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Sub-thalamic modulation of learning-related dimensions of PTSD.

丘脑下对 PTSD 学习相关维度的调节。

基本信息

批准号：
10152686
负责人：
Brian George DIAS
金额：
$ 41.71万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-04 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152686
关键词：
Address American Amygdaloid structure Animals Antidepressive Agents Auditory Behavior Cell physiology Cells Complex DRD1 gene DRD2 gene Data Dimensions Disease Dopamine Dopamine Agonists Dopamine D2 Receptor Dopaminergic Cell Exposure to Extinction (Psychology)FDA approved FOS gene Freezing Fright Future Goals Hippocampus (Brain)Human Impairment Infusion procedures Label Learning Light Link Measures Mediating Methodology Mission Molecular Molecular Genetics Moods Mus National Institute of Mental Health Neurobehavioral Manifestations Neurons Outcome Paroxetine Pathology Pathway interactions Pharmaceutical Preparations Pharmacology Play Post-Traumatic Stress Disorders Prefrontal Cortex Prevention Process Public Health Quality of life RNA Interference Research Ritalin Role Selective Serotonin Reuptake Inhibitor Serotonin Agents Sertraline Shock Signal Transduction Site Stimulus Stress Structure of subthalamic nucleus Substance abuse problem Symptoms Synapses System Technology Testing Therapeutic Time Training Trauma Ventral Tegmental Area Viral Work base conditioned fear conditioning design designer receptors exclusively activated by designer drugs dopamine system dopaminergic neuron ecstasy experience improved insight knock-down learning extinction midbrain central gray substance neural circuit neuropsychiatric disorder novel novel therapeutics optogenetics post-traumatic symptoms prevent receptor translational impact zona incerta

项目摘要

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.

项目总结