Saturday, June 14, 2025
6/14/2025
Molecular mechanisms underlying sub-thalamic influences on extinction learning - PROJECT SUMMARY. The expression of debilitating fear toward stimuli previously associated with trauma even after they no longer pose a threat is a core pathology of Post-Traumatic Stress Disorder (PTSD). Such maladaptive fear is caused by an inability to learn that the stimuli that had been previously linked to trauma are no longer threatening. These deficits in extinction learning are a highly prevalent dimension of PTSD and significantly hamper quality of life. Cognitive Behavioral Therapy in isolation or in combination with pharmacotherapies are the most widely used treatments to rescue deficits in extinction learning. Such treatments are effective in approximately 50% of treated cases, emphasizing that there is room to more effectively rescue deficits in extinction learning. One way to achieve this objective is to first understand how extinction learning is facilitated by molecular and cellular processes in neural circuitry that influences extinction learning. While several neuromodulators have been implicated in the pathophysiology of PTSD, among them, dopamine has been shown to play a central role in extinction learning. Most of our understanding of dopaminergic influences on extinction learning has come from a focus on the A10 cluster of dopaminergic cells in the ventral tegmental area (VTA). However, A10 cells are one of several distinct clusters of dopaminergic cells that are evolutionarily conserved in the mammalian brain. Gaining an appreciation for how dopaminergic cells outside of the VTA may influence extinction learning will significantly advance our understanding of how dopaminergic signaling modulates extinction learning. More importantly, leveraging any promise that manipulating dopaminergic cells may hold to reduce deficits in extinction learning requires understanding molecular pathways and physiological principles that are shared by or unique to dopaminergic cell clusters across the brain to influence extinction learning. Our long-term goal is to determine how dopaminergic cells outside of the VTA contribute to extinction learning and recall. To achieve this goal, our immediate objective with this proposal is to determine molecular and cellular mechanisms in A13 dopaminergic cells in the zona incerta (ZI) that contribute to extinction learning. To do so, we build on our work that has studied the influences of the ZI and of A13 cells on extinction learning. We will combine auditory fear conditioning in mice with intersectional molecular-genetics, inducible RNAi, optogenetic-based interference of protein action, and manipulation of cellular firing after activity-based tagging of neuronal ensembles to study molecular pathways and cellular processes that afford A13 cells the ability to influence extinction learning. This work will illuminate basic neurobiology underlying a clinically important dimension of PTSD (extinction learning). Positive results will highlight highly conserved processes via which many brain regions including dopaminergic hubs influence extinction learning. Future studies will profile how stress-induced changes in these processes in A13 cells influence their communication with targets like the periaqueductal gray and nucleus reuniens to disrupt extinction learning.
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