Prof. Lior Appelbaum

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Head of Research Lab
Research

​Sleep and sleep disorders: Sleep is an evolutionarily conserved process that is vital for animal survival. Sleep disturbances affect approximately 20% of the general population and represent a major health burden. Although sleep clearly improves brain performance, the function of sleep is still debated and includes macromolecule biosynthesis, energy conservation, metabolite clearance, memory consolidation, and synaptic plasticity. We have characterized sleep, cloned sleep genes, and visualized sleep circuits, and established the zebrafish as an attractive model to study the sleep/wake cycle in a high throughput approach. ​

Psychomotor retardation: Mental and psychomotor retardation are characterized by cognitive, social, and motor deficits. The cause for these disorders is often genetic mutations that typically lead to alteration in neurogenesis, myelination, synaptic plasticity, and the activity of neuronal circuits. In order to understand psychomotor retardation, a critical challenge is to identify and visualize functional circuits in the brain, which contains an incomprehensible dense population of neurons and their processes. We established several zebrafish models for psychomotor retardation and study the mechanism and treatment of these disorders. Remarkably, gene-specific mutations that cause psychomotor retardation in human are also linked to genetic and neuronal alterations in zebrafish. These similarities between the two vertebrate species enable rescue assays in the zebrafish model, which help to understand the mechanism and targets of specific genetic and drug treatments.

Specific projects: 

Sleep disorders and the hypocretin/orexin (Hcrt) neuronal networks

The hypothalamus regulates fundamental brain functions, such as metabolism and sleep. Understanding the function of hypothalamic neuronal circuits is critical because of its association with neurodegenerative, genetic, sleep, and metabolic disorders. The hypothalamic Hcrt neurons are regulators of feeding, emotions, reward, sleep and wake, and Hcrt neuron deficiency results in the sleep disorder narcolepsy in humans and animal models. We established a transgenic zebrafish model, enabling inducible ablation of Hcrt neurons, as a model for narcolepsy. Using combination of system-biology, genetics, live-imaging, and behavioral experiments, we identify and characterize novel Hcrt-neuron-specific genes in zebrafish. In addition, we study structural and functional connection between several neuropeptide-producing hypothalamic neuronal networks such as Hcrt, and neurotensin (Nts).

 

Sleep and synaptic plasticity

Sleep is conserved in evolution, and similar circadian and homeostatic factors regulate sleep in animals as distantly related as worms, flies, fish, and humans. Accumulating evidence shows that sleep is important for synaptic plasticity, memory, and learning. Using time-lapse two-photon imaging of excitatory and inhibitory pre- and post-synaptic markers, we study circadian and homeostatic control of rhythmic synaptic plasticity in the brain of live zebrafish.

 

Fragile X syndrome

Fragile-X syndrome (FXS) is the most common single-gene inherited neurodevelopmental disorder causing mental retardation. It is caused by mutations in 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 in synapses, and interacts with the adenosine deaminase acting on the RNA (ADAR) enzyme, which converts adenosine-to-inosine (A-to-I) and modifies the sequence of RNA transcripts. Utilizing the fmr1 zebrafish mutant (fmr1-/-), we study the link between ADAR-mediated RNA editing, neuronal circuit formation, and behavior in FXS.

 

Thyroid hormones and psychomotor retardation

Thyroid hormones (TH) are key regulators of embryonic development, metabolism, and neurogenesis in all vertebrates. The X-linked psychomotor retardation Allan-Herndon-Dudley syndrome (AHDS) is associated with mutations in the TH monocarboxylate transporter 8 (mct8). AHDS is characterized by severe intellectual deficiency, neuromuscular impairment, and high serum TH levels. We utilize mutant and transgenic zebrafish to elucidate the neurological mechanism and find potential genetic and pharmacological treatments to AHDS and other TH-related disorders.

Publications
  1. Nakajo H, Chou MY, Kinoshita M, Appelbaum L, Shimazaki H, Tsuboi T, Okamoto H (2020) Hunger and the orexin-habenula circuit induces winning in social conflicts. Cell Reports. 23;31(12):107790. doi: 10.1016/j.celrep.2020.107790.

  2. Jaggard J,  Lloyd E,  Yuiska A,  Patch A,  Fily Y, Kowalko JE,  Appelbaum L,  Duboue ER,  Keene AC. (2020) Cavefish brain atlases reveal functional and anatomical convergence across independently evolved populations. bioRxiv doi: https://doi.org/10.1101/832543.

  3. Keene AC, Appelbaum L (2019) Sleep in Fish Models. In: Handbook of Behavioral Neuroscience. Elsevier. 30, 363-374.

  4. Zada D, Appelbaum L (2019) Behavioral criteria and techniques to define sleep in zebrafish. In: Behavioral and Neural Genetics of Zebrafish. Elsevier. 141-153
  5. Admati I, Wasserman-Bartov T, Tovin A, Rozenblat R, Rozenblat R, Blitz E, Zada D, Lerer-Goldshtein T, Appelbaum L (2019) Neural alterations and hyperactivity of the hypothalamic–pituitary–thyroid axis in Oatp1c1-deficiency. Thyroid. 30:161-174.
  6. Biran J,  Gliksberg M,  Shirat I,  Swaminathan A,  Levitas-Djerbi T,  Appelbaum L,  Levkowitz G (2020) Splice-specific deficiency of the PTSD-associated gene PAC1 leads to a paradoxical age-dependent stress behavior. Scientific Reports. 10:9559. doi: 10.1038/s41598-020-66447-2

  7. Levitas-Djerbi T, Sagi D, Lebenthal-Loinger I, Lerer-Goldshtein T, Appelbaum L (2019). Neurotensin Enhances Locomotor Activity and Arousal, and Inhibits Melanin-Concentrating Hormone Signalings. Neuroendocrinology. 2019 Apr 29. doi: 10.1159/000500590

  8. Zada D, Bronshtein I, Lerer-Goldshtein T, Garini Y, Appelbaum L (2019). Sleep increases chromosome dynamics to enable reduction of accumulating DNA damage in single neurons. Nature Communication. Mar 5;10(1):895. doi: 10.1038/s41467-019-08806-w.

  9. Dvir H, Elbaz I, Havlin S, Appelbaum L, Ivanov PC, Bartsch RP (2018). Neuronal noise as an origin of sleep arousals and its role in sudden infant death syndrome. Science Advances. Apr 25;4(4):eaar6277. doi: 10.1126/sciadv.aar6277

  10. Eban-Rothschild A, Appelbaum L, de Lecea L (2018) Neuronal Mechanisms for Sleep/Wake Regulation and Modulatory Drive. Neuropsychopharmacology. Apr;43(5):937-952. doi: 10.1038/npp.2017.294. Epub 2017 Dec 5. Review

  11. Levitas-Djerbi T, Appelbaum L (2017). Modeling sleep and neuropsychiatric disorders in zebrafish. Curr Opin Neurobiol. 44:89-93 doi: 10.1016/j.conb.2017.02.017. 

  12. Zada D, Blitz E, Appelbaum L (2017). Zebrafish - An emerging model to explore thyroid hormone transporters and psychomotor retardation. Mol Cell Endocrinol. pii: S0303-7207(17)30172-7. doi: 10.1016/j.mce.2017.03.004. 

  13. Elbaz I, Levitas-Djerbi T, Appelbaum L (2016). The Hypocretin/Orexin Neuronal Networks in Zebrafish. Curr Topics Behav Neuroscience. 2017;33:75-92 doi: 10.1007/7854_2016_59. 

  14. Elbaz I, Zada D, Tovin A, Braun T, Lerer-Goldshtein T, Wang G,  Mourrain P, Appelbaum L (2016). Sleep-Dependent Structural Synaptic Plasticity of Inhibitory Synapses in the Dendrites of Hypocretin/Orexin Neurons. Molecular Neurobiology

  15. Zada D, Tovin A, Lerer-Goldshtein T, Appelbaum L  (2016). Pharmacological and BBB-targeted genetic therapies for thyroid hormone-dependent hypomyelination. Disease Models & Mechanisms.  pii: dmm.027227. 

  16. Shamay-Ramot A, Khermesh K, Porath HT, Barak M, Pinto Y, Wachtel C, Zilberberg A, Lerer-Goldshtein T, Efroni S, Levanon EY, and Appelbaum L (2015). Fmrp interacts with Adar and regulates RNA editing, synaptic density and locomotor activity in zebrafish. PLoS Genet. 11:e1005702.

  17. Yelin-Bekerman L, Elbaz I, Diber A, Dahary D, Gibbs-Bar L, Alon S, Lerer-Goldshtein T, Appelbaum L. (2015). Hypocretin neuron-specific transcriptome profiling identifies the sleep modulator Kcnh4a. eLife. 4. pii: e08638. 

  18. Oren M, Tarrant AM, Alon S, Simon-Blecher N, Elbaz I, Appelbaum L and Levy O. (2015). Profiling molecular and behavioral circadian rhythms in the non-symbiotic sea anemone Nematostella vectensis. Scientific reports. 5:11418. 

  19. Levitas-Djerbi T, Yelin-Bekerman L, Lerer-Goldshtein T, Appelbaum L.(2015). The Hypothalamic Leptin-Neurotensin-Hypocretin Neuronal Networks in Zebrafish. J Comp Neurol. 523:831-848. 

  20. Elbaz I, Lerer-Goldshtein T, Okamoto H, Appelbaum L. (2015).  Reduced synaptic density and deficient locomotor response in neuronal activity-regulated pentraxin 2a mutant zebrafish. FASEB J.  29:1220-34. 

  21. Zada D, Tovin A, Lerer-Goldshtein T, Vatine GD, Appelbaum L. (2014). Altered behavioral performance and live imaging of circuit-specific neural deficiencies in a zebrafish model for psychomotor retardation. PLoS Genet 10:e1004615. 

  22. Sharaby Y, Lahmi R, Amar O, Elbaz I, Lerer-Goldshtein T, Weiss AM, Appelbaum L, Tzur A. (2014). Gas2l3 is essential for brain morphogenesis and development. Dev Biol. 394:305-13. 

  23. Oren M, Brikner I, Appelbaum L, Levy O. (2014). Fast neurotransmission related genes are expressed in non nervous endoderm in the sea anemone Nematostella vectensis. PLoS One. 9:e93832.  

  24. Elbaz, I., Foulkes, N.S., Gothilf, Y., and Appelbaum, L. (2013). Circadian clocks, rhythmic synaptic plasticity and the sleep-wake cycle in zebrafish. Frontiers in Neural Circuits 7:9.​ 

  25. Vatine, G.D., Zada, D., Lerer-Goldshtein, T., Tovin, A., Malkinson, G., Yaniv, K., and Appelbaum, L. (2013). Zebrafish as a model for monocarboxyl transporter 8-deficiency. J Biol Chem 288, 169-180.​ 

  26. Elbaz I, Yelin-Bekerman L, Nicenboim J, Vatine G, and Appelbaum L (2012) Genetic ablation of hypocretin neurons alters behavioral state transitions in zebrafish. The Journal of Neuroscience 32:12961–12972.​ 

  27. Wang G, Grone B, Colas D, Appelbaum L and Mourrain P (2011) Synaptic plasticity in sleep: learning, homeostasis and disease. Trends in Neurosciences. 34:452-63.​ 

  28. Appelbaum L, Wang G, Yokogawa T, Skariah G, Smith SJ, Mourrain P and Mignot E (2010) Circadian and homeostatic regulation of structural synaptic plasticity in hypocretin neurons. Neuron. 68:87-98 (cover)*.​ *This paper was highlighted in Nature: Neuroscience: Brain connections have rhythm. Nature 468: 349.​

  29. Appelbaum L, Wang G, Maro G, Mori R, Tovin A, Marin W, Yokogawa Y, Kawakami K, Smith SJ, Gothilf Y, Mignot EM and Mourrain P (2009). Sleep/wake regulation and hypocretin-melatonin interaction in zebrafish. Proceedings of the National Academy of Sciences U S A. 106:21942-21947 (track II). ​

  30. Vatine G, Vallone D, Appelbaum L, Mracek P, Ben-Moshe Z, Lahiri K, Gothilf Y and Foulkes NS (2009) Light directs zebrafish period2 expression via conserved D and E boxes. PLoS Biology. 7:e1000223. 

  31. Levy O, Appelbaum L, Leggat W, Gothlif Y, Hayward DC, Miller DJ and Hoegh-Guldberg O (2007) Light-responsive cryptochromes from the simplest marine eumetazoan animals. Science. 318: 467-470.​

  32. Yokogawa T, Marin W, Faraco J, Pezeron G, Appelbaum L, Zhang J, Rosa F, Mourrain P and Mignot E (2007) Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants. PLoS Biology. 5: 2379-2397.​

  33. Appelbaum L, Skariah G, Mourrain P and Mignot E (2007) Purinergic transmission by P2X receptors and ecto-nucleoside triphosphate diphosphohydrolase 3 in hypocretin and sensory neurons in zebrafish. Brain Research. 1174: 66-75.​

  34. Zilberman-Peled* B, Appelbaum* L, Vallone D, Foulkes NS, Anava S, Anzulovich A, Coon SL, Klein DC, Falcon J,  Ron B and Gothilf Y (2007) Transcriptional regulation of arylalkylamine-N-acetyltransferase-2 gene in the pineal gland of the gilthead seabream. Journal of Neuroendocrinology. 19:46-53. *Equally contributed.​

  35. Faraco* JH, Appelbaum* L, Marin W, Gaus S, Mourrain P, Mignot E (2006) Regulation of hypocretin (orexin) expression in embryonic zebrafish. Journal of Biological Chemistry. 281: 29753-61. *Equally contributed. 

  36. 18 Appelbaum L, Gothilf Y (2006) Mechanism of pineal-specific gene expression: The role of E-box and photoreceptor conserved elements. Molecular and Cellular Endocrinology. 252: 27-33. ​

  37. Appelbaum L, Vallone D, Anzulovich A, Ziv L, Tom M, Foulkes N, Gothilf Y (2006) Zebrafish arylalkylamine-N-acetyltransferase genes - targets for regulation of circadian-clock. Journal of Molecular Endocrinology. 36: 337-347. 

  38. Appelbaum L, Anzulovich A, Baler R, Gothilf Y (2005) Homeobox-clock protein interaction in zebrafish: A shared mechanism for pineal-specific and circadian gene expression. Journal of Biological Chemistry 280: 11544–11551.​

  39. Appelbaum L, Toyama R, Dawid IB, Klein DC, Baler R, Gothilf Y (2004) Zebrafish serotonin-N-acetyltransferase-2 gene regulation: Pineal-restrictive downstream module (PRDM) contains a functional E-box and three photoreceptor conserved elements. Molecular Endocrinology 18: 1210-1221.​

  40. Appelbaum L, Achituv Y, Mokady O (2002) Speciation and the establishment of zonation in an intertidal barnacle - specific settlement versus selection. Molecular Ecology 11: 1731-1737.