Researchers have identified the specific brain mechanisms that help animals manage their instinctual fears. A recent study conducted on mice, published today in *Science*, may pave the way for new treatments for fear-related conditions like phobias, anxiety disorders, and post-traumatic stress disorder (PTSD).
Researchers at the Sainsbury Wellcome Centre (SWC) at UCL have identified the specific brain mechanisms that assist animals in managing their instinctual fears. Released today in Science, this study involving mice could lead to new therapies for fear-related issues such as phobias, anxiety, and post-traumatic stress disorder (PTSD).
Led by Dr. Sara Mederos and Professor Sonja Hofer, the research team explored how the brain learns to diminish reactions to perceived threats that are ultimately harmless.
“Humans have innate fear responses, like reacting to loud sounds or fast-moving objects,” says Dr. Mederos, a Research Fellow in the Hofer Lab at SWC. “However, we can learn to control these responses through experience—like how children can come to enjoy fireworks rather than fear their loud bangs. We aimed to uncover the brain mechanisms behind such learning.”
The researchers devised a novel experimental method where mice were presented with a shadow that mimicked an approaching predator from above. Initially, the mice sought refuge upon seeing this visual threat. However, with repeated exposure without real danger, they learned to stay calm instead of fleeing, creating a model for studying the suppression of fear responses.
Utilizing prior knowledge from the Hofer Lab, the team recognized that an area in the brain known as the ventrolateral geniculate nucleus (vLGN) could mitigate fear responses when activated and help track prior experiences of threats. Additionally, the vLGN receives significant input from visual areas in the cerebral cortex, prompting the team to investigate whether this pathway was involved in the learning process of overcoming visual threats.
The findings highlighted two crucial elements in this learning: (1) certain regions of the visual cortex were vital for this learning process and (2) the vLGN serves as a storage area for these learned memories.
“We observed that the animals could not learn to suppress their fear responses when specific visual cortical areas were inactive. However, once they had effectively learned not to flee, the cerebral cortex was no longer required,” Dr. Mederos noted.
“Our findings challenge long-held beliefs about learning and memory,” remarked Professor Hofer, the senior author of the study. “While the cerebral cortex has been considered the main hub for learning, memory, and behavioral flexibility, our research shows that the subcortical vLGN, not the visual cortex, is where these important memories are stored. This neural pathway could bridge cognitive processes in the neocortex and instinctive behaviors mediated by the brainstem, allowing animals to adjust their instinctual responses.”
The team also discovered the cellular and molecular processes behind this learning. Learning happens through increased neural activity in certain vLGN neurons, initiated by the release of endocannabinoids—molecules that regulate mood and memory. This release reduces inhibitory inputs to vLGN neurons, resulting in increased activity in response to the visual threat, which helps suppress fear responses.
The implications of this discovery reach far beyond the lab. “Our results may enhance understanding of the brain’s dysfunctions regarding fear response regulation in conditions like phobias, anxiety, and PTSD. While basic fear reactions to predators may not apply to modern humans, the brain pathway we identified also exists in humans,” explained Professor Hofer. “This insight could lead to new treatment pathways for fear disorders by targeting vLGN circuits or specific endocannabinoid systems.”
The team is looking to join forces with clinical researchers to study these brain circuits in humans, hoping to develop new, targeted treatments for maladaptive fear responses and anxiety disorders in the future.
This research received financial support from the Sainsbury Wellcome Centre core grant from the Gatsby Charity Foundation and Wellcome (090843/F/09/Z); a Wellcome Investigator Award (219561/Z/19/Z); an EMBO postdoctoral fellowship (EMBO ALTF 327-2021); and a Wellcome Early Career Award (225708/Z/22/Z).
