Prof. Appelbaum Lior
The main research interest of our lab is to elucidate the underlying molecular and cellular mechanisms related to sleep disorders and psychomotor retardation. To understand these brain deficiencies, we combine the use of genetic manipulations, real-time 2-photon imaging of single neurons and synapses, and video-tracking of behavior in live zebrafish. The zebrafish is a simple transparent vertebrate with conserved organization of the central nervous system, and the zebrafish model is ideally suited for the study of genetics and neurobiology in live animals. Our general goal is to link gene function with the development and plasticity of neuronal circuits that regulate specific behavior.
Our research program consists of two specific projects in the fields of molecular neuroscience and brain disorders:
Sleep and sleep disorders: Sleep disturbances affect approximately 20% of the general population and represent a major health burden. In spite of a century of scientific study of sleep, the function of sleep remains a biological enigma. Diverse theories have been postulated to account for the restorative effect of sleep, and intriguing hypotheses suggest that the role of sleep is to maintain synaptic homeostasis or to reactivate specific circuits that are important for memory and learning. We use the zebrafish model, which combines the power of invertebrate-like genetics with vertebrate brain structures. We have characterized sleep, cloned sleep genes, visualized sleep circuits, and established the zebrafish as an attractive model to study the sleep/wake cycle in a high throughput approach. Using FAC sorting of EGFP-labeled neurons and next-generation sequencing, we isolate and characterize novel genes that are expressed in sleep-related circuits. Gene and neuronal circuit function is elucidated using loss-of-function (TALEN- and CRISPR-mediated genome editing as well as genetic silencing and ablation of specific neuron population) and gain-of-function (transgenesis) experiments. Using these techniques, we developed transgenic and mutant zebrafish that exhibit sleep disorders, such as narcolepsy. Furthermore, unique to zebrafish is the possibility to image the same synapse longitudinally over time in all brain circuits. Thus, using time-lapse two-photon imaging of pre- and post-synaptic markers in live zebrafish, we quantify circadian and sleep-dependent structural synaptic plasticity in the whole brain. This experimental approach offers the opportunity to visualize synaptic plasticity in response to behavioral challenges and genetic manipulations.
Psychomotor retardation: The Allan-Herndon-Dudley syndrome (AHDS) is an X-linked disorder that is characterized by severe psychomotor retardation and abnormal thyroid-hormone (TH) levels. Mutations in the monocarboxylate transporter 8 (mct8) gene is linked to AHDS. The MCT8 is a TH transporter that facilitates both cellular uptake and the efflux of T4 and T3. The role of MCT8 in regulating the endocrinological and neurological phenotypes of AHDS, is poorly understood. We established an MCT8 mutant zebrafish model to understand the mechanism of psychomotor retardation. We study this and other model animal for mental retardations using genetic, time-lapse two-photon imaging and behavior assays. Our goal is advance the knowledge and treatment of mental and psychomotor retardation. As the zebrafish is well suited for a large-scale pharmacological screen, these models are also used to test potential drugs and eventually develop treatments for human patients.
Supervision of graduate and post-graduate students
Adi Tovin, Postdoctoral Fellow, 2012-present
Idan Elbaz, PhD, 1 year, 2012-present
Adi Shamay, PhD, 2014-present
Tali Levitas, PhD, 2014- present
David Zada, PhD, 2014- present
Arnon Itiel, MSc, 2013-present
Gad Vatine, Postdoctoral, 2010-2012
Idan Elbaz, MSc, 2010-2012
Adi Shamay, MSc, 2012-2014
Tali Levitas, MSc, 2012-2014
David Zada, MSc, 2012-2014
Laura Bekerman, PhD, 2010-2015
Articles in refereed journals
Shamay-Ramot A, Khermesh K, Porath HT, Barak M, Pinto Y, Wachtel C, Zilberberg A, Lerer-Goldshtein T, Efroni S, Levanon EY, Appelbaum L. (2015) Fmrp Interacts with Adar and Regulates RNA Editing, Synaptic Density and Locomotor Activity in Zebrafish. Plos Genetics 11(12):e1005702.
Yelin-Bekerman L, Elbaz I, Diber A, Dahary D, Gibbs-Bar L, Alon S, Lerer-Goldshtein T and Appelbaum L (2015) Hypocretin neutron-specific transcriptome profiling identifies the sleep modulator Kcnh4a. Elife. eLife.08638.
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,
Elbaz I, Lerer-Goldshtein T, Okamoto H and Appelbaum L (2015) Reduced synaptic density and deficient locomotor response in neuronal activity-regulated pentraxin 2a mutant zebrafish. FASEB Journal 29: 1220-1234.
Levitas-Djerbi R, Yelin-Bekerman L, Lerer-Goldshtein T, and Appelbaum L (2015) The hypothalamic leptin-neurotensin-hypocretin neuronal networks in zebrafish. Journal of Comparative Neurology 523: 831-848.
Zada D, Tovin A, Lerer-Goldshtein T, Vatine GD, and Appelbaum L (2014) Altered behavioral performance and live imaging of circuit-specific neural deficiencies in a zebrafish model for psychomotor retardation. PLoS Genetics. 10:e1004615.
Sharaby Y, Lahmi R, Amar O, Elbaz I, Lerer-Goldshtein T, Weiss AM, Appelbaum L, and Tzur A (2014) Gas2l3 is essential for brain morphogenesis and development. Developmental Biology. 394:305-313.
Oren M, Appelbaum L, and Levy O (2014) Fast neurotransmission related genes are expressed in non nervous endoderm in the sea anemone Nematostella vectensis. PLOS One. 9:e93832.
Elbaz I, Foulkes NS, Gothilf Y and Appelbaum L (2013) Circadian clocks, rhythmic synaptic plasticity and the sleep-wake cycle in zebrafish. Frontiers in Neural Circuits. 7:9 doi: 10.3389/fncir.2013.00009.
Vatine GD, Zada D, Lerer-Goldshtein T, Tovin A, Malkinson G, Yaniv K and Appelbaum L (2013) Zebrafish as a model for monocarboxyl transporter 8-deficiency. Journal of Biological Chemistry, 288:169-180.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.