradictory in preclinical studies, primarily due to the lack of data and sex-specific investigations. We sought to evaluate the effects of exercise on chronic stress-induced behavioral changes in both male and female mice. Mice were subjected to an Unpredictable Chronic Mild Stress (UCMS) paradigm with accessibility to running wheels for 2 h daily. Physiological and behavioral evaluations were conducted throughout the stress paradigm to determine if exercise blunts the effects of UCMS. Chronic stress induced voluntary wheel running (VWR) and weight loss in male and female mice. Compared to males, increased VWR was reported in females who also regained their weight lost by the end of the UCMS protocol. Exercise promoted resilience to stress-induced hyponeophagia in the novelty-suppressed feeding test and increased sucrose consumption. Exercise induced a sex-specific reduction in immobility and avoidance behavior in the tail suspension and open field tests and increased exploratory behavior in the light-dark test. These results indicate that exercise can promote resilience to the behavioral effects of chronic stress in males and females, and can affect behavior independent of chronic stress.

Cisplatin decreases voluntary wheel-running activity but does not impair food-motivated behavior in mice.

Cisplatin is a chemotherapeutic agent that is still commonly used to treat solid tumors. However, it has several toxic side effects due in large part to the mitochondrial damage that it induces. As this mitochondrial damage is likely to result in a decrease in the amount of metabolic energy that is available for behavioral activities, it is not surprising that fatigue develops in cancer patients treated with cisplatin. The present preclinical study was initiated to determine whether the detrimental effects of cisplatin were more pronounced on physical effort requiring a lot of energy versus effort that not only requires less energy but also procures energy in the form of food. For this purpose, mice were either trained to run in a wheel or to work for food in various schedules of food reinforcement before being treated with cisplatin. The experiments were carried out only in male mice as we had already reported that sex differences in cisplatin-induced neurotoxicities are minimal. Cisplatin was administered daily for one cycle of five days, or two cycles separated by a five-day rest. As observed in previous experiments, cisplatin drastically reduced voluntary wheel running. In contrast, when cisplatin was administered to food-restricted mice trained to work for a food reward in a progressive ratio schedule or in a fixed-interval schedule, it tended to increase the number of responses emitted to obtain the food rewards. This increase was not associated with any change in the temporal distribution of responses during the interval between two reinforcements in mice submitted to the fixed interval schedule of food reinforcement. When cisplatin was administered to food-restricted mice trained in an effort-based decision-making task in which they had to choose between working for a grain pellet with little effort and working for a preferred chocolate pellet with more effort, it decreased the total number of responses emitted to obtain food rewards. However, this effect was much less marked than the decrease in wheel running induced by cisplatin. The decrease in the effort invested in the procurement of food rewards was not associated with any change in the relative distribution of effort between low reward and high reward during the time course of the test session. These findings show that cisplatin decreases energy-consuming activities but not energy-procuring activities unless they require a choice between options differing in their cost-benefit ratio. Furthermore, they indicate that the physical dimension of fatigue is more likely to develop in cisplatin-treated individuals than the motivational dimension of fatigue.

Differential Fractal and Circadian Patterns in Motor Activity in Spontaneously Hypertensive Rats at the Stage of Prehypertension.

One possible pathological mechanism underlying hypertension and its related health consequences is dysfunction of the circadian system-a network of coupled circadian clocks that generates and orchestrates rhythms of ≈24 h in behavior and physiology. To better understand the role of circadian function during the development of hypertension, circadian regulation of motor activity is investigated in spontaneously hypertensive rats (SHRs) before the onset of hypertension and in their age-matched controls-Wistar Kyoto rats (WKYs). Two complementary properties in locomotor activity fluctuations are examined to assessthe multiscale regulatory function of the circadian control network: 1) rhythmicity at ≈24 h and 2) fractal patterns-similar temporal correlation at different time scales (≈0.5-8 h). Compared to WKYs, SHRs have more stable and less fragmented circadian activity rhythms but the changes in the rhythms (e.g., period and amplitude) from constant dark to light conditions are reduced or opposite. SHRs also have altered fractal activity patterns, displaying activity fluctuations with excessive regularity at small timescales that are linked to rigid physiological states. These different rhythmicity/fractal patterns and their different responses to light in SHRs indicate that an altered circadian function may be involved in the development of hypertension.

Energy Expenditure Estimation From Respiratory Magnetometer Plethysmography: A Comparison Study.

Physical activity (PA) quantification by estimating energy expenditure (EE) is essential to health. Reference methods for EE estimation often involve expensive and cumbersome systems to wear. To address these problems, light-weighted and cost-effective portable devices are developed. Respiratory magnetometer plethysmography (RMP) is among such devices, based on the measurements of thoraco-abdominal distances. The aim of this study was to conduct a comparative study on EE estimation with low to high PA intensity with portable devices including the RMP. Fifteen healthy subjects aged 23.84±4.36 years were equipped with an accelerometer, a heart rate (HR) monitor, a RMP device and a gas exchange system, while performing 9 sedentary and physical activities: sitting, standing, lying, walking at 4 and 6 km/h, running at 9 and 12 km/h, biking at 90 and 110 W. An artificial neural network (ANN) as well as a support vector regression algorithm were developed using features derived from each sensor separately and jointly. We compared also three validation approaches for the ANN model: leave one out subject, 10 fold cross-validation, and subject-specific. Results showed that 1. for portable devices the RMP provided better EE estimation compared to accelerometer and HR monitor alone; 2. combining the RMP and HR data further improved the EE estimation performances; and 3. the RMP device was also reliable in EE estimation for various PA intensities.

Development of the Movement Pattern Observation Tool (MPOT)-An Observational Tool to Measure Limb Movements during Elementary School Recess.

BACKGROUND: The US Center for Disease Control estimates that only 24% of American elementary-aged children participate in the recommended 60 min of daily physical activity. As activity levels decline, elementary schools should consider increasing movement opportunities. Activity-driven school days, where children can move their limbs freely, may increase memory retention performance, behavioral impulse control, as well as bone density, and muscle strength. Unstructured, outdoor play (recess) may provide an opportunity for the brain, bone, and muscle-stimulating limb movements to be utilized. To date, no research has focused on whether the modern child actively uses limb movements during recess, nor to what degree. The purpose of this study was to develop a reliable assessment tool (Movement Pattern Observation Tool, MPOT) to observe and record limb movements (unilateral, bilateral, and contralateral movements) of elementary children during recess, defined in this study as unstructured, outdoor play. METHODS: Three observers used the MPOT to complete thirty-five observations at one elementary school during kindergarten through fifth-grade recess breaks. RESULTS: Interrater reliability approached excellent, being that excellent is above 0.90. The ICC of the master observer and observer 3 value was 0.898 (95% CI 0.757-0.957), and the ICC of the master observer and observer 2 was 0.885 (95% CI 0.599-0.967), p < 0.03. CONCLUSION: Inter-rater reliability was achieved through a three-phase process. This reliable recess observation tool will contribute to the body of research linking recess to physical and cognitive health.

Effects of Voluntary Wheel Running Exercise on Chemotherapy-Impaired Cognitive and Motor Performance in Mice.

Chemotherapy-induced cognitive impairment (chemobrain) and muscle wasting (cachexia) are persisting side effects which adversely affect the quality of life of cancer survivors. We therefore investigated the efficacy of physical exercise as a non-pharmacological intervention to reverse the adverse effects of chemotherapy. We examined whether physical exercise in terms of voluntary wheel running could prevent chemotherapy-induced cognitive and motor impairments in mice treated with the multi-kinase inhibitor sorafenib. Adult male BALB/c mice were subdivided into runner and non-runner groups and orally administered with sorafenib (60 mg/kg) or vehicle continuously for four weeks. Mice could freely access the running wheel anytime during sorafenib or vehicle treatment. We found that sorafenib treatment reduced body weight gain (% of change, vehicle: 3.28 ± 3.29, sorafenib: -9.24 ± 1.52, p = 0.0004), impaired hippocampal-dependent spatial memory in the Y maze (exploration index, vehicle: 35.57 ± 11.38%, sorafenib: -29.62 ± 7.90%, p < 0.0001), increased anhedonia-like behaviour in the sucrose preference test (sucrose preference, vehicle: 66.57 ± 3.52%, sorafenib: 44.54 ± 4.25%, p = 0.0005) and impaired motor skill acquisition in rotarod test (latency to fall on day 1: 37.87 ± 8.05 and day 2: 37.22 ± 12.26 s, p > 0.05) but did not induce muscle wasting or reduce grip strength. Concomitant voluntary running reduced anhedonia-like behaviour (sucrose preference, sedentary: 44.54 ± 4.25%, runners: 59.33 ± 4.02%, p = 0.0357), restored impairment in motor skill acquisition (latency to fall on day 1: 50.85 ± 15.45 and day 2: 168.50 ± 37.08 s, p = 0.0004), but failed to rescue spatial memory deficit. Immunostaining results revealed that sorafenib treatment did not affect the number of proliferating cells and immature neurons in the hippocampal dentate gyrus (DG), whereas running significantly increased cell proliferation in both vehicle- (total Ki-67+ cells, sedentary: 16,687.34 ± 72.63, exercise: 3320.03 ± 182.57, p < 0.0001) and sorafenib-treated mice (Ki-67+ cells in the ventral DG, sedentary: 688.82.34 ± 38.16, exercise: 979.53 ± 73.88, p < 0.0400). Our results suggest that spatial memory impairment and anhedonia-like behaviour precede the presence of muscle wasting, and these behavioural deficits are independent of the changes in adult hippocampal neurogenesis. Running effectively prevents body weight loss, improves motor skill acquisition and reduces anhedonia-like behaviour associated with increased proliferating cells and immature neurons in DG. Taken together, they support physical exercise rehabilitation as an effective strategy to prevent chemotherapy side effects in terms of mood dysregulation and motor deficit.

Systemic vascular photobiomodulation accelerates the recovery of motor activity in rats following spinal cord injury.

OBJECTIVES: Spinal cord injury (SCI) causes the discontinuity of the spinal canal, leading to functional and sensorial losses in areas below the injury, which are often irreversible. Photobiomodulation (PBM) can enhance the neuromuscular repair process, especially in cases of peripheral nerve injuries. However, there is little knowledge regarding the effects of this therapeutic modality on recovery following a SCI, especially the noninvasive systemic form denominated vascular PBM (VPBM). To analyze the effects of VPBM in the immediate, acute and intermediate phases following a compression-induced SCI on morphological aspects of neuromuscular tissue repair, functional recovery and the protein expression of brain-derived neurotrophic factor (BDNF). METHODS: Wistar rats were divided into five groups: control, SCI, SCI + VPBM-Im (immediate administration of VPBM), SCI + VPBM-2h (VPBM administered 2 h after injury) and SCI + VPBM-14d (VPBM administered 14 days after injury). VPBM was administered in the region of the caudal vein/artery with low-level laser (AsGaAl, 780 nm, 80 J/cm², 40 mW for 80 s, totaling an energy of 3.2 J over a single point) for 14 consecutive days. During the analysis periods (1, 3, 7, 14, 21, 28 and 35 days after injury), functioning was evaluated using the Basso-Beattie-Bresnahan (BBB) index. At the end of each experimental period, blood samples were collected for the determination of the concentration of circulating BDNF using ELISA. Muscle tissue and nerve tissue samples were also extracted for morphological and histological analyses using H&E staining. RESULTS: SCI + VPBM-Im and SCI + VPBM-2 h led to the recovery of motor function beginning on the 7th day after injury (p < 0.05), an increase in the cross-sectional area (CSA) of the muscle fibers in the second week (p < 0.05) and an increase in muscle fiber diameter beginning on Day 14 (p < 0.05). Early irradiation had a greater effect on the reduction in the size of the cavity, with stabilization of the cavity found on Day 7 (p < 0.05). Considering the circulating BDNF levels, no changes was found during the experimental periods. CONCLUSION: The present results showed that VPBM was capable of modulating morphological and functional recovery following SCI, especially when administered early. The positive effects on functional recovery were demonstrated by the BBB index; the reestablishment of the structure of the muscle and nerve tissue was demonstrated by the preservation of CSA and diameter of muscle fiber and reduction in the area of the injury (cavity size) respectively. Thus, noninvasive VPBM may be an important component of treatment for spinal cord injuries.

Resolution of cisplatin-induced fatigue does not require endogenous interleukin-10 in male mice.

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 µg/day for three days) five days later. In the second experiment, they were treated with cisplatin (2.3 mg/kg/day for 5 days twice at a five-day interval) and IL10na (12 µg/day for three days) immediately after the last injection of cisplatin. In both experiments, cisplatin decreased body weight and reduced voluntary wheel running. However, IL-10na did not impair recovery from these effects. These results show that the recovery from the cisplatin-induced decrease in wheel running does not require endogenous IL-10 in contrast to the recovery from cisplatin-induced peripheral neuropathy.