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Open Access Publications from the University of California

Scholarly Works (24 results)

  • Thesis
  • Peer Reviewed
UC Davis Electronic Theses and Dissertations (2021)

Neurodevelopmental disorders (NDDs) are a broad group of conditions characterized by abnormal development of the nervous system that includes intellectual disability and autism spectrum disorders. NDDs are pervasive, lifelong, and increasing in prevalence, yet neither targeted pharmacological nor precision medicine therapies are currently available. This unmet need is in large part due to the complex and relatively unknown etiology of many NDDs. Multiple genetic loci, in combination with exposure to environmental risk factors during critical periods of development, contribute to both NDD susceptibility and symptom severity. In an effort to improve our understanding of NDD etiology, as well as help develop effective treatments, we used Sprague Dawley rats to examine the effects of two environmental risk factors and one causal genetic mutation on behaviors and neurobiological outcomes relevant to NDDs. While the mouse has predominated in recent decades as the species of choice for modeling NDDs, we sought to take advantage of the broader and more nuanced social communication repertoire of the rat. Therefore, we measured effects on a variety of behavioral domains including motor and cognition and gave particular focus to social and communication behaviors. Chapter 1 serves as an introduction to the study of social communication in rodent models of NDDs and provides detailed rationales behind many of the assays utilized in subsequent chapters. Chapters 2 and 3 investigate environmental factors that have been associated with increased risk for NDDs: air pollution and pesticides, respectively. Our findings support the hypothesis that developmental exposure to heavily trafficked roadways, or to the commonly used pesticide chlorpyrifos, increases NDD risk. Then, Chapters 4 and 5 characterize a novel genetic rat model of the NDD Angelman Syndrome, which is caused by dysfunction of the gene UBE3A (ubiquitin protein ligase E3A). We discovered that the Ube3a deletion rat model of Angelman Syndrome recapitulated many of the core behavioral and neurobiological phenotypes of the disorder, including elevated expression of positive affect signals, and thereby utilized the rat model in Chapter 6 to test the efficacy of a candidate therapeutic, insulin-like growth factor 2. Although treatment with insulin-like growth factor 2 failed to rescue the model’s deficits, the outcome measures used were robust and reproducible, indicating that the Ube3a deletion rat offers a strong preclinical model of Angelman Syndrome. Finally, Chapter 7 investigates a leading-edge “gene therapy-like” antisense oligonucleotide treatment in the rat model of Angelman Syndrome. Multiple clinical trials are currently evaluating antisense oligonucleotide therapies in humans with Angelman Syndrome and, while they have demonstrated remarkable efficacy, serious adverse reactions have been observed. By identifying an antisense oligonucleotide with molecular efficacy in the rat and delivering it via the brain, the cisterna magna, and lumbar puncture, we established a paradigm through which to elucidate the pathophysiology underlying the adverse clinical reactions. Taken together, this research advances our understanding of the complex etiology of NDDs, represents significant progress in modeling NDDs preclinically, and provides insights with direct implications to the ongoing pursuit of pharmacological treatments targeted to NDDs.

    Cover page: Behavioral and Neurobiological Outcomes Following Genetic and Environmental Insults to the Developing Brain
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2012)
      Cover page: A laboratory exercise using a physical model for demonstrating countercurrent heat exchangeCreative Commons 'BY' version 4.0 license
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2021)
      The COVID-19 pandemic triggered an unprecedented expansion of telemedicine, leading to development of new workflows. We conducted a survey of telemedicine practice among pediatric gastroenterology practitioners on March 26, 2020. Responses were coded and analyzed. The survey garnered 33 responses. Most centers were 3 weeks into the implementation. The most commonly used telemedicine software was Zoom followed by FaceTime, telephone, and Epic software. Provider education was through online meetings, webinars, and tip sheets. Patient education was by nonclinical staff at the time of visit scheduling or tip sheets. A major barrier was the need for patients to enroll in an electronic portal. Two thirds of practices offered telemedicine to both new and return patients. Most sites billed based on time. This represents a record of the very early response of the pediatric gastroenterology community to the COVID-19 telemedicine expansion and can inform follow-up studies.
        Cover page: Telemedicine Expansion in Pediatric Gastroenterology in Response to COVID-19: Early Results of an International Physician Survey.
        • Article
        • Peer Reviewed
        LBL Publications (2021)
        Near-surface seismic velocity structure plays a critical role in ground motion amplification during large earthquakes. In particular, the local Vp/Vs ratio strongly influences the amplitude of Rayleigh waves. Previous studies have separately imaged 3D seismic velocity and Vp/Vs ratio at seismogenic depth, but lack regional coverage and/or fail to constrain the shallowest structure. Here, we combine three datasets with complementary sensitivity in a Bayesian joint inversion for shallow crustal shear velocity and near-surface Vp/Vs ratio across Southern California. Receiver functions–including with an apparent delayed initial peak in sedimentary basins, and long considered a nuisance in receiver function imaging studies–highly correlate with short-period Rayleigh wave ellipticity measurements and require the inclusion of a Vp/Vs parameter. The updated model includes near-surface low shear velocity more in line with geotechnical layer estimates, and generally lower than expected Vp/Vs outside the basins suggesting widespread shallow fracturing and/or groundwater undersaturation.
          Cover page: Shallow Crustal Shear Velocity and Vp/Vs Across Southern California: Joint Inversion of Short‐Period Rayleigh Wave Ellipticity, Phase Velocity, and Teleseismic Receiver Functions
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2022)
          Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and motor coordination deficits. Motor abilities are an important outcome measure in AS as they comprise a broad repertoire of metrics including ataxia, hypotonia, delayed ambulation, crouched gait, and poor posture, and motor dysfunction affects nearly every individual with AS. Guided by collaborative work with AS clinicians studying gait, the goal of this study was to perform an in-depth gait analysis using the automated treadmill assay, DigiGait. Our hypothesis is that gait presents a strong opportunity for a reliable, quantitative, and translational metric that can serve to evaluate novel pharmacological, dietary, and genetic therapies. In this study, we used an automated gait analysis system, in addition to standard motor behavioral assays, to evaluate components of motor, exploration, coordination, balance, and gait impairments across the lifespan in an AS mouse model. Our study demonstrated marked global motoric deficits in AS mice, corroborating previous reports. Uniquely, this is the first report of nuanced aberrations in quantitative spatial and temporal components of gait in AS mice compared to sex- and age-matched wildtype littermates followed longitudinally using metrics that are analogous in AS individuals. Our findings contribute evidence toward the use of nuanced motor outcomes (i.e., gait) as valuable and translationally powerful metrics for therapeutic development for AS, as well as other genetic neurodevelopmental syndromes. LAY SUMMARY: Movement disorders affect nearly every individual with Angelman Syndrome (AS). The most common motor problems include spasticity, ataxia of gait (observed in the majority of ambulatory individuals), tremor, and muscle weakness. This report focused on quantifying various spatial and temporal aspects of gait as a reliable, translatable outcome measure in a preclinical AS model longitudinally across development. By increasing the number of translational, reliable, functional outcome measures in our wheelhouse, we will create more opportunities for identifying and advancing successful medical interventions.
            Cover page: Gait as a quantitative translational outcome measure in Angelman syndrome
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2021)

            Background

            Angelman Syndrome (AS) is a rare neurodevelopmental disorder for which there is currently no cure or effective therapeutic. Since the genetic cause of AS is known to be dysfunctional expression of the maternal allele of ubiquitin protein ligase E3A (UBE3A), several genetic animal models of AS have been developed. Both the Ube3a maternal deletion mouse and rat models of AS reliably demonstrate behavioral phenotypes of relevance to AS and therefore offer suitable in vivo systems in which to test potential therapeutics. One promising candidate treatment is insulin-like growth factor-2 (IGF-2), which has recently been shown to ameliorate behavioral deficits in the mouse model of AS and improve cognitive abilities across model systems.

            Methods

            We used both the Ube3a maternal deletion mouse and rat models of AS to evaluate the ability of IGF-2 to improve electrophysiological and behavioral outcomes.

            Results

            Acute systemic administration of IGF-2 had an effect on electrophysiological activity in the brain and on a metric of motor ability; however the effects were not enduring or extensive. Additional metrics of motor behavior, learning, ambulation, and coordination were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition.

            Limitations

            The generalizability of these results to humans is difficult to predict and it remains possible that dosing schemes (i.e., chronic or subchronic dosing), routes, and/or post-treatment intervals other than that used herein may show more efficacy.

            Conclusions

            Despite a few observed effects of IGF-2, our results taken together indicate that IGF-2 treatment does not profoundly improve behavioral deficits in mouse or rat models of AS. These findings shed cautionary light on the potential utility of acute systemic IGF-2 administration in the treatment of AS.
              Cover page: Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome
              • Article
              • Peer Reviewed
              UC Davis Previously Published Works (2020)

              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.
                Cover page: Translational Outcomes Relevant to Neurodevelopmental Disorders Following Early Life Exposure of Rats to Chlorpyrifos
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2022)
                With the coronavirus disease 2019 public health emergency (PHE), telehealth (TH) became essential for continued delivery of care. Members of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) formed the Telehealth for Pediatric Gastrointestinal Care Now (TPGCN) working group and rapidly organized a telemedicine webinar to provide education and guidance. We aim to describe the webinar development and prospectively assess the effectiveness of this webinar-based educational intervention.

                Methods

                NASPGHAN members who registered for the TPGCN webinar received pre- and post-webinar surveys. Outcome measures included a modified Telehealth Acceptance Model (TAM) survey and a Student Evaluation of Educational Quality (SEEQ) standardized instrument.

                Results

                Seven hundred seventy-six NASPGHAN members participated in the webinar, 147 (33%) completed the pre-webinar survey; of these, 25 of 147 (17%) completed a post-webinar survey. Before the PHE, 50.3% of the pre-webinar survey participants had no TH knowledge. Webinar participants trended to have increased acceptance of TH for follow-up visits (pre-webinar, 68% versus post-webinar, 81%; P = 0.15) and chronic disease care (pre-webinar, 57% vs post-webinar, 81%; P = 0.01). The overall acceptance of TH as shown by TAM pre-webinar was 1.74 ± 0.8, which improved to 1.62 ± 0.8 post-webinar (lower scores indicate greater acceptance; P < 0.001). SEEQ results indicate that webinar material was understandable (post-webinar, 95%). Participants found breakout sessions informative and enjoyable (post-webinar, 91%).

                Conclusion

                The TPGCN TH webinar was an effective educational intervention that fostered increased TH usage for follow-up and chronic care visits, improved TAM scores, and was well received by participants as seen by high SEEQ scores. Sustained and expanded pediatric gastrointestinal TH usage beyond the coronavirus disease 2019 PHE is expected.
                  Cover page: Telehealth for Pediatric Gastroenterology Care Now
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2019)
                  Ubiquitin E3 ligase 3A (UBE3A) encodes an E3 ubiquitin ligase whose loss from the maternal allele causes the neurodevelopmental disorder Angelman syndrome (AS). Previous studies of UBE3A function have not examined full Ube3a deletion in mouse, the complexity of imprinted gene networks in brain nor the molecular basis of systems-level cognitive dysfunctions in AS. We therefore utilized a systems biology approach to elucidate how UBE3A loss impacts the early postnatal brain in a novel CRISPR/Cas9-engineered rat Angelman model of a complete Ube3a deletion. Strand-specific transcriptome analysis of offspring from maternally or paternally inherited Ube3a deletions revealed the expected parental expression patterns of Ube3a sense and antisense transcripts by postnatal day 2 (P2) in hypothalamus and day 9 (P9) in cortex, compared to wild-type littermates. The dependency of genome-wide effects on parent-of-origin, Ube3a genotype and time (P2 and P9) was investigated through transcriptome (RNA sequencing of cortex and hypothalamus) and methylome (whole-genome bisulfite sequencing of hypothalamus). Weighted gene co-expression and co-methylation network analyses identified co-regulated networks in maternally inherited Ube3a deletion offspring enriched in postnatal developmental processes including Wnt signaling, synaptic regulation, neuronal and glial functions, epigenetic regulation, ubiquitin, circadian entrainment and splicing. Furthermore, we showed that loss of the paternal Ube3a antisense transcript resulted in both unique and overlapping dysregulated gene pathways with maternal loss, predominantly at the level of differential methylation. Together, these results provide a holistic examination of the molecular impacts of UBE3A loss in brain, supporting the existence of interactive epigenetic networks between maternal and paternal transcripts at the Ube3a locus.
                    • Article
                    • Peer Reviewed
                    UC Davis Previously Published Works (2020)

                    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 may not be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with 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 that 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 intellectual delay or disability, 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, 0.3, or 1.0 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-exposed rats and the corresponding vehicle controls using strict false discovery correction; however, there were interesting trends in females in the 0.3 mg/kg dose group.

                    Conclusions

                    This work generated and characterized 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 the brain or blood. These data suggest that current regulations regarding safe levels of CPF need to be reconsidered.
                      Cover page: Translational outcomes relevant to neurodevelopmental disorders following early life exposure of rats to chlorpyrifos
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