Browsing by Author "Fleming, Elizabeth"

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    Embryonic exposure to benzo[a]pyrene causes age-dependent behavioral alterations and long-term metabolic dysfunction in zebrafish.
    (Neurotoxicology and teratology, 2022-09) Hawkey, Andrew B; Piatos, Perry; Holloway, Zade; Boyda, Jonna; Koburov, Reese; Fleming, Elizabeth; Di Giulio, Richard T; Levin, Edward D
    Polycyclic aromatic hydrocarbons (PAH) are products of incomplete combustion which are ubiquitous pollutants and constituents of harmful mixtures such as tobacco smoke, petroleum and creosote. Animal studies have shown that these compounds exert developmental toxicity in multiple organ systems, including the nervous system. The relative persistence of or recovery from these effects across the lifespan remain poorly characterized. These studies tested for persistence of neurobehavioral effects in AB* zebrafish exposed 5-120 h post-fertilization to a typical PAH, benzo[a]pyrene (BAP). Study 1 evaluated the neurobehavioral effects of a wide concentration range of BAP (0.02-10 μM) exposures from 5 to 120 hpf during larval (6 days) and adult (6 months) stages of development, while study 2 evaluated neurobehavioral effects of BAP (0.3-3 μM) from 5 to 120 hpf across four stages of development: larval (6 days), adolescence (2.5 months), adulthood (8 months) and late adulthood (14 months). Embryonic BAP exposure caused minimal effects on larval motility, but did cause neurobehavioral changes at later points in life. Embryonic BAP exposure led to nonmonotonic effects on adolescent activity (0.3 μM hyperactive, Study 2), which attenuated with age, as well as startle responses (0.2 μM enhanced, Study 1) at 6 months of age. Similar startle changes were also detected in Study 2 (1.0 μM), though it was observed that the phenotype shifted from reduced pretap activity to enhanced posttap activity from 8 to 14 months of age. Changes in the avoidance (0.02-10 μM, Study 1) and approach (reduced, 0.3 μM, Study 2) of aversive/social cues were also detected, with the latter attenuating from 8 to 14 months of age. Fish from study 2 were maintained into aging (18 months) and evaluated for overall and tissue-specific oxygen consumption to determine whether metabolic processes in the brain and other target organs show altered function in late life based on embryonic PAH toxicity. BAP reduced whole animal oxygen consumption, and overall reductions in total basal, mitochondrial basal, and mitochondrial maximum respiration in target organs, including the brain, liver and heart. The present data show that embryonic BAP exposure can lead to neurobehavioral impairment across the life-span, but that these long-term risks differentially emerge or attenuate as development progresses.
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    Roles of Inhibition in Shaping Sensory Representations in the Cerebellar Input Layer
    (2021) Fleming, Elizabeth

    The cerebellum plays a central role in motor learning by establishing sensorimotor associations necessary for coordinated movement. To do so, the cerebellum’s input layer, the granule cell layer, has been proposed to integrate and transform sensorimotor input in a way that creates unique population ensembles that can be easily learned by downstream Purkinje cells. For my thesis work, I used calcium indicators in combination with a specific pharmacological block of inhibition to measure single and combined sensory responses in granule cells in awake, behaving mice to test if local synaptic inhibition sparsens and diversifies granule cell ensembles. I have also tested if this feature can be a component of cerebellar learning, and whether neuromodulation can influence inhibition in a manner consistent with regulating sensorimotor representations. I have found that local synaptic inhibition sparsens and thresholds sensory responses, as well as sculpts population responses by establishing intensity preferences and selectively suppressing inputs. I have also found that inhibition to granule cells is necessary for performance of a cerebellum-dependent sensorimotor task. Additionally, serotonin modulates inhibition to suppress granule cell output, suggesting that it could enable learning flexibility to accommodate changes in environment or internal states. Together, my data suggest that synaptic inhibition has an important role in forming sensorimotor associations in the cerebellum.