The neural network in the brain that controls defensive behavior in threatening situations has been identified and characterized by researchers at the Friedrich Miescher Institute for Biomedical Research.

Andreas Lüthi and his group show, in a newly publisher study, which neurons trigger fear-related freezing and how the freezing pathway interacts with pathways responsible for flight.

In recent decades, researchers have been investigating the processes in the brain which give rise to fear, and how fear is learned. But it has not been clear to date how the state of fear triggers a response which extends all the way to the muscles.

These processes have now been studied by Philip Tovote, a postdoctoral fellow at the Friedrich Miescher Institute for Biomedical Research, in collaboration with other members of Andreas Lüthi’s group and with Soledad Esposito from Silvia Arber’s group.

Circuitry Behind Freezing In Fear

Using circuit-based optogenetic, in vivo and in vitro electrophysiological, and neuroanatomical tracing methods in combination with physiological approaches, the researchers identified neurons in the midbrain that are activated during freezing. They then identified an output pathway leading to a medullary area involved in motor control.

At the same time, they identified a pathway leading from the central nucleus of the amygdala (the forebrain structure controlling fear responses) to the midbrain.

Lüthi explains: “We’ve now defined the neuronal circuitry underlying the execution of freezing, from the central nucleus of the amygdala to the neurons that control our muscles."

Fear protects us in a world full of dangers. This is particularly evident in small rodents, such as mice, which exhibit various reactions to threats: freezing, flight or, as a last resort, defensive attack.

Often, the behavioral response to a threat needs to be rapidly adapted; for example, there may be a switch from freezing to flight. The researchers therefore investigated whether and how freezing is influenced by the flight pathway. Tovote comments:

“There is evidence that the circuit that triggers freezing interacts with the flight circuit. Not only are neurons from the two circuits anatomically connected, but there is also functional interaction."

Evolutionarily conserved strategies for coping with fear – essential for survival – are deployed by a wide variety of species. Similar mechanisms exist in humans. Lüthi concludes:

“It’s conceivable that malfunction of the circuitry we’ve identified also plays a role in people with anxiety disorders."

Tovote P, Esposito MS, Botta P, Chaudun F, Fadok JP, Markovic M, Wolff SBE, Ramakrishnan C, Fenno L, Deisseroth K, Herry C, Arber S, Lüthi A (2016) Midbrain circuits for defensive behavior Nature, doi:10.1038/nature17996

Image: Stefan Rheone/Flickr

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