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Blue light triggers memory and emphatic fear in mice via a non-invasive approach

- Improved optogenetic technique without the need of optic fiber implants controls calcium signaling in the brain of mice changing their behavior -

Researchers at the Center for Cognition and Sociality, within the Institute for Basic Science (IBS) in South Korea, have engineered an improved biological tool that controls calcium (Ca2+) levels in the brain via blue light. Published in Nature Communications, this optogenetic construct, called monster-OptoSTIM1 or monSTIM1 for short, causes a change in mice’s fear learning behavior without the need of optic fiber implants in the brain.

The brain utilizes Ca2+ signaling to regulate a variety of functions, including memory, emotion, and movement. Several evidences show correlation between abnormally regulated Ca2+ levels in certain brain cells and neurodegenerative diseases, but the details still remain obscure. For understanding the precise role of Ca2+ signaling, the IBS team is studying Ca2+-specific modulators that can be triggered in different parts of the brain at a designated time.

Optogenetics uses light to control Ca2+ signaling in the mouse brain. Since the brain is surrounded by hair, skin and skull, which prevent light from reaching deep tissues, optic fiber insertion in the brain used to be the norm in optogenetics. However, these implants can cause inflammation, morphological changes of neurons and disconnection of neural circuits. In this study, the research team improved their optogenetic tool so that it works with an external source of blue light, shone from the ceiling of the mouse cage, and without the need of brain implants.

MonSTIM1 is made of a part (CRY2) that responds to blue light and another part (STIM1) that activates calcium channels. Compared to the previously developed optogenetic techniques, the researchers were able to enhance CRY2’s light-sensitivity approximately 55-fold and also avoid the increase of basal Ca2+ levels. The monSTIM1 construct was injected into the mouse brain through a virus, and was shown to activate Ca2+ signals in the cortex as well as in the deeper hippocampus and thalamus regions.

The team observed behavioral changes in mice with monSTIM1 expressed in excitatory neurons in the anterior cingulate cortex, a brain region that has a central function in empathic emotions. Mice with activated monSTIM1 froze with fear by looking at other mice, which experienced a mild electric foot shock. Twenty-four hours later the same mice remembered about it and showed again an enhanced fear response, indicating that Ca2+ signaling contributed to both short- and long-term social fear responses.

“MonSTIM1 can be applied to a wide range of brain calcium research and brain cognitive science research, because it allows easy manipulation of intracellular calcium signals without damaging the brain,” says Won Do Heo (KAIST professor), leading author of this research.

Figure 1. Schematic image of monSTIM1 working mechanism. Upon blue light illumination, this optogenetic tool opens calcium channels (CRAC channels), so that calcium (Ca2+) can enter inside the cells. It is formed by two parts: CRY2, and STIM1. CRY2 is sensitive to blue light, and STIM1 activates calcium channels. GFP produces green light and is added to allow the researchers to track monSTIM1 location.
Figure 1. Schematic image of monSTIM1 working mechanism. Upon blue light illumination, this optogenetic tool opens calcium channels (CRAC channels), so that calcium (Ca2+) can enter inside the cells. It is formed by two parts: CRY2, and STIM1. CRY2 is sensitive to blue light, and STIM1 activates calcium channels. GFP produces green light and is added to allow the researchers to track monSTIM1 location.

Figure 2. Observational fear learning in mice via non-invasive light stimulation. Blue light shone on the cage of the observer mouse triggers monSTIM1 activation, increasing Ca2+ signals in its brain, and behavioral changes. Compared to the controls without monSTIM1, the observer mouse shows an enhanced fear response while the demonstrator receives mild foot shock.
Figure 2. Observational fear learning in mice via non-invasive light stimulation. Blue light shone on the cage of the observer mouse triggers monSTIM1 activation, increasing Ca2+ signals in its brain, and behavioral changes. Compared to the controls without monSTIM1, the observer mouse shows an enhanced fear response while the demonstrator receives mild foot shock.

Notes for editors

- References
Sungsoo Kim, Taeyoon Kyung, Jae-Hee Chung, Nury Kim, Sehoon Keum, Jinsu Lee, Hyerim Park, Ho Min Kim, Sangkyu Lee, Hee-Sup Shin, Won Do Heo. Non-invasive optical control of endogenous Ca2+ channels in awake mice. Nature Communications (2020). DOI: 10.1038/s41467-019-14005-4

- Media Contact
For further information or to request media assistance, please contact Won Do Heo (+82-42-350-5642, wondo@kaist.ac.kr), IBS Center for Cognition and Sociality, Mr. Kyungyoon Min, Head of IBS Communications Team (+82-42-878-8156, kymin@ibs.re.kr); or Ms. Carol Kim, Public Information Officer of IBS & Science Communicator (+82-42-878-8133, clitie620@ibs.re.kr)

- About the Institute for Basic Science (IBS)
IBS was founded in 2011 by the government of the Republic of Korea with the sole purpose of driving forward the development of basic science in South Korea. IBS has launched 30 research centers as of January 2020. There are ten physics, two mathematics, six chemistry, six life science, one earth science, and five interdisciplinary research centers.

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    Last Update 2019-12-17 14:52