Summary: Scientists have identified how the brain learns to suppress instinctive fear responses when repeated threats turn out to be harmless. Their work in mice links learning in the visual cortex to long-term changes in a deep brain structure, revealing a circuit and molecular mechanism that reduce defensive reactions. This discovery may point to new therapeutic strategies for anxiety, phobias and PTSD.
Using a controlled visual threat model, researchers showed that activity in specific visual cortical areas is required to learn that a looming visual stimulus is not dangerous, but those cortical regions are not where the resulting memory is stored. Instead, the ventrolateral geniculate nucleus (vLGN), a subcortical visual structure, retains the learning-induced changes that suppress fear behavior. The cellular mechanism relies on endocannabinoid signaling that disinhibits vLGN neurons, increasing their responsiveness to the previously threatening stimulus and thereby reducing escape responses.
Key Facts:
- Fear suppression memory: The ventrolateral geniculate nucleus (vLGN) stores the experience-dependent memory that suppresses innate escape reactions to a harmless visual threat.
- Learning vs memory storage: Posterolateral higher visual areas (plHVAs) in the cortex are necessary to instruct learning, but they are not required to maintain the learned suppression once it is established.
- Neural mechanism: Endocannabinoid-mediated reduction of inhibitory input to vLGN neurons enhances their activity in response to the visual stimulus, which suppresses instinctive fear behaviors.
- Clinical relevance: Targeting vLGN circuits or local endocannabinoid signaling offers a potential avenue for developing treatments for phobias, anxiety disorders and post-traumatic stress disorder (PTSD).
Source: Sainsbury Wellcome Centre
Researchers at the Sainsbury Wellcome Centre (SWC) at UCL have mapped the circuit that lets animals override hard-wired fear responses.
Published in Science, the study used mice exposed to an expanding overhead shadow that mimics an approaching aerial predator. When first presented with this looming stimulus, mice instinctively escape to shelter. With repeated exposure in the absence of actual harm, mice progressively stop escaping and remain calm. This behavioral transition provided a tractable model to study how the brain learns to suppress innate defensive reactions.
Led by Dr Sara Mederos and Professor Sonja Hofer, the team combined behavioral experiments with circuit manipulations and cellular-level analyses to identify where and how the learning signal is formed and stored. They found that posterolateral higher visual areas (plHVAs) provide a top-down instructive input to the vLGN that is critical for acquiring the suppressed response. When these cortical areas were inactivated during training, animals failed to learn to stop escaping. However, once animals had successfully learned, silencing the cortex did not reinstate escape behavior, indicating the memory had shifted out of the cortex.
Further analysis showed that learning induces synaptic and cellular plasticity within vLGN populations. Specifically, endocannabinoid signaling reduces inhibitory drive onto vLGN neurons, enabling those cells to increase their responses to the looming stimulus. This heightened vLGN activity in turn suppresses the downstream circuits that elicit escape, allowing the animal to override the instinctive reaction.
These results challenge a narrow view that the cerebral cortex alone stores learning and memory for behavioral flexibility. Instead, the work demonstrates a division of labor: cortical regions instruct experience-dependent change, while a subcortical node—the vLGN—implements and stores the change that modifies an innate behavior. This cortical-to-subcortical pathway provides a clear mechanism for how flexible, learned information can modulate hard-wired brainstem-mediated responses.
Professor Hofer emphasizes the potential translational impact: while the precise predator-escape behaviors studied are ethologically specific to animals, the underlying circuit elements and endocannabinoid mechanisms are conserved across mammals. Understanding how fear suppression is encoded could reveal targets for therapeutic interventions when fear regulation breaks down in conditions such as phobias, generalized anxiety and PTSD.
The team plans to extend this work by collaborating with clinical researchers to assess comparable circuits in humans and to explore whether modulating vLGN activity or local endocannabinoid signaling can ameliorate maladaptive fear responses.
Funding: This research was supported by 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).
About this fear and neuroscience research news
Author: April Cashin-Garbutt
Source: Sainsbury Wellcome Centre
Contact: April Cashin-Garbutt – Sainsbury Wellcome Centre
Image: The image is credited to Neuroscience News
Original Research: Closed access. “Overwriting an instinct: Visual cortex instructs learning to suppress fear responses” by Sara Mederos et al., Science.
Abstract
Overwriting an instinct: Visual cortex instructs learning to suppress fear responses
Fast instinctive responses to environmental stimuli can be crucial for survival but are not always optimal. Animals can adapt their behavior and suppress instinctive reactions, but the neural pathways mediating such ethologically relevant forms of learning remain unclear.
We found that posterolateral higher visual areas (plHVAs) are crucial for learning to suppress escapes from innate visual threats through a top-down pathway to the ventrolateral geniculate nucleus (vLGN). plHVAs are no longer necessary after learning; instead, the learned behavior relies on plasticity within vLGN populations that exert inhibitory control over escape 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.
We thus reveal the detailed circuit, cellular, and synaptic mechanisms underlying experience-dependent suppression of fear responses.