[[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 interactions between neuromodulators that mediate learning and neural circuitry that play important roles in such learning. Learning that an aversive outcome does not occur when a stimulus previously associated with trauma is encountered is a key component of extinction learning. Dopamine plays a central role in signaling such prediction errors. Most work on the influence of dopamine on extinction learning has focused on the A10 cluster of dopaminergic cells in the ventral tegmental area (VTA). In contrast, the contributions of other distinct clusters of dopaminergic cells that are evolutionarily conserved in the mammalian brain to extinction learning is unknown. Filling this gap will not only significantly advance our knowledge of dopaminergic influences on extinction learning, but also once these contributions are established, we can analyze across dopaminergic cell clusters, molecular perturbations that may cause deficits in extinction learning and potentially identify new pharmacotherapy to rescue these deficits. Recent work published by us and others have demonstrated a novel role for the zona incerta (ZI) in fear-related behavior, including extinction learning. Motivated by the presence of A13 dopaminergic cells in the ZI, we will combine auditory fear conditioning in mice with pharmacological, molecular-genetic, viral-mediated circuit tracing, optogenetic and chemogenetic methodology to test the hypothesis that A13 cells in the ZI influence extinction learning. More specifically, we will trace the connectivity of dopaminergic cells in the ZI, manipulate their activity and perturb function of specific dopaminergic receptors during extinction training, while examining the consequence of these manipulations on normative and disrupted extinction learning. Our work will illuminate basic neurobiology underlying a clinically important dimension of PTSD (deficits in extinction learning). Positive results will shed light on how an understudied circuit modulates normative extinction learning via molecular and physiological function of dopamine, while being able to rescue deficits in extinction learning. This work will position us to compare and contrast stress-induced changes across dopaminergic cell clusters in the brain to identify unique and shared molecular pathways that could be targeted to reduce deficits in extinction learning.]]
Resulting from being unable to learn that stimuli previously linked to trauma are no longer dangerous (deficits in extinction learning), fear of trauma-associated stimuli even after they have ceased to be threats is a core pathology of Post-Traumatic Stress Disorder (PTSD). Of relevance to the Strategic Objectives #1 and #3 of NIMH's mission which are to ?define mechanisms of complex behaviors while striving for preventions and cures?, our proposal will shed light on how sub-thalamic neural circuitry influences extinction learning. The proposed research is relevant to public health because our results will provide a foundation from which future studies could identify new molecular pathways underlying extinction learning, eventually resulting in new pharmacotherapies to reduce the burden of maladaptive fear associated with PTSD.
