Browsing by Subject "Motor Activity"

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Open Access
A comparison of activity patterns for captive Propithecus tattersalli and Propithecus coquereli.
(Zoo Biol, 2016-03) Wallace, Gregory L; Paquette, Lisa B; Glander, Kenneth E
The activity patterns and social interactions of two species of captive sifaka were observed during a 2-year period. Allogrooming was not observed in golden-crowned sifaka and they spent significantly more time resting than the Coquerel's sifaka. Females of both species were found to be dominant to males. The golden-crowned sifaka (Propithecus tattersalli) spent significantly less time feeding than the Coquerel's sifaka. Temperature, time of day, species, and interpair comparisons for the golden-crowned sifaka were found to affect activity and social interactions, while gender did not. Like the Coquerel's sifaka, the golden-crowned sifaka was found to be diurnal; however, they differed in that the golden-crowned sifaka did not descend to the ground.
Open Access
A framework for integrating the songbird brain.
(J Comp Physiol A Neuroethol Sens Neural Behav Physiol, 2002-12) Jarvis, ED; Smith, VA; Wada, K; Rivas, MV; McElroy, M; Smulders, TV; Carninci, P; Hayashizaki, Y; Dietrich, F; Wu, X; McConnell, P; Yu, J; Wang, PP; Hartemink, AJ; Lin, S
Biological systems by default involve complex components with complex relationships. To decipher how biological systems work, we assume that one needs to integrate information over multiple levels of complexity. The songbird vocal communication system is ideal for such integration due to many years of ethological investigation and a discreet dedicated brain network. Here we announce the beginnings of a songbird brain integrative project that involves high-throughput, molecular, anatomical, electrophysiological and behavioral levels of analysis. We first formed a rationale for inclusion of specific biological levels of analysis, then developed high-throughput molecular technologies on songbird brains, developed technologies for combined analysis of electrophysiological activity and gene regulation in awake behaving animals, and developed bioinformatic tools that predict causal interactions within and between biological levels of organization. This integrative brain project is fitting for the interdisciplinary approaches taken in the current songbird issue of the Journal of Comparative Physiology A and is expected to be conducive to deciphering how brains generate and perceive complex behaviors.
Open Access
Activity of neurons in monkey globus pallidus during oculomotor behavior compared with that in substantia nigra pars reticulata.
(J Neurophysiol, 2010-04) Shin, SooYoon; Sommer, Marc A
The basal ganglia are a subcortical assembly of nuclei involved in many aspects of behavior. Three of the nuclei have high firing rates and inhibitory influences: the substantia nigra pars reticulata (SNr), globus pallidus interna (GPi), and globus pallidus externa (GPe). The SNr contains a wide range of visual, cognitive, and motor signals that have been shown to contribute to saccadic eye movements. Our hypothesis was that GPe and GPi neurons carry similarly diverse signals during saccadic behavior. We recorded from GPe, GPi, and SNr neurons in monkeys that made memory-guided saccades and found that neurons in all three structures had increases or decreases in activity synchronized with saccade generation, visual stimulation, or reward. Comparing GPe neurons with GPi neurons, we found relatively more visual-related activity in GPe and more reward-related activity in GPi. Comparing both pallidal samples with the SNr, we found a greater resemblance between GPe and SNr neurons than that between GPi and SNr neurons. As expected from a known inhibitory projection from GPe to SNr, there was a general reversal of sign in activity modulations between the structures: bursts of activity were relatively more common in GPe and pauses more common in SNr. We analyzed the response fields of neurons in all three structures and found relatively narrow and lateralized fields early in trials (during visual and saccadic events) followed by a broadening later in trials (during reward). Our data reinforce an emerging, new consensus that the GPe and GPi, in addition to the SNr, contribute to oculomotor behavior.
Open Access
Adherence to diabetes guidelines for screening, physical activity and medication and onset of complications and death.
(J Diabetes Complications, 2015-11) Chen, Yiqun; Sloan, Frank A; Yashkin, Arseniy P
AIMS: Analyze relationships between adherence to guidelines for diabetes care - regular screening; physical activity; and medication - and diabetes complications and mortality. METHODS: Outcomes were onset of congestive heart failure (CHF), stroke, renal failure, moderate complications of lower extremities, lower-limb amputation, proliferative diabetic retinopathy (PDR), and mortality during follow-up. Participants were persons aged 65+ in the Health and Retirement Study (HRS) 2003 Diabetes Study and had Medicare claims in follow-up period (2004-8). RESULTS: Adherence to screening recommendations decreased risks of developing CHF (odds ratio (OR)=0.83; 95% confidence interval (CI): 0.72-0.96), stroke (OR=0.80; 95% CI: 0.68-0.94); renal failure (OR=0. 82; 95% CI: 0.71-0.95); and death (OR=0.86; 95% CI: 0.74-0.99). Adherence to physical activity recommendation reduced risks of stroke (OR=0.64; 95% CI: 0.45-0.90), renal failure (OR=0.71; 95% CI: 0.52-0.97), moderate lower-extremity complications (OR=0.71; 95% CI: 0.51-0.99), having a lower limb amputation (OR=0.31, 95% CI: 0.11-0.85), and death (OR=0.56, 95% CI: 0.41-0.77). Medication adherence was associated with lower risks of PDR (OR=0.35, 95% CI: 0.13-0.93). CONCLUSIONS: Adherence to screening, physical activity and medication guidelines was associated with lower risks of diabetes complications and death. Relative importance of adherence differed among outcome measures.
Open Access
Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.
(J Clin Invest, 2001-04) Freeman, K; Lerman, I; Kranias, EG; Bohlmeyer, T; Bristow, MR; Lefkowitz, RJ; Iaccarino, G; Koch, WJ; Leinwand, LA
The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.
Open Access
Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.
(PLoS One, 2010-08-20) Jiang, Yong-Hui; Pan, Yanzhen; Zhu, Li; Landa, Luis; Yoo, Jong; Spencer, Corinne; Lorenzo, Isabel; Brilliant, Murray; Noebels, Jeffrey; Beaudet, Arthur L
Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.
Open Access
An operant-based detection method for inferring tinnitus in mice.
(Journal of neuroscience methods, 2017-11) Zuo, Hongyan; Lei, Debin; Sivaramakrishnan, Shobhana; Howie, Benjamin; Mulvany, Jessica; Bao, Jianxin
Background
Subjective tinnitus is a hearing disorder in which a person perceives sound when no external sound is present. It can be acute or chronic. Because our current understanding of its pathology is incomplete, no effective cures have yet been established. Mouse models are useful for studying the pathophysiology of tinnitus as well as for developing therapeutic treatments.
New method
We have developed a new method for determining acute and chronic tinnitus in mice, called sound-based avoidance detection (SBAD). The SBAD method utilizes one paradigm to detect tinnitus and another paradigm to monitor possible confounding factors, such as motor impairment, loss of motivation, and deficits in learning and memory.
Results
The SBAD method has succeeded in monitoring both acute and chronic tinnitus in mice. Its detection ability is further validated by functional studies demonstrating an abnormal increase in neuronal activity in the inferior colliculus of mice that had previously been identified as having tinnitus by the SBAD method.
Comparison with existing methods
The SBAD method provides a new means by which investigators can detect tinnitus in a single mouse accurately and with more control over potential confounding factors than existing methods.
Conclusion
This work establishes a new behavioral method for detecting tinnitus in mice. The detection outcome is consistent with functional validation. One key advantage of mouse models is they provide researchers the opportunity to utilize an extensive array of genetic tools. This new method could lead to a deeper understanding of the molecular pathways underlying tinnitus pathology.
Open Access
Association between increased magnetic susceptibility of deep gray matter nuclei and decreased motor function in healthy adults.
(Neuroimage, 2015-01-15) Li, Wei; Langkammer, Christian; Chou, Ying-Hui; Petrovic, Katja; Schmidt, Reinhold; Song, Allen W; Madden, David J; Ropele, Stefan; Liu, Chunlei
In the human brain, iron is more prevalent in gray matter than in white matter, and deep gray matter structures, particularly the globus pallidus, putamen, caudate nucleus, substantia nigra, red nucleus, and dentate nucleus, exhibit especially high iron content. Abnormally elevated iron levels have been found in various neurodegenerative diseases. Additionally, iron overload and related neurodegeneration may also occur during aging, but the functional consequences are not clear. In this study, we explored the correlation between magnetic susceptibility--a surrogate marker of brain iron--of these gray matter structures with behavioral measures of motor and cognitive abilities, in 132 healthy adults aged 40-83 years. Latent variables corresponding to manual dexterity and executive functions were obtained using factor analysis. The factor scores for manual dexterity declined significantly with increasing age. Independent of gender, age, and global cognitive function, increasing magnetic susceptibility in the globus pallidus and red nuclei was associated with decreasing manual dexterity. This finding suggests the potential value of magnetic susceptibility, a non-invasive quantitative imaging marker of iron, for the study of iron-related brain function changes.
Open Access
Associations between BMI and home, school and route environmental exposures estimated using GPS and GIS: do we see evidence of selective daily mobility bias in children?
(Int J Health Geogr, 2015-02-06) Burgoine, Thomas; Jones, Andy P; Namenek Brouwer, Rebecca J; Benjamin Neelon, Sara E
BACKGROUND: This study examined whether objective measures of food, physical activity and built environment exposures, in home and non-home settings, contribute to children's body weight. Further, comparing GPS and GIS measures of environmental exposures along routes to and from school, we tested for evidence of selective daily mobility bias when using GPS data. METHODS: This study is a cross-sectional analysis, using objective assessments of body weight in relation to multiple environmental exposures. Data presented are from a sample of 94 school-aged children, aged 5-11 years. Children's heights and weights were measured by trained researchers, and used to calculate BMI z-scores. Participants wore a GPS device for one full week. Environmental exposures were estimated within home and school neighbourhoods, and along GIS (modelled) and GPS (actual) routes from home to school. We directly compared associations between BMI and GIS-modelled versus GPS-derived environmental exposures. The study was conducted in Mebane and Mount Airy, North Carolina, USA, in 2011. RESULTS: In adjusted regression models, greater school walkability was associated with significantly lower mean BMI. Greater home walkability was associated with increased BMI, as was greater school access to green space. Adjusted associations between BMI and route exposure characteristics were null. The use of GPS-actual route exposures did not appear to confound associations between environmental exposures and BMI in this sample. CONCLUSIONS: This study found few associations between environmental exposures in home, school and commuting domains and body weight in children. However, walkability of the school neighbourhood may be important. Of the other significant associations observed, some were in unexpected directions. Importantly, we found no evidence of selective daily mobility bias in this sample, although our study design is in need of replication in a free-living adult sample.
Open Access
Axonal regrowth after spinal cord injury via chondroitinase and the tissue plasminogen activator (tPA)/plasmin system.
(The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011-10) Bukhari, Noreen; Torres, Luisa; Robinson, John K; Tsirka, Stella E
Spinal cord injury (SCI) causes permanent debilitation due to the inability of axons to grow through established scars. Both the sugar chains and core proteins of chondroitin sulfate proteoglycans (CSPGs) are inhibitory for neurite regrowth. Chondroitinase ABC (ChABC) degrades the sugar chains and allows for synaptic plasticity, suggesting that after the sugar chain cleavage additional steps occur promoting a permissive microenvironment in the glial scar region. We report that the clearance of the core protein by the tissue plasminogen activator (tPA)/plasmin proteolytic system partially contributes to ChABC-promoted plasticity. tPA and plasmin are upregulated after SCI and degrade the deglycosylated CSPG proteins. Mice lacking tPA (tPA(-/-)) exhibit attenuated neurite outgrowth and blunted sensory and motor recovery despite ChABC treatment. Coadministration of ChABC and plasmin enhanced the tPA(-/-) phenotype and supported recovery in WT SCI mice. Collectively, these findings show that the tPA/plasmin cascade may act downstream of ChABC to allow for synergistic sensory and motor improvement compared with each treatment alone and suggest a potential new approach to enhance functional recovery after SCI.
Open Access
Brain research to ameliorate impaired neurodevelopment--home-based intervention trial (BRAIN-HIT).
(BMC pediatrics, 2010-04-30) Wallander, Jan L; McClure, Elizabeth; Biasini, Fred; Goudar, Shivaprasad S; Pasha, Omrana; Chomba, Elwyn; Shearer, Darlene; Wright, Linda; Thorsten, Vanessa; Chakraborty, Hrishikesh; Dhaded, Sangappa M; Mahantshetti, Niranjana S; Bellad, Roopa M; Abbasi, Zahid; Carlo, Waldemar; BRAIN-HIT Investigators
This randomized controlled trial aims to evaluate the effects of an early developmental intervention program on the development of young children in low- and low-middle-income countries who are at risk for neurodevelopmental disability because of birth asphyxia. A group of children without perinatal complications are evaluated in the same protocol to compare the effects of early developmental intervention in healthy infants in the same communities. Birth asphyxia is the leading specific cause of neonatal mortality in low- and low-middle-income countries and is also the main cause of neonatal and long-term morbidity including mental retardation, cerebral palsy, and other neurodevelopmental disorders. Mortality and morbidity from birth asphyxia disproportionately affect more infants in low- and low-middle-income countries, particularly those from the lowest socioeconomic groups. There is evidence that relatively inexpensive programs of early developmental intervention, delivered during home visit by parent trainers, are capable of improving neurodevelopment in infants following brain insult due to birth asphyxia.This trial is a block-randomized controlled trial that has enrolled 174 children with birth asphyxia and 257 without perinatal complications, comparing early developmental intervention plus health and safety counseling to the control intervention receiving health and safety counseling only, in sites in India, Pakistan, and Zambia. The interventions are delivered in home visits every two weeks by parent trainers from 2 weeks after birth until age 36 months. The primary outcome of the trial is cognitive development, and secondary outcomes include social-emotional and motor development. Child, parent, and family characteristics and number of home visits completed are evaluated as moderating factors.The trial is supervised by a trial steering committee, and an independent data monitoring committee monitors the trial. Findings from this trial have the potential to inform about strategies for reducing neurodevelopmental disabilities in at-risk young children in low and middle income countries.
Open Access
Chronic spinal cord electrical stimulation protects against 6-hydroxydopamine lesions.
(Scientific reports, 2014-01-23) Yadav, Amol P; Fuentes, Romulo; Zhang, Hao; Vinholo, Thais; Wang, Chi-Han; Freire, Marco Aurelio M; Nicolelis, Miguel AL
Although L-dopa continues to be the gold standard for treating motor symptoms of Parkinson's disease (PD), it presents long-term complications. Deep brain stimulation is effective, but only a small percentage of idiopathic PD patients are eligible. Based on results in animal models and a handful of patients, dorsal column stimulation (DCS) has been proposed as a potential therapy for PD. To date, the long-term effects of DCS in animal models have not been quantified. Here, we report that DCS applied twice a week in rats treated with bilateral 6-OHDA striatal infusions led to a significant improvement in symptoms. DCS-treated rats exhibited a higher density of dopaminergic innervation in the striatum and higher neuronal cell count in the substantia nigra pars compacta compared to a control group. These results suggest that DCS has a chronic therapeutical and neuroprotective effect, increasing its potential as a new clinical option for treating PD patients.
Open Access
Cognitive and Behavioral Impairments Evoked by Low-Level Exposure to Tobacco Smoke Components: Comparison with Nicotine Alone.
(Toxicological sciences : an official journal of the Society of Toxicology, 2016-06) Hall, Brandon J; Cauley, Marty; Burke, Dennis A; Kiany, Abtin; Slotkin, Theodore A; Levin, Edward D
Active maternal smoking has adverse effects on neurobehavioral development of the offspring, with nicotine (Nic) providing much of the underlying causative mechanism. To determine whether the lower exposures caused by second-hand smoke are deleterious, we administered tobacco smoke extract (TSE) to pregnant rats starting preconception and continued through the second postnatal week, corresponding to all 3 trimesters of fetal brain development. Dosing was adjusted to produce maternal plasma Nic concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers. We then compared TSE effects to those of an equivalent dose of Nic alone, and to a 10-fold higher Nic dose. Gestational exposure to TSE and Nic significantly disrupted cognitive and behavioral function in behavioral tests given during adolescence and adulthood (postnatal weeks 4-40), producing hyperactivity, working memory deficits, and impairments in emotional processing, even at the low exposure levels corresponding to second-hand smoke. Although TSE effects were highly correlated with those of Nic, the effects of TSE were much larger than could be attributed to just the Nic in the mixture. Indeed, TSE effects more closely resembled those of the 10-fold higher Nic levels, but still exceeded their magnitude. In combination with our earlier findings, this study thus completes the chain of causation to prove that second-hand smoke exposure causes neurodevelopmental deficits, originating in disruption of neurodifferentiation, leading to miswiring of neuronal circuits, and as shown here, culminating in behavioral dysfunction. As low level exposure to Nic alone produced neurobehavioral teratology, 'harm reduction' Nic products do not abolish the potential for neurodevelopmental damage.
Open Access
Comparative effects of multilevel muscle tendon surgery, osteotomies, and dorsal rhizotomy on functional and gait outcome measures for children with cerebral palsy.
(PM & R : the journal of injury, function, and rehabilitation, 2015-05) Feger, Mark A; Lunsford, Christopher D; Sauer, Lindsay D; Novicoff, Wendy; Abel, Mark F
Objective
To compare the impact of common surgical interventions (selective dorsal rhizotomy, muscle-tendon surgery, and osteotomies) for patients with cerebral palsy (CP) on Gross Motor Function Measure and temporal, kinematic, and kinetic gait variables as assessed via 3-dimensional motion analysis.
Design
Retrospective cohort study.
Setting
Motion analyses laboratory.
Participants
Ninety-four patients with CP, 56 of whom underwent surgery (37, muscle-tendon surgery; 11, osteotomy; and 8, selective dorsal rhizotomy) and 38 of whom did not have surgery; the patients were ages 4-18 years, with a Gross Motor Function Classification System classification of I, II, or III.
Interventions
Single-event, multilevel muscle tendon surgery, selective dorsal rhizotomy, and osteotomy.
Main outcome measures
Change scores (postintervention - preintervention) in Gross Motor Function Measure and temporal, kinematic, and kinetic gait variables.
Results
No statistically significant differences in change scores were found between groups in the Gross Motor Function Measure, velocity, or stride length measures after the observation period. The selective dorsal rhizotomy group had greater improvements in knee extension when compared with the nonsurgical group and greater hip and knee total range of motion during the gait cycle when compared with nonsurgical group and the muscle-tendon surgery and osteotomy cohorts. Lastly, the muscle-tendon surgery group had greater improvements in total knee range of motion compared with the nonsurgical group.
Conclusions
Patients who undergo selective dorsal rhizotomy and, to a lesser extent, muscle tendon procedures demonstrate greater improvements in kinematic gait variables compared with nonsurgical interventions in patients with spasticity resulting from CP.
Open Access
Correlates of sedentary time and physical activity among preschool-aged children.
(Prev Chronic Dis, 2011-11) Dolinsky, Diana H; Brouwer, Rebecca J Namenek; Evenson, Kelly R; Siega-Riz, Anna Maria; Østbye, Truls
INTRODUCTION: Few studies have examined the correlates of objectively measured amounts of sedentary time and physical activity in young children. We evaluated the demographic, biological, behavioral, social, and environmental correlates of the amount of sedentary time and moderate-to-vigorous physical activity (MVPA) as measured by accelerometry in preschool-aged children. METHODS: We obtained baseline measurements of physical activity by using an Actical accelerometer among 337 preschool-aged children (aged 2-5) of overweight or obese mothers. For children, we defined sedentary time as less than 12 counts per 15 seconds and MVPA as 715 or more counts per 15 seconds. Body mass index of the mother and child (calculated from measured height and weight) and maternal physical activity as measured by accelerometer were included as potential correlates. Mothers self-reported all other potential correlates. We used multivariable linear regression analyses to examine correlates of the amount of sedentary time and MVPA. RESULTS: Children had an average of 6.1 hours per day of sedentary time and 14.9 minutes per day of MVPA. In multivariable analysis, boys (P <.001) had fewer minutes per day of sedentary time, whereas older children (P <.001), boys (P <.001), children in high-income households (>$60,000/y [P = .005]), and children who spent more time outdoors (P = .001) had more MVPA. CONCLUSION: Both modifiable and nonmodifiable factors were correlated with preschool children's amount of MVPA, which can be helpful when designing interventions for this age group. The lack of correlates for sedentary time indicates the need for further investigation into this behavior.
Open Access
Critical developmental periods for effects of low-level tobacco smoke exposure on behavioral performance.
(Neurotoxicology, 2018-09) Cauley, Marty; Hall, Brandon J; Abreu-Villaça, Yael; Junaid, Shaqif; White, Hannah; Kiany, Abtin; Slotkin, Theodore A; Levin, Edward D
Tobacco exposure during development leads to neurobehavioral dysfunction in children, even when exposure is limited to secondhand smoke. We have previously shown in rats that developmental exposure to tobacco smoke extract (TSE), at levels mimicking secondhand smoke, starting preconception and extending throughout gestation, evoked subsequent locomotor hyperactivity and cognitive impairment. These effects were greater than those caused by equivalent exposures to nicotine alone, implying that other agents in tobacco smoke contributed to the adverse behavioral effects. In the present study, we examined the critical developmental windows of vulnerability for these effects, restricting TSE administration (0.2 mg/kg/day nicotine equivalent, or DMSO vehicle, delivered by subcutaneously-implanted pumps) to three distinct 10 day periods: the 10 days preceding mating, the first 10 days of gestation (early gestation), or the second 10 days of gestation (late gestation). The principal behavioral effects revealed a critical developmental window of vulnerability, as well as sex selectivity. Late gestational TSE exposure significantly increased errors in the initial training on the radial-arm maze in female offspring, whereas no effects were seen in males exposed during late gestation, or with either sex in the other exposure windows. In attentional testing with the visual signal detection test, male offspring exposed to TSE during early or late gestation showed hypervigilance during low-motivating conditions. These results demonstrate that gestational TSE exposure causes persistent behavioral effects that are dependent on the developmental window in which exposure occurs. The fact that effects were seen at TSE levels modeling secondhand smoke, emphasizes the need for decreasing involuntary tobacco smoke exposure, particularly during pregnancy.
Open Access
Developmental exposure of zebrafish to vitamin D receptor acting drugs and environmental toxicants disrupts behavioral function.
(Neurotoxicology and teratology, 2020-09) Oliveri, Anthony N; Glazer, Lilah; Mahapatra, Debabrata; Kullman, Seth W; Levin, Edward D
Vitamin D receptor (VDR) signaling is important for optimal neurobehavioral development. Disruption of VDR signaling by environmental toxicants during early development might contribute to the etiology of behavioral dysfunction. In the current set of studies, we examined ten compounds known to affect VDR function in vitro for neurobehavioral effects in vivo in zebrafish. Zebrafish embryos were exposed to concentrations of the compounds in their water during the first 5 days post-fertilization. On day 5, the embryos were tested in an alternating light-dark locomotor assay using a computerized video tracking system. We found that most of the compounds produced significant changes in locomotor behavior in exposed zebrafish larvae, although the direction of the effect (i.e., hypo- or hyperactivity) and the sensitivity of the effect to changes in illumination condition varied across the compounds. The nature of the behavioral effects generally corresponded to the effects these compounds have been shown to exert on VDR. These studies lay a foundation for further investigation to determine whether behavioral dysfunction persists into adulthood and if so which behavioral functions are affected. Zebrafish can be useful for screening compounds identified in high throughput in vitro assays to provide an initial test for how those compounds would affect construction and behavioral function of a complex nervous system, helping to bridge the gap between in vitro neurotoxicity assays and mammalian models for risk assessment in humans.
Open Access
Developmental Exposure to Low Concentrations of Organophosphate Flame Retardants Causes Life-Long Behavioral Alterations in Zebrafish.
(Toxicological sciences : an official journal of the Society of Toxicology, 2018-10) Glazer, Lilah; Hawkey, Andrew B; Wells, Corinne N; Drastal, Meghan; Odamah, Kathryn-Ann; Behl, Mamta; Levin, Edward D
As the older class of brominated flame retardants (BFRs) are phased out of commercial use because of findings of neurotoxicity with developmental exposure, a newer class of flame retardants have been introduced, the organophosphate flame retardants (OPFRs). Presently, little is known about the potential for developmental neurotoxicity or the behavioral consequences of OPFR exposure. Our aim was to characterize the life-long neurobehavioral effects of 4 widely used OPFRs using the zebrafish model. Zebrafish embryos were exposed to 0.1% DMSO (vehicle control); or one of the following treatments; isopropylated phenyl phosphate (IPP) (0.01, 0.03, 0.1, 0.3 µM); butylphenyl diphenyl phosphate (BPDP) (0.003, 0.03, 0.3, 3 µM); 2-ethylhexyl diphenyl phosphate (EHDP) (0.03, 0.3, 1 µM); isodecyl diphenyl phosphate (IDDP) (0.1, 0.3, 1, 10 µM) from 0- to 5-days postfertilization. On Day 6, the larvae were tested for motility under alternating dark and light conditions. Finally, at 5-7 months of age the exposed fish and controls were tested on a battery of behavioral tests to assess emotional function, sensorimotor response, social interaction and predator evasion. These tests showed chemical-specific short-term effects of altered motility in larvae in all of the tested compounds, and long-term impairment of anxiety-related behavior in adults following IPP, BPDP, or EHDP exposures. Our results show that OPFRs may not be a safe alternative to the phased-out BFRs and may cause behavioral impacts throughout the lifespan. Further research should evaluate the risk to mammalian experimental models and humans.
Restricted
Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice.
(Arthritis Res Ther, 2010) Griffin, Timothy M; Fermor, Beverley; Huebner, Janet L; Kraus, Virginia B; Rodriguiz, Ramona M; Wetsel, William C; Cao, Li; Setton, Lori A; Guilak, Farshid
INTRODUCTION: Obesity is a major risk factor for the development of osteoarthritis in both weight-bearing and nonweight-bearing joints. The mechanisms by which obesity influences the structural or symptomatic features of osteoarthritis are not well understood, but may include systemic inflammation associated with increased adiposity. In this study, we examined biomechanical, neurobehavioral, inflammatory, and osteoarthritic changes in C57BL/6J mice fed a high-fat diet. METHODS: Female C57BL/6J mice were fed either a 10% kcal fat or a 45% kcal fat diet from 9 to 54 weeks of age. Longitudinal changes in musculoskeletal function and inflammation were compared with endpoint neurobehavioral and osteoarthritic disease states. Bivariate and multivariate analyses were conducted to determine independent associations with diet, percentage body fat, and knee osteoarthritis severity. We also examined healthy porcine cartilage explants treated with physiologic doses of leptin, alone or in combination with IL-1α and palmitic and oleic fatty acids, to determine the effects of leptin on cartilage extracellular matrix homeostasis. RESULTS: High susceptibility to dietary obesity was associated with increased osteoarthritic changes in the knee and impaired musculoskeletal force generation and motor function compared with controls. A high-fat diet also induced symptomatic characteristics of osteoarthritis, including hyperalgesia and anxiety-like behaviors. Controlling for the effects of diet and percentage body fat with a multivariate model revealed a significant association between knee osteoarthritis severity and serum levels of leptin, adiponectin, and IL-1α. Physiologic doses of leptin, in the presence or absence of IL-1α and fatty acids, did not substantially alter extracellular matrix homeostasis in healthy cartilage explants. CONCLUSIONS: These results indicate that diet-induced obesity increases the risk of symptomatic features of osteoarthritis through changes in musculoskeletal function and pain-related behaviors. Furthermore, the independent association of systemic adipokine levels with knee osteoarthritis severity supports a role for adipose-associated inflammation in the molecular pathogenesis of obesity-induced osteoarthritis. Physiologic levels of leptin do not alter extracellular matrix homeostasis in healthy cartilage, suggesting that leptin may be a secondary mediator of osteoarthritis pathogenesis.
Open Access
Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle.
(Mol Genet Metab, 2011-06) Koeberl, Dwight D; Luo, Xiaoyan; Sun, Baodong; McVie-Wylie, Alison; Dai, Jian; Li, Songtao; Banugaria, Suhrad G; Chen, Y-T; Bali, Deeksha S
Enzyme replacement therapy (ERT) with acid α-glucosidase has become available for Pompe disease; however, the response of skeletal muscle, as opposed to the heart, has been attenuated. The poor response of skeletal muscle has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle compared to heart. To further understand the role of CI-MPR in Pompe disease, muscle-specific CI-MPR conditional knockout (KO) mice were crossed with GAA-KO (Pompe disease) mice. We evaluated the impact of CI-MPR-mediated uptake of GAA by evaluating ERT in CI-MPR-KO/GAA-KO (double KO) mice. The essential role of CI-MPR was emphasized by the lack of efficacy of ERT as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with the administration of the same therapeutic doses in GAA-KO mice. Clenbuterol, a selective β(2)-agonist, enhanced the CI-MPR expression in skeletal tissue and also increased efficacy from GAA therapy, thereby confirming the key role of CI-MPR with regard to enzyme replacement therapy in Pompe disease. Biochemical correction improved in both muscle and non-muscle tissues, indicating that therapy could be similarly enhanced in other lysosomal storage disorders. In summary, enhanced CI-MPR expression might improve the efficacy of enzyme replacement therapy in Pompe disease through enhancing receptor-mediated uptake of GAA.

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