Discovery of the neural circuit for fear conditioning of fish

April 25, 2018, Research Organization of Information and Systems
A section of the zebrafish telencephalon. The neurons essential for fear conditioning are illuminated with GFP (green fluorescence protein). Scale bars: 200 μm. Credit: Koichi Kawakami

Animals are often noted sensing signs of danger and reacting. A simple form of this phenomenon is called fear conditioning, which is a type of learning commonly seen in every animal. By manipulating the activity of specific neurons of the zebrafish brain, scientists at the National Institute of Genetics (NIG) in Japan have elucidated a neuronal population essential for fear conditioning in zebrafish. The study, published in the April 25 issue of BMC Biology, suggests that such a neural circuit essential for fear conditioning exists and is conserved during vertebrate evolution.

How can avoid danger to survive? If animals experienced dangerous events in conjunction with specific signs, animals remember the sign and exhibit in response, for instance, reacting with an escape behavior. In mammals including humans, the amygdala, one of the structures of the brain, plays an important role in . However, how the brain structure and neural circuits essential for fear conditioning have been conserved (or changed) during was unknown. Zebrafish, a popular model animal in biological studies, exhibit fear conditioning similarly to humans and other mammals. Professor Kawakami's group has succeeded in developing technologies for visualizing and manipulating specific brain in zebrafish by employing the yeast transcription factor Gal4, the green fluorescent protein (GFP), and the botulinum neurotoxin (BoTx). They have generated a collection of transgenic lines being used to study brain functions as well as other various organs by other researchers all over the world. Of the nearly 2,000 such transgenic fish lines in his lab, one played an important role in the current study that labels neurons in the dorsomedial (Dm) area of the telencephalon of zebrafish.

"In mammals including humans and mice, fear conditioning is mediated by a brain area called the amygdala. The amygdala integrates information about dangerous events, like electric shock, and some signs such as visual or auditory stimuli. However, in fish, such neurons have not been found." Prof. Kawakami said.

Active avoidance fear conditioning of zebrafish. The fish was placed in a plastic box with two compartments. 10 seconds after LED was on, an electric shock was given (day 1). This was repeated 10 times a day for five consecutive days. On day 5, when LED was on, the fish escaped to another compartment. Credit: Koichi Kawakami
"It is important to explore such neurons in fish, because we can increase the knowledge about fundamental neural circuits for animals to perform evolutionary conserved fear conditioning."

For this purpose, Dr. Lal, a former graduate student in his lab, developed a behavioral analysis system. Fish were placed with a small tank with two compartments. Ten times a day for five consecutive days, the researchers administered electric shocks while shining green LEDs in the tanks. Finally, in response to the green LEDs, the fish learned to escape from the compartment that was illuminated, and moved to another compartment.

"It is fun to see how smart they are," Dr. Lal said.

3-D image of the neurons essential for fear conditioning in zebrafish. A transparent brain was prepared from the transgenic fish and analyzed by light-sheet microscopy. Cell bodies located in the dorsomedial telencephalon (Dm) and their projections to the hypothalamic area are visualized. Credit: Koichi Kawakami

Using these technologies and resources, they have found that neurons in the region called Dm of the telencephalon of fish are essential for fear conditioning. These neurons are a functional equivalent of the amygdala of mammals. This result is a clue to clarify the structure and evolution of the essential for fear conditioning.

Prof. Kawakami's facility has thousands of fish tanks, each of which contains genetically different fish that can turn on, or drive the GFP or BoTx expression in different types of neurons in the brain or in the body.

"This work showcases a successful application of our genetic resources in the study of the function. It is also expected to be the basis for clarifying the causes and treatment of diseases involving fear and anxiety and PTSD," Prof. Kawakami said.

Explore further: Fear responses of zebrafish controlled by brain structures of previously unknown function

More information: Pradeep Lal et al, Identification of a neuronal population in the telencephalon essential for fear conditioning in zebrafish, BMC Biology (2018). DOI: 10.1186/s12915-018-0502-y

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