Periodic Reporting for period 1 - EthoFearless (Attenuation of ethological traumatic memories)
Período documentado: 2023-09-01 hasta 2026-02-28
Understanding How the Brain Overcomes Trauma: A New Approach to Fear and Memory.
Traumatic experiences, like life-threatening events or interpersonal violence, leave deep emotional scars, often leading to conditions such as Post-Traumatic Stress Disorder (PTSD). While our brains have a natural ability to reduce fear associate dto traumatic memories over time, this process sometimes fails, leaving people trapped in cycles of anxiety and distress. But how does the brain actually overcome traumatic memories? And why does this process work for some people but not others?
This project aims to answer these questions by mapping the brain circuits responsible for reducing fear after naturalistic traumas, not just simple lab-induced fears, but the complex, real-life experiences that shape our deepest emotions. Most research on fear extinction has relied on simplified models, like mild electric shocks, which don’t capture the complexity of human trauma. Here, we’re taking a different approach: using mice exposed to predatory threats and social conflicts to model the kinds of traumatic events humans face, such as violence or life-threatening situations. This allows us to study how the brain processes and updates memories of fear, moving beyond freezing responses to include a range of behaviors like avoidance, aggression, or submission.
Why This Matters:
Trauma doesn’t just create a single, simple memory—it weaves a complex web of emotions, behaviors, and physical reactions. Current therapies, like exposure therapy for PTSD, help some people but not others. We believe the key lies in understanding how the brain’s "hub regions"—particularly an area called the thalamus—act as a bridge between higher-thinking brain regions (like the cortex) and deeper, instinct-driven areas (like the amygdala and hypothalamus). If we can uncover how these hubs work, we might find ways to enhance therapy or even develop new treatments using non-invasive brain stimulation techniques already emerging in clinics.
Traumatic experiences, like life-threatening events or interpersonal violence, leave deep emotional scars, often leading to conditions such as Post-Traumatic Stress Disorder (PTSD). While our brains have a natural ability to reduce fear associate dto traumatic memories over time, this process sometimes fails, leaving people trapped in cycles of anxiety and distress. But how does the brain actually overcome traumatic memories? And why does this process work for some people but not others?
This project aims to answer these questions by mapping the brain circuits responsible for reducing fear after naturalistic traumas, not just simple lab-induced fears, but the complex, real-life experiences that shape our deepest emotions. Most research on fear extinction has relied on simplified models, like mild electric shocks, which don’t capture the complexity of human trauma. Here, we’re taking a different approach: using mice exposed to predatory threats and social conflicts to model the kinds of traumatic events humans face, such as violence or life-threatening situations. This allows us to study how the brain processes and updates memories of fear, moving beyond freezing responses to include a range of behaviors like avoidance, aggression, or submission.
Why This Matters:
Trauma doesn’t just create a single, simple memory—it weaves a complex web of emotions, behaviors, and physical reactions. Current therapies, like exposure therapy for PTSD, help some people but not others. We believe the key lies in understanding how the brain’s "hub regions"—particularly an area called the thalamus—act as a bridge between higher-thinking brain regions (like the cortex) and deeper, instinct-driven areas (like the amygdala and hypothalamus). If we can uncover how these hubs work, we might find ways to enhance therapy or even develop new treatments using non-invasive brain stimulation techniques already emerging in clinics.
Establishment of a mouse model to study traumatic memory attenuation in the mouse.
We successfully established an innovative mouse behavioral platform to study how the brain overcomes fear after naturalistic traumas. Unlike traditional experiments that rely on simple electric shocks, our approach exposes mice to real-world threats: aggressive social encounters (modeling interpersonal violence) and predatory threats (modeling life-threatening danger). This allows us to explore complex fear responses, such as avoidance, freezing, and flight, that netter mirror human trauma-associated reactions.
Our findings revealed a surprising and critical difference: while mice exposed to foot shocks gradually reduced their fear during extinction, those exposed to social defeat showed persistent fear, resisting extinction. This discovery highlights how different types of trauma may leave distinct imprints on the brain, offering new insights into why some fears are harder to overcome than others.
Mapping the Brain’s Fear Extinction Circuits (Aim 1)
To identify which brain regions are activated during fear extinction, we developed a cutting-edge pipeline for whole-brain mapping, combining two open-source tools: ABBA and BraiAn. This technology allows us to automatically register, quantify, and visualize brain activity across the entire brain—a task that was previously limited to small, manually analyzed sections. Our pipeline has already led to a major publication in Cell Reports (2025), where we compared how different "immediate early genes" (markers of brain activity) respond to fear learning. We found that these genes are not interchangeable—each provides unique insights into brain activity, challenging decades of assumptions in neuroscience. ABBA and BraiAn have since been downloaded over 11,000 times and cited in top journals like Nature and Science, proving their value to the global research community.
We are now using this pipeline to map the entire brain’s activity during fear extinction, revealing how different traumas activate distinct neural networks.
Decoding the Brain’s Fear Hubs (Aim 2)
We focused on the nucleus reuniens (NRe), a brain region we believe acts as a central hub for fear extinction. Using advanced viral tracing and our ABBA+BraiAn pipeline, we discovered that NRe neurons connecting to the cortex (involved in higher thinking) receive mostly cortical inputs, while those connecting to the amygdala (involved in instinctive fear) receive subcortical inputs. This segregation suggests that the NRe may route different types of fear memories through distinct pathways.
To test this, we are now using chemogenetic tools to selectively activate or silence these pathways, aiming to determine their causal role in fear extinction. This could reveal whether enhancing activity in these hubs might improve therapies for PTSD and other trauma-related disorders.
Recording the Brain during fear attenuation (Aim 3)
To understand how the NRe orchestrates fear extinction in real time, we are y using fiber photometry, a powerful method to record brain activity. Our recordings showed that NRe activity isn’t just linked to freezing behavior, but it also correlates with stretch postures and flight behaviors, and its patterns change as fear extinguishes. These findings are now guiding optogenetic experiments, where we will use light to precisely control NRe activity and observe how it affects fear extinction. This work could pave the way for targeted brain stimulation therapies to help people overcome trauma.
We successfully established an innovative mouse behavioral platform to study how the brain overcomes fear after naturalistic traumas. Unlike traditional experiments that rely on simple electric shocks, our approach exposes mice to real-world threats: aggressive social encounters (modeling interpersonal violence) and predatory threats (modeling life-threatening danger). This allows us to explore complex fear responses, such as avoidance, freezing, and flight, that netter mirror human trauma-associated reactions.
Our findings revealed a surprising and critical difference: while mice exposed to foot shocks gradually reduced their fear during extinction, those exposed to social defeat showed persistent fear, resisting extinction. This discovery highlights how different types of trauma may leave distinct imprints on the brain, offering new insights into why some fears are harder to overcome than others.
Mapping the Brain’s Fear Extinction Circuits (Aim 1)
To identify which brain regions are activated during fear extinction, we developed a cutting-edge pipeline for whole-brain mapping, combining two open-source tools: ABBA and BraiAn. This technology allows us to automatically register, quantify, and visualize brain activity across the entire brain—a task that was previously limited to small, manually analyzed sections. Our pipeline has already led to a major publication in Cell Reports (2025), where we compared how different "immediate early genes" (markers of brain activity) respond to fear learning. We found that these genes are not interchangeable—each provides unique insights into brain activity, challenging decades of assumptions in neuroscience. ABBA and BraiAn have since been downloaded over 11,000 times and cited in top journals like Nature and Science, proving their value to the global research community.
We are now using this pipeline to map the entire brain’s activity during fear extinction, revealing how different traumas activate distinct neural networks.
Decoding the Brain’s Fear Hubs (Aim 2)
We focused on the nucleus reuniens (NRe), a brain region we believe acts as a central hub for fear extinction. Using advanced viral tracing and our ABBA+BraiAn pipeline, we discovered that NRe neurons connecting to the cortex (involved in higher thinking) receive mostly cortical inputs, while those connecting to the amygdala (involved in instinctive fear) receive subcortical inputs. This segregation suggests that the NRe may route different types of fear memories through distinct pathways.
To test this, we are now using chemogenetic tools to selectively activate or silence these pathways, aiming to determine their causal role in fear extinction. This could reveal whether enhancing activity in these hubs might improve therapies for PTSD and other trauma-related disorders.
Recording the Brain during fear attenuation (Aim 3)
To understand how the NRe orchestrates fear extinction in real time, we are y using fiber photometry, a powerful method to record brain activity. Our recordings showed that NRe activity isn’t just linked to freezing behavior, but it also correlates with stretch postures and flight behaviors, and its patterns change as fear extinguishes. These findings are now guiding optogenetic experiments, where we will use light to precisely control NRe activity and observe how it affects fear extinction. This work could pave the way for targeted brain stimulation therapies to help people overcome trauma.
Our project has delivered both technical and scientific breakthroughs:
• ABBA+BraiAn is the first fully automated, user-friendly pipeline for whole-brain mapping, filling a critical gap in neuroscience tools. Its widespread adoption reflects its transformative potential.
• Our behavioral platform is the first to model complex, real-world traumas, revealing that not all fears extinguish equally—a discovery with profound implications for therapy.
• By identifying the NRe as a key hub for fear extinction, we are uncovering how the brain updates emotional memories, which could lead to new treatments for PTSD, phobias, and anxiety disorders.
These advances are not just pushing the boundaries of neuroscience—they are bridging the gap between lab research and real-world healing, offering hope for millions affected by trauma.
• ABBA+BraiAn is the first fully automated, user-friendly pipeline for whole-brain mapping, filling a critical gap in neuroscience tools. Its widespread adoption reflects its transformative potential.
• Our behavioral platform is the first to model complex, real-world traumas, revealing that not all fears extinguish equally—a discovery with profound implications for therapy.
• By identifying the NRe as a key hub for fear extinction, we are uncovering how the brain updates emotional memories, which could lead to new treatments for PTSD, phobias, and anxiety disorders.
These advances are not just pushing the boundaries of neuroscience—they are bridging the gap between lab research and real-world healing, offering hope for millions affected by trauma.