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.
