’Tug of war’ between neurons tells the brain when to fear — and when not to be afraid

Intercalated neurons (yellow) control information flow through the amygdala. Neu

Intercalated neurons (yellow) control information flow through the amygdala. Neuronal activity is shown in purple.

Fear protects us by making us alert to danger, but the persistence of fearful memories can lead to serious mental conditions. Now, an international team of researchers co-led by Andreas Lüthi has found that the activity of different cells in the brain’s threat-detector hub regulates the switch between high and low fear states. The finding could help to understand why some individuals are more susceptible to anxiety and trauma-related disorders.

Fear learning, which links a stimulus with a painful experience in an animal’s brain, can be undone through a process called fear extinction, which occurs when the animal expects a bad experience to happen but this experience does not actually happen. Scientists have known that distinct neural circuits drive fear learning and extinction, but how exactly these circuits interact remains a mystery.

Working in mice, Kenta Hagihara from the Lüthi group and his collaborators at the US National Institutes of Health looked at the activity of different clusters of brain cells that are arranged much like a net around the amygdala, a brain region that regulates fear and other emotions. These neurons, called intercalated neurons, are thought to control information flow through the amygdala.

First, the team analyzed the mice’s neuronal activities while the animals heard a sound and received an unpleasant stimulus to their feet. The stimulus caused the mice to freeze in place — a behavior indicative of fear — and triggered the activation of a specific group of intercalated neurons around the amygdala. As mice associated the unpleasant stimulus with the sound, that specific tone alone was enough to trigger the activation of the ’high fear’ intercalated neurons.

Next, the mice experienced a different scenario: the sound previously connected with the unpleasant stimulus was no longer followed by it. When the stimulus that the animals expected to occur did not actually occur, a second group of intercalated neurons fired in response. These ’low fear’ neurons continued to get activated as the mice learned not to be afraid of the tone.

Further experiments showed that the balance of activity between the ’high fear’ and ’low fear’ neurons determines the fear state of the animal. Activating ’high fear’ neurons increased the freezing reaction in response to the sound, whereas blocking ’low fear’ neurons made mice less prone to learn not to be afraid of the tone. "These two clusters of intercalated neurons act as a sort of ’yin and yang’ system: because they’re connected by inhibitory connections, when one cluster is stronger, the other is weaker — and vice versa," Lüthi says. "It’s a ’winner takes it all’ mechanism that can push the behavior of the mice in one or the other direction," he says.

Since intercalated neurons are present also in the human brain, the findings suggest that imbalances in the activity of these brain cells could increase the risk to develop anxiety and other disorders associated with stress and trauma. But Lüthi suspects that the tug of war between groups of intercalated neurons could govern more than just fear. "It could regulate behavioral states that are important for taking risks or not taking risks — for being in a defensive mode or in an exploratory mode," he says.

Original publication : Kenta M. Hagihara, Olena Bukalo, Martin Zeller, Ayla Aksoy-Aksel, Nikolaos Karalis, Aaron Limoges, Tanner Rigg, Tiffany Campbell, Adriana Mendez, Chase Weinholtz, Mathias Mahn, Larry S. Zweifel, Richard D. Palmiter, Ingrid Ehrlich, Andreas Luethi*, Andrew Holmes* Competition between intercalated amygdala clusters orchestrates a switch in fear state. Nature (2021). Advance online publication.
*co-corresponding authors

About the first author:
Kenta Hagihara was born in Sapporo, a large city on Hokkaido, the northernmost island of Japan. Before joining the FMI as a PhD candidate in 2015, Kenta attended a medical school in Fukuoka, Japan. In the Lüthi group, Kenta seeks to understand the circuit and cellular mechanisms of learning and memory, and how they are affected in disease. After completing his PhD, he plans to do a postdoc in the US. Kenta has many interests outside the lab: he plays the guitar in a band and likes photography, skiing, and powerlifting. He has recently launched a podcast (available only in Japanese for now) where he discusses neuroscience with his friend and Harvard’s postdoc Takeyuki Miyawaki.