Brian G. Dias, Ph.D. - US grants

PROJECT SUMMARY Post Traumatic Stress Disorder (PTSD) is a devastating neuropsychiatric disorder that develops after trauma. A previous history of stress exposure significantly increases the likelihood of developing PTSD after a traumatic event. Deficits in extinction learning are a debilitating and core symptom of PTSD. This inability to learn that stimuli previously linked to trauma are no longer threatening causes maladaptive fear expression toward these stimuli. Efforts to reduce stress-induced deficits in extinction learning have included identifying stress-induced perturbations of molecular pathways in the brain. Most of this work has either treated brain regions as a homogeneous population of cells or mainly focused on neurons. While glia are the most populous cells in the nervous system, we have little appreciation for their contribution to stress-induced deficits in extinction learning. In this proposal, we examine how molecular events in astrocytes (the most predominant glial cell population) influence stress-induced deficits in extinction learning. More specifically, we study the relationship between astrocytes in the infra-limbic prefrontal cortex, a brain region important for extinction learning and stress-induced deficits in extinction learning. We hypothesize that in the adult brain, stress- induced deficits in extinction learning are, in part, mediated by stress hormone action and increased activity of developmental signaling pathways, in astrocytes of the infra-limbic prefrontal cortex. To test this hypothesis, we will study stress-induced deficits in extinction learning after manipulating stress hormone receptor function and the activity of developmental signaling cascades in astrocytes of the infra-limbic prefrontal cortex. Successful outcomes from our work will shed new light on how molecular function in astrocytes contribute to stress-induced impairments in extinction learning. Additionally, our work has the potential to recommend new cell-type specific molecular pathways that could be targeted to mitigate a highly prevalent and debilitating memory-related dimension of PTSD.

PROJECT SUMMARY Post-Traumatic Stress Disorder (PTSD) is a devastating neuropsychiatric disorder that develops after trauma. The expression of debilitating fear toward stimuli previously associated with trauma even after they no longer pose a threat is a core pathology of 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 when presented in safe contexts and with no aversive outcome. These deficits in extinction learning are a highly prevalent symptom of PTSD and significantly hamper quality of life. Efforts to reduce deficits in extinction learning have focused on understanding the contributions of regions like the amygdala, prefrontal cortex, hippocampus and periaqueductal gray to this process. Despite progress made from this focus, sertraline and paroxetine are the only FDA-approved treatments for PTSD. These drugs are serotonin selective reuptake inhibitors and antidepressants. As such they improve mood-related symptoms of PTSD but do not directly address learning- related symptoms like deficits in extinction learning. With 24 million Americans living with PTSD, there is a need for new therapeutic options to treat deficits in extinction learning. Dopamine plays an important role in extinction learning and drugs that increase dopamine levels like methylphenidate and MDMA improve extinction learning. However, these drugs are not specific to the dopaminergic system and could result in substance abuse disorders, in part, via their action on dopaminergic cells in the ventral tegmental area. In this proposal, we propose to study whether dopaminergic cells in a sub-thalamic nucleus called the zona incerta (ZI) can reduce deficits in extinction learning via dopamine-mediated signaling. To test this hypothesis, we will combine auditory fear conditioning in mice with pharmacological, molecular-genetic, viral-mediated circuit tracing, optogenetic and chemogenetic methodology. More specifically, we will trace the connectivity of dopaminergic cells in the ZI, manipulate the activity of these cells and perturb function of specific dopaminergic receptors during extinction training while examining the consequence of these manipulations on extinction learning. Additionally, we will examine how these dopaminergic cells respond to extinction training after exposure to stress ? a factor that impairs extinction learning. Successful outcomes from our work could highlight a novel function for dopaminergic cells in the ZI in modulating fear-related extinction learning. Our results may have translational impact by suggesting that stimulating ZI-located dopaminergic cells and administering dopamine receptor agonists during exposure therapy may improve extinction learning and reduce maladaptive fear that accompanies PTSD.

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 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.]]