Dr. Gil Levkowitz and his team in the Molecular Cell Biology Department have now revealed a new kind of ON-OFF switch in the brain for regulating the production of a main biochemical signal from the brain that stimulates cortisol release in the body. This finding, which was recently published in Neuron, may be relevant to research into a number of stress-related neurological disorders.
This signal is corticotropin releasing hormone (CRH). CRH is manufactured and stored in special neurons in the hypothalamus. Within this small brain region the danger is sensed, the information processed and the orders to go into stress-response mode are sent out. As soon as the CRH-containing neurons have depleted their supply of the hormone, they are already receiving the directive to produce more.
The research – on zebrafish – was performed in Levkowitz's lab and spearheaded by Dr. Liat Amir- Zilberstein together with Drs. Janna Blechman, Adriana Reuveny and Natalia Borodovsky, and Maayan Tahor. The team found that a protein called Otp is involved in several stages of CRH production. As well as directly activating the genes encoding CRH, it also regulates the production of two different receptors on the neurons' surface for receiving and relaying CRH production signals – in effect, ON and OFF switches.
The team found that both receptors are encoded in a single gene. To get two receptors for the price of one, Otp regulates a gene-editing process known as alternative splicing, in which some of the elements in the sequence encoded in a gene can be "cut and pasted" to make slightly different "sentences." In this case, it generates two variants of a receptor called PAC1: The short version produces the ON receptor; the long version, containing an extra sequence, encodes the OFF receptor. The researchers found that as the threat passed and the supply of CRH was replenished, the ratio between the two types of PAC1 receptor on the neurons' surface gradually changed from more ON to mostly OFF. In collaboration with Drs Laure Bally-Cuif and William Norton of the Institute of Neurobiology Alfred Fessard at the Centre National de la Recherche Scientifique (CNRS) in France, the researchers showed that blocking the production of the long receptor variant causes an anxiety like behavior in zebrafish.
Together with Drs. Alon Chen and Yehezkel Sztainberg of the Neurobiology Department, Levkowitz's team found the same alternatively-spliced switch in mice. This conservation of the mechanism through the evolution of fish and mice implies that a similar means of turning CRH production on and off exists in the human brain.
Faulty switching mechanisms may play a role in a number of stress-related disorders. The action of the PAC1 receptor has recently been implicated in post-traumatic stress disorder, as well as in schizophrenia and depression. Malfunctions in alternative splicing have also been associated with epilepsy, mental retardation, bipolar disorder and autism.
Dr. Gil Levkowitz's research is supported by the estate of Lore Lennon; the Kirk Center for Childhood Cancer and Immunological Disorders; and the Irwin Green Alzheimer's Research Fund. Dr. Levkowitz is the incumbent of the Tauro Career Development Chair in Biomedical Research.
Dr. Alon Chen's research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the Nella and Leon Benoziyo Center for Neurological Diseases; the European Research Council; Roberto and Renata Ruhman, Brazil; Martine Turcotte and Friends, Canada; Mark Besen and the Pratt Foundation, Australia; the estate of Nathan Baltor; the estate of Lola Asseof; and the Women's Health Research Center funded by the Bennett-Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research, the Harry and Jeanette Weinberg Women's Health Research Endowment and the Oprah Winfrey Biomedical Research Fund. Dr. Chen is the incumbent of the Philip Harris and Gerald Ronson Career Development Chair.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,700 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
Weizmann Institute news releases are posted on the World Wide Web at http://wis-wander.weizmann.ac.il, and are also available at http://www.eurekalert.org.
Yivsam Azgad | EurekAlert!
Cnidarians remotely control bacteria
21.09.2017 | Christian-Albrechts-Universität zu Kiel
Immune cells may heal bleeding brain after strokes
21.09.2017 | NIH/National Institute of Neurological Disorders and Stroke
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
21.09.2017 | Physics and Astronomy
21.09.2017 | Life Sciences
21.09.2017 | Health and Medicine