Assessing Healthspan and Lifespan Measures in Aging Mice: Optimization of Testing Protocols, Replicability, and Rater Reliability

Rizzo, Stacey J. Sukoff; Anderson, Laura; Green, Torrian L.; McGarr, Tracy C.; Wells, Gaylynn; Winter, Shawn S.

doi:10.1002/cpmo.45

Cited by 60 publications

(69 citation statements)

References 38 publications

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“…We observed high levels of repetitive motor behavior in the TRAP-exposed group, using a low-order motor stereotypy measure of grooming. Spontaneous alternation in T or Y maze, which may be mimicking higher order restricted, repetitive behaviors, are easily observable in mice [85][86][87][88] . Surprisingly, we did not observe deficits on our two standard assays of learning and memory, contextual and cued fear conditioning and novel object recognition, due to TRAP exposure.…”

Section: Discussionmentioning

confidence: 99%

Developmental exposure to near roadway pollution produces behavioral phenotypes relevant to neurodevelopmental disorders in juvenile rats

et al. 2020

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Epidemiological studies consistently implicate traffic-related air pollution (TRAP) and/or proximity to heavily trafficked roads as risk factors for developmental delays and neurodevelopmental disorders (NDDs); however, there are limited preclinical data demonstrating a causal relationship. To test the effects of TRAP, pregnant rat dams were transported to a vivarium adjacent to a major freeway tunnel system in northern California where they were exposed to TRAP drawn directly from the face of the tunnel or filtered air (FA). Offspring remained housed under the exposure condition into which they were born and were tested in a variety of behavioral assays between postnatal day 4 and 50. To assess the effects of near roadway exposure, offspring of dams housed in a standard research vivarium were tested at the laboratory. An additional group of dams was transported halfway to the facility and then back to the laboratory to control for the effect of potential transport stress. Near roadway exposure delayed growth and development of psychomotor reflexes and elicited abnormal activity in open field locomotion. Near roadway exposure also reduced isolation-induced 40-kHz pup ultrasonic vocalizations, with the TRAP group having the lowest number of call emissions. TRAP affected some components of social communication, evidenced by reduced neonatal pup ultrasonic calling and altered juvenile reciprocal social interactions. These findings confirm that living in close proximity to highly trafficked roadways during early life alters neurodevelopment.

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Section: Discussionmentioning

confidence: 99%

Developmental exposure to near roadway pollution produces behavioral phenotypes relevant to neurodevelopmental disorders in juvenile rats

et al. 2020

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“…At PND 52, a task of adhesive removal was used to assess sensory and find motor ability using a previously described mouse protocol modified for rats 78 . Rats individually habituated to an observation arena for 10 min and then a small round adhesive sticker (0.64 cm d; Avery Products Corporation, Strongsville, OH) was placed on the forehead.…”

Section: Adhesive Removalmentioning

confidence: 99%

Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome

et al. 2020

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Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3a m−/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3a m+/p− paternal transmission cohort. We also discovered Ube3a m−/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3a m−/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3a m+/p− did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS.

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“…Taken together, there is a lack of consistency and corroboration suggesting that locomotor activity is not a sensitive, reproducible and rigorous endpoint for low-level OP exposures in preclinical rodent models. Adverse effects on performance are often observed in a single laboratory, and follow-up literature is unable to reproduce or delineate cognitive impairments from motoric dysfunction (Sukoff Rizzo et al 2018; Rizzo and Silverman 2016). Future directions intended to comprehensively assess motor behavior with a speci c behavioral battery that includes gait, balance, coordination, velocity, temporal and spatial dynamic metrics over rudimentary activity and/or habituation will lead to improved translational value.…”

Section: Discussionmentioning

confidence: 99%

Translational Outcomes Relevant to Neurodevelopmental Disorders Following Early Life Exposure of Rats to Chlorpyrifos

Berg

Ching

Bruun

et al. 2020

Preprint

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Background: Neurodevelopmental disorders (NDDs), including intellectual disability, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are pervasive, lifelong disorders for which pharmacological interventions are not readily available. Substantial increases in the prevalence of NDDs over a relatively short period cannot be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with exposure(s) to environmental risk factors during critical periods of neurodevelopment influence NDD susceptibility and symptom severity. Organophosphorus (OP) pesticides have been identified as potential environmental risk factors. Epidemiological studies suggest children exposed prenatally to the OP pesticide chlorpyrifos (CPF) have significant mental and motor delays and strong positive associations for the development of a clinical diagnosis of developmental delay, ADHD, or ASD. Methods: We tested the hypothesis that developmental CPF exposure impairs behavior relevant to NDD phenotypes, i.e., deficits in social communication and repetitive, restricted behavior. Male and female rat pups were exposed to CPF at 0.1, 1.0, or 3.0 mg/kg (s.c.) from postnatal days 1-4. Results: These CPF doses did not significantly inhibit acetylcholinesterase activity in the blood or brain but significantly impaired pup ultrasonic vocalizations (USV) in both sexes. Social communication in juveniles via positive affiliative 50-kHz USV playback was absent in females exposed to CPF at 0.3 mg/kg and 1.0 mg/kg. In contrast, this CPF exposure paradigm had no significant effect on gross locomotor abilities or contextual and cued fear memory. Ex vivo magnetic resonance imaging largely found no differences between the CPF rats and the corresponding vehicle controls; however there were some interesting trends in females at a dosage of 0.3 mg/kg. Conclusions: This work characterizes a rat model of developmental CPF exposure that exhibits adverse behavioral phenotypes resulting from perinatal exposures at levels that did not significantly inhibit acetylcholinesterase activity in brain or blood. These data suggest that current regulations regarding safe levels of CPF need to be reconsidered.

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Assessing Healthspan and Lifespan Measures in Aging Mice: Optimization of Testing Protocols, Replicability, and Rater Reliability

Cited by 60 publications

References 38 publications

Developmental exposure to near roadway pollution produces behavioral phenotypes relevant to neurodevelopmental disorders in juvenile rats

Developmental exposure to near roadway pollution produces behavioral phenotypes relevant to neurodevelopmental disorders in juvenile rats

Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome

Translational Outcomes Relevant to Neurodevelopmental Disorders Following Early Life Exposure of Rats to Chlorpyrifos

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