Jason Rihel

Jason Rihel
University College London | UCL · Department of Cell and Developmental Biology

PhD

About

65
Publications
9,230
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4,416
Citations
Introduction
I study the genes and neurons that regulate sleep in zebrafish.
Additional affiliations
September 2017 - present
University College London
Position
  • Lecturer
February 2012 - October 2017
University College London
Position
  • Fellow
January 2006 - December 2011
Harvard University
Education
September 1998 - May 2004
Harvard University
Field of study
  • Biochemistry
September 1994 - May 1998
West Virginia University
Field of study
  • Biology and Chemistry

Publications

Publications (65)
Preprint
Full-text available
Sleep-wake disturbances are among the earliest symptoms of Alzheimer's disease (AD) and contribute to disease severity. Since a major driver of AD— the accumulation of amyloid-beta (Aβ) in the brain— is modulated by sleep, a "vicious" feedforward cycle has been proposed in which Aβ buildup disrupts sleep, leading to more Aβ secretion and further wo...
Article
Manganese neurotoxicity is a hallmark of Hypermanganesemia with Dystonia 2, an inherited manganese transporter defect caused by mutations in SLC39A14. To identify novel potential targets of manganese neurotoxicity we performed transcriptome analysis of slc39a14−/- mutant zebrafish unexposed and exposed to MnCl2. Differentially expressed genes mappe...
Article
Full-text available
Hundreds of human genes are associated with neurological diseases, but translation into tractable biological mechanisms is lagging. Larval zebrafish are an attractive model to investigate genetic contributions to neurological diseases. However, current CRISPR-Cas9 methods are difficult to apply to large genetic screens studying behavioural phenotyp...
Preprint
Full-text available
A bstract Sleep is a nearly universal feature of animal behaviour, yet many of the molecular, genetic, and neuronal substrates that orchestrate sleep/wake transitions lie undiscovered. Employing a viral insertion sleep screen in larval zebrafish, we identified a novel mutant, dreammist ( dmist ), with altered sleep-wake dynamics. CRISPR/Cas9-mediat...
Article
Sleep is a nearly universal feature of animal behaviour, yet many of the molecular, genetic, and neuronal substrates that orchestrate sleep/wake transitions lie undiscovered. Employing a viral insertion sleep screen in larval zebrafish, we identified a novel mutant, dreammist (dmist), with altered sleep-wake dynamics. CRISPR/Cas9-mediated disruptio...
Article
Full-text available
Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. Studies implicating the phenotypic consequences of SNX14 mutations to be consequences of subcellular disruption to autophagy and lipid metabolism have been limited to in vitro investigation of patient-derived dermal fibroblasts, labora...
Article
Full-text available
Disrupted sleep is a major feature of Alzheimer’s disease (AD), often arising years before symptoms of cognitive decline. Prolonged wakefulness exacerbates the production of amyloid-beta (Aβ) species, a major driver of AD progression, suggesting that sleep loss further accelerates AD through a vicious cycle. However, the mechanisms by which Aβ affe...
Article
Full-text available
Disrupted sleep is a major feature of Alzheimer’s disease (AD), often arising years before symptoms of cognitive decline. Prolonged wakefulness exacerbates the production of amyloid-beta (Aβ) species, a major driver of AD progression, suggesting that sleep loss further accelerates AD through a vicious cycle. However, the mechanisms by which Aβ affe...
Article
Full-text available
Disrupted sleep is a major feature of Alzheimer’s disease (AD), often arising years before symptoms of cognitive decline. Prolonged wakefulness exacerbates the production of amyloid-beta (Aβ) species, a major driver of AD progression, suggesting that sleep loss further accelerates AD through a vicious cycle. However, the mechanisms by which Aβ affe...
Preprint
Full-text available
Hundreds of human genes are associated with neurological diseases, but translation into tractable biological mechanisms is lagging. Larval zebrafish are an attractive model to investigate genetic contributions to neurological diseases. However, current CRISPR-Cas9 methods are difficult to apply to large genetic screens studying behavioural phenotyp...
Article
Animal behavior is dynamic, evolving over multiple timescales from milliseconds to days and even across a lifetime. To understand the mechanisms governing these dynamics, it is necessary to capture multi-timescale structure from behavioral data. Here, we develop computational tools and study the behavior of hundreds of larval zebrafish tracked cont...
Article
Full-text available
Research over the last 20 years has firmly established the existence of sleep states across the animal kingdom. Work in non-mammalian animal models such as nematodes, fruit flies, and zebrafish has now uncovered many evolutionarily conserved aspects of sleep physiology and regulation, including shared circuit architecture, homeostatic and circadian...
Article
Full-text available
The vertebrate CNS is surrounded by the meninges, a protective barrier comprised of the outer dura mater and the inner leptomeninges, which includes the arachnoid and pial layers. While the dura mater contains lymphatic vessels, no conventional lymphatics have been found within the brain or leptomeninges. However, non-lumenized cells called Brain/M...
Chapter
The explosion of genome-wide association studies and whole genome sequencing of tens of thousands of individual humans have led to the rapid discovery of many genetic alterations implicated in neurodevelopmental and neuropsychiatric disorders, including schizophrenia, intellectual disability, and autism spectrum disorder (ASD). This wealth of genet...
Preprint
Full-text available
Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. SCAR20 is understood to involve subcellular disruption to autophagy and lipid metabolism. Previously reported studies on the phenotypic consequences of SNX14 mutations have been limited to in vitro investigation of patient-derived derm...
Article
Sleep pressure increases during wake and dissipates during sleep, but the molecules and neurons that measure homeostatic sleep pressure remain poorly understood. We present a pharmacological assay in larval zebrafish that generates short-term increases in wakefulness followed by sustained rebound sleep after washout. The intensity of global neurona...
Preprint
Full-text available
Animal behaviour is dynamic, evolving over multiple timescales from milliseconds to days and even across a lifetime. To understand the mechanisms governing these dynamics, it is necessary to capture multi-timescale structure from behavioural data. Here, we develop computational tools and study the behaviour of hundreds of larval zebrafish tracked c...
Preprint
Full-text available
Disrupted sleep is a major feature of Alzheimer’s Disease (AD), often arising years before symptoms of cognitive decline. Prolonged wakefulness exacerbates the production of amyloid-beta (Aβ) species, a major driver of AD progression, suggesting that sleep loss further accelerates AD through a vicious cycle. However, the mechanisms by which Aβ affe...
Preprint
Full-text available
Sleep pressure homeostatically increases during wake and dissipates during sleep, but the molecular signals and neuronal substrates that measure homeostatic sleep pressure remain poorly understood. A pharmacological assay that generates acute, short-term increases in wakefulness in larval zebrafish, revealed that subsequent rebound sleep is depende...
Article
Full-text available
The lipid transporters of the phosphatidylinositol transfer protein (PITP) family dictate phosphoinositide compartmentalization, and specific phosphoinositides play crucial roles in signaling cascades, membrane traffic, ion channel regulation, and actin dynamics. Although PITPs are enriched in the brain, their physiological functions in neuronal si...
Data
Document S1. Supplemental Experimental Procedures, Figures S1–S4, and Tables S1–S3
Article
Understanding how metals contribute to brain function is a major health priority. A new study combining pharmacology and genetics implicates the accumulation of copper in a brain arousal center as a regulator of zebrafish activity.
Article
Full-text available
Sleep is an essential and evolutionarily conserved behavioral state whose regulation remains poorly understood. To identify genes that regulate vertebrate sleep, we recently performed a genetic screen in zebrafish, and here we report the identification of neuropeptide Y (NPY) as both necessary for normal daytime sleep duration and sufficient to pro...
Article
The zebrafish represents an excellent compromise between system complexity and practical simplicity, features that make it useful for modeling and mechanistic analysis of complex brain disorders. Also promising are screens for psychoactive drugs with effects on larval and adult zebrafish behavior. This review, based upon a recent symposium held at...
Data
Zebrafish embryos from an incross of Tg(flt1enh:tdTomato); Tg(flt4:mCitrine) heterozygous for the mutant ccbe1hu10965 allele were analyzed by fluorescent stereomicroscopy at 5dpf for the presence or absence of flt4:mCitrine expressing ECs in the head (as depicted in Figure 4C and D).Following analysis embryos were genotyped for the presence of the...
Article
The lymphatic system controls fluid homeostasis and the clearance of macromolecules from interstitial compartments. In mammals brain lymphatics were only recently discovered, with significant implications for physiology and disease. We examined zebrafish for the presence of brain lymphatics and found loosely connected endothelial cells with lymphat...
Article
Full-text available
Introduction Phosphatidylinositol transfer proteins (PITPs) regulate phosphoinositide metabolism and play diverse roles in multicellular organisms, from cancer regulation to sensory neuron signal transduction. One class II PITP family member, Piptnc1, has been implicated in cancer metastasis yet is also expressed in the developing and adult vertebr...
Article
Full-text available
Introduction The control of sleep and wakefulness is a fundamental biological process that ensures health and cognitive performance across species. The need to sleep (sleep pressure) is determined by two processes: the circadian clock, which modulates behaviour around the 24-hour day, and a homeostatic process, which measures prior wakefulness. Com...
Article
Full-text available
Detailed descriptions of brain-scale sensorimotor circuits underlying vertebrate behavior remain elusive. Recent advances in zebrafish neuroscience offer new opportunities to dissect such circuits via whole-brain imaging, behavioral analysis, functional perturbations, and network modeling. Here, we harness these tools to generate a brain-scale circ...
Article
Full-text available
Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-ons...
Chapter
The zebrafish (Danio rerio) is a cost-effective vertebrate model system amenable to pharmacological investigation. Many of the available drug assays are relatively straightforward to perform, as small molecules dissolved directly in the water can be directly taken up by the zebrafish to elicit biological effects in target tissues. The low cost and...
Article
Full-text available
Light affects animal physiology and behavior more than simply through classical visual, image-forming pathways. Nonvisual photoreception regulates numerous biological systems, including circadian entrainment, DNA repair, metabolism , and behavior. However, for the majority of these processes, the photoreceptive molecules involved are unknown. Given...
Article
Many studies in diverse organisms, including humans, have demonstrated a fundamental role for sleep in the formation of memories. A new study by Berry et al. indicates that, in fruit flies, sleep accomplishes this in part by preventing an active process of forgetting. Copyright © 2015 Elsevier Inc. All rights reserved.
Chapter
Full-text available
The zebrafish (Danio rerio) is a cost-effective vertebrate model system amenable to pharmacological investigation. Many of the available drug assays are relatively straightforward to perform, as small molecules dissolved directly in the water can be directly taken up by the zebrafish to elicit biological effects in target tissues. The low cost and...
Conference Paper
Background: Whole-exome sequencing has rapidly expanded the list of ASD-associated genes, while co-expression network analysis is beginning to reveal points of spatio-temporal convergence among these genes. Moreover, these new ASD risk genes are elucidating novel biological mechanisms, such as chromatin modification (CHD8) and ion channels (SCN2A),...
Article
Full-text available
How sleep is homeostatically regulated remains a mystery. In this issue of Neuron, Donlea et al. (2014) provide evidence in Drosophila that a set of sleep-inducing neurons require Crossveinless-c, a specific Rho-GTPase-activating protein (Rho-Gap), to alter their membrane excitability in response to sleep deprivation.
Article
Small molecules have been used since antiquity to regulate our sleep. Despite the explosion of diverse drugs to treat problems of too much or too little sleep, the detailed mechanisms of action and especially the neuronal targets by which these compounds alter human behavioural states are not well understood. Research efforts in model systems such...
Article
The larval zebrafish has emerged asa vertebrate model system amenable to small molecule screens for probing diverse biological pathways. Two large-scale small molecule screens examined the effects of thousands of drugs on larval zebrafish sleep/wake and photomotor response behaviors. Both screens identified hundreds of molecules that altered zebraf...
Article
Zebrafish has emerged in the past 5 years as a model for the study of sleep and wake behaviors. Experimental evidence has shown that periods of behavioral quiescence in zebrafish larvae and adults are sleep-like states, as these rest bouts are regulated by the circadian cycle, are associated with decreases in arousal, and are increased following re...
Article
Full-text available
Darkness serves as a stimulus for vertebrate photoreceptors; they are actively depolarized in the dark and hyperpolarize in the light. Here, we show that larval zebrafish essentially turn off their visual system at night when they are not active. Electroretinograms recorded from larval zebrafish show large differences between day and night; the res...
Article
Full-text available
A major obstacle for the discovery of psychoactive drugs is the inability to predict how small molecules will alter complex behaviors. We report the development and application of a high-throughput, quantitative screen for drugs that alter the behavior of larval zebrafish. We found that the multidimensional nature of observed phenotypes enabled the...
Article
Full-text available
Transient receptor potential (TRP) ion channels have been implicated in detecting chemical, thermal, and mechanical stimuli in organisms ranging from mammals to Caenorhabditis elegans. It is well established that TRPA1 detects and mediates behavioral responses to chemical irritants. However, the role of TRPA1 in detecting thermal and mechanical sti...
Article
Full-text available
The optokinetic reflex (OKR) is a basic visual reflex exhibited by most vertebrates and plays an important role in stabilizing the eye relative to the visual scene. However, the OKR requires that an animal detect moving stripes and it is possible that fish that fail to exhibit an OKR may not be completely blind. One zebrafish mutant, the no optokin...
Article
Full-text available
Whereas the zebrafish retina has long been an important model system for developmental and genetic studies, little is known about the responses of the inner retinal neurons. Here we report single-unit ganglion cell recordings from 5- to 6-day-old zebrafish larvae. In wild-type larvae we identify at least five subtypes of ganglion cell responses to...
Article
Full-text available
As many as 10% of humans suffer chronic sleep disturbances, yet the genetic mechanisms that regulate sleep remain essentially unknown. It is therefore crucial to develop simple and cost-effective vertebrate models to study the genetic regulation of sleep. The best characterized mammalian sleep/wake regulator is hypocretin/orexin (Hcrt), whose loss...
Article
The invention provides methods of monitoring expression of a plurality of genes in a cell or small population of cells. Preferred methods entail contacting an array of probes with a population of nucleic acids derived from a population of fewer than 1000 cells then determining the relative hybridization of the probes to the population of nucleic ac...
Article
Full-text available
MicroRNAs (miRNAs) comprise 1 to 3% of all vertebrate genes, but their in vivo functions and mechanisms of action remain largely unknown. Zebrafish miR-430 is expressed at the onset of zygotic transcription and regulates morphogenesis during early development. By using a microarray approach and in vivo target validation, we find that miR-430 direct...
Article
Full-text available
In order to gain insights into the regulatory control of neuronal diversity in the mammalian olfactory system, we have identified the transcriptional profile of individual olfactory neurons. A single cell microarray strategy was performed to search for candidate genes involved in the molecular specification of dorso-ventral zones of olfactory recep...
Article
Full-text available
The extraordinary cellular heterogeneity of the mammalian nervous system has largely hindered the molecular analysis of neuronal identity and diversity. In order to uncover mechanisms involved in neuronal differentiation and diversification, we have monitored the expression profiles of individual neurons and progenitor cells collected from dissocia...
Article
Full-text available
The Drosophila double-time (dbt) gene, which encodes a protein similar to vertebrate epsilon and delta isoforms of casein kinase I, is essential for circadian rhythmicity because it regulates the phosphorylation and stability of period (per) protein. Here, the circadian phenotype of a short-period dbt mutant allele (dbt(S)) was examined. The circad...
Article
Thesis (Ph. D.)--Harvard University, 2004. Submitted to: Dept. of Molecular and Cellular Biology. Thesis advisor: Catherine Dulac. Includes bibliographical references (leaves 153-170).