Researchers at the Sainsbury Wellcome Center (SWC) at University College London have uncovered a neural mechanism in the brains of mice that enables the animals to overcome instinctive fears. The investigators suggest the findings could have implications for developing therapeutics for fear-related disorders such as phobias, anxiety and post-traumatic stress disorder (PTSD).
Headed by Professor Sonja Hofer, PhD, and Sara Mederos, PhD, the team mapped out how the brain learns to suppress responses to perceived threats that prove harmless over time. “Humans are born with instinctive fear reactions, such as responses to loud noises or fast-approaching objects,” explained Mederos, Research Fellow in the Hofer Lab at SWC. “However, we can override these instinctive responses through experience—like children learning to enjoy fireworks rather than fear their loud bangs. We wanted to understand the brain mechanisms that underlie such forms of learning.”
The study is reported in Science, in a paper titled “Overwriting an instinct: Visual cortex instructs learning to suppress fear responses.”
Instinctive behaviors are automatic responses to specific environmental challenges that have evolved to furnish animals with a repertoire of behaviors vital for survival and reproductive success, the authors wrote. Fear responses to visual threats, such as escaping from an approaching predator, are particularly critical instinctive reactions for survival. Such responses are primarily managed by neural circuits involving the medial superior colliculus and periaqueductal gray.
These reflexive actions are typically automatic and independent of higher brain regions. “This visuo-motor pathway in the brainstem autonomously drives escape responses independently of the forebrain,” the team explained. Animals can suppress these fear responses upon learning that a perceived threat is harmless, but the neural mechanisms and brain regions behind this form of learning, which modifies instinctive reactions, isn’t well understood. “Animals can adapt their behavior and suppress instinctive reactions, but the neural pathways mediating such ethologically relevant forms of learning remain unclear” the team noted.
Escape behavior in response to a looming visual stimulus is a well-established measure of instinctive fear in mice, where naïve animals will typically flee to a shelter when presented with such a threat, the authors explained. “These behaviors allow animals to quickly detect and respond to potential dangers or opportunities in their environment without the need for prior learning or experience, and are usually implemented by brainstem pathways independent of neural processes in the forebrain.”
For their reported study Mederos and colleagues designed an experiment in which mice were prevented from accessing shelter by a visual stimulation threat rendered from a projector—three consecutive expanding black spots in a three-second period. Over time, the mice learned to stop escaping from the black spots.
Based on previous work in the Hofer Lab, the team knew that an area of the brain called the ventrolateral geniculate nucleus (vLGN) could suppress fear reactions when active and was able to track knowledge of previous experience of threat. The vLGN also receives strong input from visual areas in the cerebral cortex, and so the researchers explored whether this neural pathway had a role in learning not to fear a visual threat.
Using optogenetic techniques during various stages of the animals’ learning process, the investigators found that posterolateral higher visual areas (plHVA)—a group of brain regions in the visual cortex—are crucial for learning to suppress instinctive fear responses. However, the visual cortex is not necessary for maintaining the behavior once learned. Instead, they found, plasticity occurs downstream in the vLGN, where neurons receive inhibitory modulation driven by experience. “plHVAs are no longer necessary after learning,” they wrote. “… instead, the learned behavior relies on plasticity within vLGN populations that exert inhibitory control over escape responses.”
The researchers also uncovered the cellular and molecular mechanisms behind this process. Learning occurs through increased neural activity in specific vLGN neurons, triggered by the release of endocannabinoids (eCBs)—brain-internal messenger molecules known to regulate mood and memory. This release decreases inhibitory input to vLGN neurons, resulting in heightened activity in this brain area when the visual threat stimulus is encountered, which suppresses fear responses. “vLGN neurons receiving input from plHVAs enhance their responses to visual threat stimuli during learning through endocannabinoid-mediated long-term suppression of their inhibitory inputs,” the team noted. “eCBs have long been implicated in the regulation of fear and anxiety and are necessary for extinction of fear conditioning.”
Mederos further stated, “We found that animals failed to learn to suppress their fear responses when specific cortical visual areas where inactivated. However, once the animals had already learned to stop escaping, the cerebral cortex was no longer necessary.”
Added Hofer, “Our results challenge traditional views about learning and memory. While the cerebral cortex has long been considered the brain’s primary centre for learning, memory and behavioral flexibility, we found the subcortical vLGN and not the visual cortex actually stores these crucial memories. This neural pathway can provide a link between cognitive neocortical processes and ‘hard-wired’ brainstem-mediated behaviors, enabling animals to adapt instinctive behaviors.”
The implications of the discoveries extend beyond the laboratory, the team suggests. Dysfunction of pathways through vLGN or impairments in eCB-dependent plasticity could contribute to fear and anxiety disorders and PTSD, the team suggested. “… targeting these pathways, for example, by using deep brain stimulation, or enhancing eCB-dependent plasticity within these circuits may facilitate suppression of maladaptive fear responses, suggesting new therapeutic strategies for fear-related disorders.”
Hofer stated, “Our findings could also help advance our understanding of what is going wrong in the brain when fear response regulation is impaired in conditions such as phobias, anxiety and PTSD. While instinctive fear reactions to predators may be less relevant for modern humans, the brain pathway we discovered exists in humans too. This could open new avenues for treating fear disorders by targeting vLGN circuits or localized endocannabinoid systems.”
The research team is now planning to collaborate with clinical researchers to study these brain circuits in humans, with the hope of someday developing new, targeted treatments for maladaptive fear responses and anxiety disorders.
