Video description

 
 

The main research interest of our lab is to elucidate the underlying molecular and cellular mechanisms of genetic psychiatric disorders such as psychomotor retardation, Fragile X syndrome (FXS), and sleep disturbances.

 

To understand these brain deficiencies, we combine the use of genetic manipulations, real-time 2-photon imaging of single organelles, synapses and neurons, and video-tracking of behavior in live zebrafish. The zebrafish is a simple transparent vertebrate with conserved organization of the central nervous system. Furthermore, it is ideally suited for genetic manipulation and high-resolution imaging of the entire brain in a live animal.

We develop zebrafish models for human brain disorders. The function of genes and neuronal circuits is determined using loss-of-function (CRISPR-mediated genome editing as well as genetic silencing and ablation of a specific neuronal population) and gain-of-function (transposon-mediated transgenesis) experiments.

 

Our general goal is to link gene function with the development and plasticity of neuronal circuits that regulate specific behavior.

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.





 

2010- hcrt neurons in zebrafish brain.jp

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Why do we sleep?

 

Live imaging of the cellular mechanisms of sleep.

Prolonged sleep deprivation can be lethal, and sleep disturbances are associated with various deficiencies in brain performance. However, it is unclear what effects sleep has at a cellular level. This is because sleep has previously been defined by behavioural criteria and EEG, as it has not been possible to study sleep-dependent cellular processes under the microscope. We developed a new method for time-lapse imaging of single molecules in individual neurons of live zebrafish. Using this approach, we show that sleep increases the movement of chromosomes (chromosome dynamics), which alters their structure to enable reduction of DNA damage, while neuronal activity has the opposite effect. In addition, chromosome dynamics could be a potential marker to define individual sleeping neurons. Thus, sleep increases chromosome dynamics that clear out DNA damage accumulated during waking hours. The current research focus on nuclear and cellular mechanisms of sleep.

 

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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.

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Specific Projects

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.

 
LAB MEMBERS
Dr. Lior Appelbaum
Principal investigator
Email: Lior.Appelbaum@biu.ac.il
Dr. Tali Lerer
Lab manager
Email: appelbaumlab@gmail.com
Dr. David Zada
Postdoctoral Fellow
Email: zadavid@walla.com
Talya Wasserman
PhD. Student
Rotem Rozenblat
PhD. Student
Dana sagi
PhD. Student
Yuval Rave
PhD. Student
Adir Monsanego
MSc. Student
Daniel Forer
MSc. Student
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Joint Students with Prof. Oren Levi
Amir Harduf
PhD. Student
Dr. Raphael Aguillon
Postdoctoral Fellow
Shachaf Ben-Ezra
MSc. Student
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Alumni

Dr. Tali Levitas-Djerbi

Alumna Phd.Student

 

Dr. Adi Shamay

Alumna Phd. Student

 

Inbal Adnati

Alumna MSc. Student

 

Ricarina Rabinovitz

MSc

 

Dr. Einat Blitz

Alumna Postdoctoral Fellow Email: einat.blitz@gmail.com

 

Dr. Adi Tovin

Alumna Postdoctoral Fellow Email: aditovin@gmail.com

Dr. Idan Elbaz

Alumnus Ph.D. student Email: idanelbaz99@yahoo.com

 

Dr. Laura Yelin-Bekerman

Alumna Ph.D. student Email: bekerman.laura@gmail.com

 

Arnon Itiel

Alumnus M.Sc. student Email: arnonetl@gmail.com

 

Dr. Gad Vatine

Alumnus Postdoctoral Fellow

 
SELECTED PUBLICATIONS

Thyroid

Behavioral and Neural Genetics of Zebrafish

2019- whole head and single cell.tif
2018- calcium imaging in the habenula.ti

Science Advances

2017- synapses in dendrites near the eye

Curr Opin Neurobiol

Mol Cell Endocrinol

Neuropsychopharmacology

2016- Schwann cells wrapping motor neuro

Curr Topics Behav Neuroscience

Molecular Neurobiology

Disease Models & Mechanisms

2015-pentraxin 2a neurons in zebrafish l

PLoS Genet

eLife

Scientific reports

J Comp Neurol

FASEB J

PLoS Genet

Dev Biol

PLoS One

2013- MCT8 expressed in the eye.tif

Frontiers in Neural Circuits

J Biol Chem

The Journal of Neuroscience

2011- glial cells (green) and neuronal c

Trends in Neurosciences

2010- hcrt neurons in zebrafish brain.jp

Nature

Proceedings of the National Academy of Sciences U S A

PLoS Biology

Science

PLoS Biology

Brain Research

Journal of Neuroendocrinology

Journal of Biological Chemistry

Molecular and Cellular Endocrinology

Journal of Molecular Endocrinology

Journal of Biological Chemistry

Molecular Endocrinology

Molecular Ecology

 
SELECTED PUBLICATIONS
2020
2019- whole head and single cell.tif
2019
2018- calcium imaging in the habenula.ti
2018
2017- synapses in dendrites near the eye
2017
2016- Schwann cells wrapping motor neuro
2016
2015-pentraxin 2a neurons in zebrafish l
2015
2014
2013- MCT8 expressed in the eye.tif
2013
2012
2011- glial cells (green) and neuronal c
2011
2010- hcrt neurons in zebrafish brain.jp
2010
2009
2007
2006
2005
2004
2002
IN THE NEWS
 
PHOTO GALLERY

1/19
 
CONTACT
Lior Appelbaum

The Faculty of Life Sciences and The Multidisciplinary Brain Research Center

The Nanotechnology Building (206), Room B-938

Bar Ilan University, Ramat Gan 5290002

Telephone: +972-3-7384536

Email: Lior.Appelbaum@biu.ac.il

Lab

Nanotechnology building (206), Room B-937 (9th floor)

Telephone: +972-3-7384538

Fax: +972-3-7384537

Lab manager: Dr. Tali Lerer

Email: appelbaumlab@gmail.com