Lior Appelbaum's research while affiliated with Bar Ilan University and other places
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Publications (92)
The circadian clock enables anticipation of the day/night cycle in animals ranging from cnidarians to mammals. Circadian rhythms are generated through a transcription-translation feedback loop (TTFL) involving negative and positive factors. CLOCK is a central conserved positive factor in the animal kingdom. However, the functional evolutionary orig...
The circadian clock enables anticipation of the day/night cycle in animals ranging from cnidarians to mammals. Circadian rhythms are generated through a transcription-translation feedback loop (TTFL) involving negative and positive factors. CLOCK is a central conserved positive factor in the animal kingdom. However, the functional evolutionary orig...
The ability of an animal to effectively capture prey and defend against predators is pivotal for its survival. Venom, a mixture of many toxin proteins, shapes predator-prey interactions. Here, we use the sea anemone Nematostella vectensis to test how toxin genotypes impact predator-prey interactions. We developed a new genetic manipulation tool whi...
The circadian clock is a crucial biological mechanism that enables organisms to anticipate the daily light/dark cycle. While the circadian clock factors underlying the molecular mechanism were characterized in a few model organisms, the evolutionary functional origin of the core clock proteins is unclear. In cnidarians, the expression of the putati...
Thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), regulate growth, metabolism, and neurodevelopment. THs secretion is controlled by the pituitary thyroid-stimulating hormone (TSH) and the hypothalamic-pituitary-thyroid (HPT) axis. The organic anion-transporting polypeptide 1C1 (OATP1C1/Slco1c1) and the monocarboxylate transporter 8...
Thyroid hormones (THs; T3 and T4) enter cells using specific transporters and regulate development and metabolism. Mutation in the TH transporter monocarboxylate transporter 8 (MCT8, SLC16A2) is associated with brain hypothyroidism and neurological impairment. We established mct8 mutant (mct8−/−) zebrafish as a model for MCT8 deficiency, which caus...
The circadian clock, which drives a wide range of bodily rhythms in synchrony with the day–night cycle, is based on a molecular oscillator that ticks with a period of approximately 24 h. Timed proteasomal degradation of clock components is central to the fine-tuning of the oscillator’s period. FBXL3 is a protein that functions as a substrate-recogn...
The characteristics of the sleep drivers and the mechanisms through which sleep relieves the cellular homeostatic pressure are unclear. In flies, zebrafish, mice, and humans, DNA damage levels increase during wakefulness and decrease during sleep. Here, we show that 6 h of consolidated sleep is sufficient to reduce DNA damage in the zebrafish dorsa...
Barnacles of the genus Chthamalus are commonly encountered rocky intertidal shores. The phylogeography of the different species in the Western Indian Ocean is unclear. Using morphological characteristics as well as the molecular markers mitochondrial cytochrome oxygenase subunit I (COI) and the nuclear sodium-potassium ATPase (NaKA), we identified...
The multifunctional, hypothalamic hypocretin/orexin (HCRT)-producing neurons regulate an array of physiological and behavioral states including arousal, sleep, feeding, emotions, stress, and reward. How a presumably uniform HCRT neuron population regulates such a diverse set of functions is not clear. The role of the HCRT neuropeptides may vary dep...
A-to-I RNA editing is a common post transcriptional mechanism, mediated by the Adenosine deaminase that acts on RNA (ADAR) enzymes, that increases transcript and protein diversity. The study of RNA editing is limited by the absence of editing maps for most model organisms, hindering the understanding of its impact on various physiological condition...
Hypothyroidism is a common pathological condition that is characterized by insufficient activity of the thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), in the whole body or in specific tissues. Hypothyroidism is associated with inadequate development of the intestine as well as gastrointestinal diseases. We utilized a zebrafish mo...
Environmental perturbation can drive behavioral evolution and associated changes in brain structure and function. The Mexican fish species, Astyanax mexicanus, includes eyed river-dwelling surface populations and multiple independently evolved populations of blind cavefish. We used whole-brain imaging and neuronal mapping of 684 larval fish to gene...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
The pituitary adenylate cyclase-activating polypeptide receptor (PAC1, also known as ADCYAP1R1) is associated with post-traumatic stress disorder and modulation of stress response in general. Alternative splicing of PAC1 results in multiple gene products, which differ in their mode of signalling and tissue distribution. However, the roles of distin...
Many animals fight for dominance between conspecifics. Because winners could obtain more resources than losers, fighting outcomes are important for the animal’s survival, especially in a situation with insufficient resources, such as hunger. However, it remains unclear whether and how hunger affects fighting outcomes. Herein, we investigate the eff...
The pituitary adenylate cyclase-activating polypeptide receptor (PAC1, also known as ADCYAP1R1) is associated with post-traumatic stress disorder and modulation of stress response in general. Alternative splicing of PAC1 results in multiple gene products, which differ in their mode of signalling and tissue distribution. However, the roles of distin...
Sleep is an essential physiological state in the animal kingdom including humans. Sleep benefits the brain in varied levels ranging from maintenance of single cells to plasticity of neuronal networks, memory, and learning. While in mammals, birds, and some reptiles, sleep can be defined by electroencephalography and behavior, in other species, incl...
Background:
The thyroid hormones (THs) triiodothyronine (T3) and thyroxine (T4) are crucial regulators of brain development and function. Cell-specific transporter proteins facilitate TH uptake and efflux across the cell membrane, and insufficient TH transport causes hypothyroidism and mental retardation. Mutations in the TH transporters monocarbox...
Environmental perturbation can drive the evolution of behavior and associated brain structure and function. Generation of high-resolution whole-brain atlases have provided insights into neuroanatomy and neural circuit connectivity associated with behaviors in many model systems, but these approaches have yet to be applied to models of brain evoluti...
Background: Hypothalamic neurotensin (Nts)-secreting neurons regulate fundamental physiological processes including metabolism and feeding. However, the role of Nts in modulation of locomotor activity, sleep and arousal is unclear. We previously identified and characterized Nts neurons in the zebrafish hypothalamus.
Materials and methods:
In orde...
Sleep is essential to all animals with a nervous system. Nevertheless, the core cellular function of sleep is unknown, and there is no conserved molecular marker to define sleep across phylogeny. Time-lapse imaging of chromosomal markers in single cells of live zebrafish revealed that sleep increases chromosome dynamics in individual neurons but no...
In addition to regular sleep/wake cycles, humans and animals exhibit brief arousals from sleep. Although much is known about consolidated sleep and wakefulness, the mechanism that triggers arousals remains enigmatic. Here, we argue that arousals are caused by the intrinsic neuronal noise of wake-promoting neurons. We propose a model that simulates...
Humans have been fascinated by sleep for millennia. After almost a century of scientific interrogation, significant progress has been made in understanding the neuronal regulation and functions of sleep. The application of new methods in neuroscience that enable the analysis of genetically defined neuronal circuits with unprecedented specificity an...
Sleep is tightly regulated by the circadian clock and homeostatic mechanisms. Although the sleep/wake cycle is known to be associated with structural and physiological synaptic changes that benefit the brain, the function of sleep is still debated. The hypothalamic hypocretin/orexin (Hcrt) neurons regulate various functions including feeding, rewar...
What are the molecular and cellular mechanisms that link neurological disorders and sleep disturbances? The transparent zebrafish model could bridge this gap in knowledge due to its unique genetic and imaging toolbox, and amenability to high-throughput screening. Sleep is well-characterized in zebrafish and key regulators of the sleep/wake cycle ar...
Thyroid hormones (THs) regulate a variety of fundamental physiological processes, including the development and maintenance of the brain. For decades, it was thought that THs enter the cells by passive diffusion. However, it is now clear that TH transport across the cell membrane requires specific transporter proteins that facilitate the uptake and...
The hypothalamic Hypocretin/Orexin (Hcrt) neurons secrete two Hcrt neuropeptides. These neurons and peptides play a major role in the regulation of feeding, sleep wake cycle, reward-seeking, addiction, and stress. Loss of Hcrt neurons causes the sleep disorder narcolepsy. The zebrafish has become an attractive model to study the Hcrt neuronal netwo...
Hypomyelination is a key symptom of the Allan-Herndon-Dudley syndrome (AHDS), a psychomotor retardation associated with mutations in the thyroid-hormone (TH) transporter MCT8. AHDS is characterized by severe intellectual deficiency, neuromuscular impairment, and brain hypothyroidism. In order to understand the mechanism for TH-dependent hypomyelina...
Fragile X syndrome (FXS) is the most frequent inherited form of mental retardation. The cause for this X-linked disorder is the silencing of the fragile X mental retardation 1 (fmr1) gene and the absence of the fragile X mental retardation protein (Fmrp). The RNA-binding protein Fmrp represses protein translation, particularly in synapses. In Droso...
Uniformity in the mean number of aligned PCR products (reads) of all amplicons tested in fmr1-/- and WT samples.
Correlation analysis of output reads shows independence of RNA sample origin. The high correlation between fmr1-/- and WT larvae reads shows unaffected coverage depth (Pearson correlation score, r = 0.978; R2 = 0.96).
(TIF)
Clusters of multiple editing sites (hyperediting) in zebrafish.
The genomic location, strand, and sequence triplet of all HE sites detected.
(TXT)
RNA editing—cluster analysis.
The levels of RNA editing recorded for each of the two adjacent editing sites in the gria2a and gria3a genes, as well as the calculated differential editing levels of these sites between fmr1-/- and WT larvae. The table also shows the calculated relative abundance for each mRNA transcript formed by editing in addition...
Validation of RNA editing sites by comparing cDNA and genomic DNA sequences.
(A) Validation of microfluidic-based multiplex PCR (mmPCR) results was performed by Sanger sequencing. Three representative RNA editing sites are shown. Sanger sequencing was performed on both genomic DNA (gDNA) and cDNA. Black arrow indicates the genomic location of each...
Clusters of multiple editing sites (hyperediting) in gene coding sequences in zebrafish.
The genomic location, strand, and sequence triplet of all HE sites detected in the CDS region.
(XLSX)
Novel RNA editing sites in zebrafish.
Gene name, genomic location, editing percentage, editing percentage SE, and annotation of novel RNA editing sites detected in fmr1-/- and WT larvae.
(TIF)
The target set of novel RNA editing sites.
Locations, strand specificity, annotations, and mmPCR results of the target-set RNA editing sites.
(XLSX)
Endogenous circadian clocks are poorly understood within early-diverging animal lineages. We have
characterized circadian behavioral patterns and identified potential components of the circadian
clock in the starlet sea anemone, Nematostella vectensis: a model cnidarian which lacks algal
symbionts. Using automatic video tracking we showed that Nema...
Endogenous circadian clocks are poorly understood within early-diverging animal lineages. We have
characterized circadian behavioral patterns and identified potential components of the circadian
clock in the starlet sea anemone, Nematostella vectensis: a model cnidarian which lacks algal
symbionts. Using automatic video tracking we showed that Nema...
Neuronal-activity-regulated pentraxin (NARP/NPTX2/NP2) is a secreted synaptic protein that regulates the trafficking of glutamate receptors and mediates learning, memory, and drug addiction. The role of NPTX2 in regulating structural synaptic plasticity and behavior in a developing vertebrate is indefinite. We characterized the expression of nptx2a...
Neurotensin (NTS) is a 13 amino acid neuropeptide that is expressed in the hypothalamus. In mammals, NTS-producing neurons that express leptin receptor (LepRb) regulate the function of hypocretin/orexin (HCRT) and dopamine neurons. Thus, the hypothalamic leptin/NTS/HCRT neuronal network orchestrates key homeostatic output, including sleep, feeding...
The mechanisms and treatment of psychomotor retardation, which includes motor and cognitive impairment, are indefinite. The Allan-Herndon-Dudley syndrome (AHDS) is an X-linked psychomotor retardation characterized by delayed development, severe intellectual disability, muscle hypotonia, and spastic paraplegia, in combination with disturbed thyroid...
Cnidarian nervous systems utilize chemical transmission to transfer signals through synapses and neurons. To date, ample evidence has been accumulated for the participation of neuropeptides, primarily RFamides, in neurotransmission. Yet, it is still not clear if this is the case for the classical fast neurotransmitters such as GABA, Glutamate, Acet...
The circadian clock and homeostatic processes are fundamental mechanisms that regulate sleep. Surprisingly, despite decades of research, we still do not know why we sleep. Intriguing hypotheses suggest that sleep regulates synaptic plasticity and consequently has a beneficial role in learning and memory. However, direct evidence is still limited an...
Allan Herndon Dudley syndrome (AHDS) is a severe psychomotor retardation characterized by neurological impairment and abnormal thyroid hormone (TH) levels. Mutations in the TH transporter, monocarboxylate transporter 8 (MCT8), are associated with AHDS. MCT8-knockout mice exhibit impaired TH levels; however, they lack neurological defects. Here, the...
Sleep is an essential biological need of all animals studied to date. The sleep disorder narcolepsy is characterized by excessive daytime sleepiness, fragmentation of nighttime sleep, and cataplexy. Narcolepsy is caused by selective degeneration of hypothalamic hypocretin/orexin (HCRT) neurons. In mammals, HCRT neurons primarily regulate the sleep/...
Sleep is a fundamental and evolutionarily conserved aspect of animal life. Recent studies have shed light on the role of sleep in synaptic plasticity. Demonstrations of memory replay and synapse homeostasis suggest that one essential role of sleep is in the consolidation and optimization of synaptic circuits to retain salient memory traces despite...
Neurons exhibit rhythmic activity that ultimately affects behavior such as sleep. In living zebrafish larvae, we used time-lapse two-photon imaging of the presynaptic marker synaptophysin in hypocretin/orexin (HCRT) neurons to determine the dynamics of synaptic modifications during the day and night. We observed circadian rhythmicity in synapse num...
In mammals, hypocretin/orexin (HCRT) neuropeptides are important sleep-wake regulators and HCRT deficiency causes narcolepsy. In addition to fragmented wakefulness, narcoleptic mammals also display sleep fragmentation, a less understood phenotype recapitulated in the zebrafish HCRT receptor mutant (hcrtr-/-). We therefore used zebrafish to study th...
EGFP expression in Tg(-0.43per2:EGFP)tlv1. Confocal in vivo Z-stack of a 2-d-old Tg(-0.43per2:EGFP)tlv1 embryos. The per2 promoter drives ubiquitous EGFP expression that is augmented in the pineal gland. Thus per2 promoter drives expression in virtually all peripheral clock-containing cells and expression is enhanced in the master clock located in...
Co-localization of per2- and aanat2-driven expression in the pineal gland. A double transgenic line was generated by crossing Tg(-0.43per2:EGFP)tlv1 with Tg(aanat2:mRFP)y164, which exhibits red fluorescence specifically in the melatonin producing photoreceptor cells of the pineal gland. Confocal in vivo analysis reveals co-localized EGFP and mRFP e...
For most species, light represents the principal environmental signal for entraining the endogenous circadian clock. The zebrafish is a fascinating vertebrate model for studying this process since unlike mammals, direct exposure of most of its tissues to light leads to local clock entrainment. Importantly, light induces the expression of a set of g...
The hypocretin/orexin (HCRT/ORX) excitatory neuropeptides are expressed in a small population of lateral hypothalamic cells in mammals and fish. In humans, loss of these cells causes the sleep disorder narcolepsy. Identification of genes expressed in HCRT-producing cells may be revealing as to the regulation of sleep and the pathophysiology of narc...
Hundreds of species of reef-building corals spawn synchronously over a few nights each year, and moonlight regulates this
spawning event. However, the molecular elements underpinning the detection of moonlight remain unknown. Here we report the
presence of an ancient family of blue-light–sensing photoreceptors, cryptochromes, in the reef-building c...
Sleep is a fundamental biological process conserved across the animal kingdom. The study of how sleep regulatory networks are conserved is needed to better understand sleep across evolution. We present a detailed description of a sleep state in adult zebrafish characterized by reversible periods of immobility, increased arousal threshold, and place...
Activation of Fish by Food Restriction and Activity Resulting from Feeding
After habituation and regular feeding in the recording apparatus, fish of the three genotypes were studied for 6 d without administration of food. Left: baseline activity at 3 p.m. on day 1. Right: baseline activity after 6 d of food deprivation and response of the three gen...
Sleep Deprivation and Reactivity of Fish at the Onset of the Sleep Deprivation Procedure
The video was recorded 10 min after the start of the sleep deprivation procedure. The fish in the upper chamber is submitted to an electrical stimulation (at infrared light) every time sleep is achieved (activity < 6 pixels/s for at least 6 s). The fish in the...
Habituation of Fish of Three Genotypes When Moved from Their Usual Aquaria to the Recording Chamber
Note diurnal fluctuation of activity of decreasing amplitude every successive day. Importantly, the diminution is parallel and identical across the three genotypes, indicating that the hcrtr168 mutants are not more disturbed or activated than wild-ty...
Food Satiety Studies in the Three Genotypes
Fish of the three genotypes were studied under their regular environment but separated in individual aquaria. At the usual feeding time, a batch of 200 brine shrimp (233/100 μl) was delivered in each aquarium. After complete consumption of the brine shrimp, another batch was delivered every 5 min multiple...
Example of a Sleep Period, as Observed in an Adult Fish during the Daytime
Note high activity level prior to sleep period. In a second phase, the fish slows down and its caudal fin droops occasionally. It then moves to the bottom of tank, caudal fin down, and rests for approximately 1 min, before resuming activity.
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Increased Arousal Threshold during Rest
Fish are stimulated with a 10-ms pulse of 1 V (onset of stimulation is shown by an infrared light dot on the left side of video). Note immediate reactivity of active fish (left), but not of immobile fish (right).
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Effect of Constant Light (11 d) on Mean Activity Levels and Sleep Time
Mean activity levels (per 2 h, top, n = 8) and sleep time (percent time per 2 h, bottom, n = 8). For details on the sleep recording system, see legend to Figure 1. Note that in this experiment fish were fed normally. Shaded area indicates normal light/dark conditions, followed b...