Dopaminergic modulation of fear extinction

恐惧消退的多巴胺能调节

• 批准号: 9377035
• 负责人: BEN N GREENWOOD
• 金额: $ 46.65万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-16 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9377035
• 关键词: Acute; Affinity; Agonist; Anxiety; Behavior; Brain; Chronic; Collaborations; Corpus striatum structure; Cues; Data; Development; Diestrus; Disease; Dopamine; Dopamine D1 Receptor; Dorsal; Educational process of instructing; Estradiol; Estrogens; Estrus; Exercise; Extinction (Psychology); Female; Fluorescent in Situ Hybridization; Frequencies; Fright; Future; Goals; Heart; High Prevalence; Impairment; Knowledge; Learning; Medial; Mediating; Mediator of activation protein; Memory; Mental Health; Mental disorders; Messenger RNA; Metestrus; Microinjections; Molecular; Motor; Neurons; Pathway interactions; Periodicity; Pharmacology; Phase; Post-Traumatic Stress Disorders; Process; Rattus; Receptor Signaling; Recovery; Recruitment Activity; Relapse; Reporting; Resistance; Retrieval; Role; Scanning; Signal Pathway; Signal Transduction; Substantia nigra structure; System; Techniques; Testing; Therapeutic; Time; Trauma; Ventral Tegmental Area; Viral; anxiety treatment; conditioned fear; conventional therapy; designer receptors exclusively activated by designer drugs; dopaminergic neuron; emotion regulation; learning extinction; male; neural circuit; neurochemistry; novel; novel strategies; pars compacta; prevent; relating to nervous system; response; success; targeted treatment; treatment strategy

Project Summary Anxiety and trauma-related disorders such as post-traumatic stress disorder are common and debilitating mental health disorders, but conventional treatment options are limited in long-term efficacy. Common therapeutic strategies aim to enhance fear extinction, the process by which the fear response to a fear-eliciting cue decays over time. However, fear extinction memories are labile and susceptible to the return of fear (relapse), even following successful extinction. Unfortunately, many of the manipulations that have been reported to enhance fear extinction memory either have not been tested for their ability to reduce fear relapse, or have failed to reliably do so. Identification of novel strategies to prevent fear relapse after extinction is thus of utmost importance to mental health. The nigrostriatal dopamine (NS DA) pathway, consisting of DA neurons in the substantia nigra pars compacta (SNc) projecting to the dorsal medial striatum (DMS), is classically considered in the context of motor behavior, but growing evidence supports a role for NS DA in emotional regulation. Further extending the purview of NS DA functions to include fear extinction learning, we observed that increasing high-frequency (phasic) activity of the NS DA pathway during fear extinction with viral-mediated chemogenetic techniques enhances extinction memory and prevents the return of fear after extinction. Phasic DA release preferentially signals through low-affinity D1 receptors, and our preliminary data suggest that D1 receptors in the DMS mediate the observed effects of NS DA pathway activation. We observed both that 1) neurons expressing D1 receptors in the DMS are recruited during fear extinction learning, and 2) pharmacological activation of DMS D1 receptors during fear extinction strengthens fear extinction memory. These data suggest that the NS DA pathway represents a previously unidentified component of fear extinction; activation of which could strengthen extinction. Harnessing NS DA during extinction could be especially important for females, who have a particularly high prevalence of anxiety, as well as a fear extinction retrieval deficit when fear extinction is learned during phases of the estrus cycle when estrogen is low. Consistent with the idea that phasic activity of NS DA enhances relapse- resistant fear extinction, we observed that voluntary exercise increases phasic DA release in the DMS, strengthens fear extinction, and reduces fear relapse in males. In females, exercise rescues the fear extinction retrieval deficit present when extinction is learned during estrus phases when estrogen is low. The goal of this proposal is to test the hypothesis, supported by our preliminary data, that NS DA represents a novel circuit for the enhancement of relapse-resistant fear extinction in males & females. Using chemogenetic, neurochemical and pharmacological strategies, we aim to determine whether activation of the NS DA pathway & D1 receptor signaling in the DS 1) enhances the learning of relapse-resistant fear extinction & 2) is necessary for the ability of acute exercise to augment fear extinction & prevent relapse.

项目摘要 焦虑和创伤相关疾病，如创伤后应激障碍，是常见的和令人衰弱的精神疾病。 健康障碍，但传统的治疗选择在长期疗效有限。常见治疗方法 策略的目的是加强恐惧消退，即恐惧对引发恐惧的线索的反应衰退的过程。 随着时间的推移。然而，恐惧消退的记忆是不稳定的，容易受到恐惧的回归(复发)的影响，甚至 在成功灭绝之后。不幸的是，据报道，许多操纵行为都会增强 恐惧消退记忆要么没有被测试其减少恐惧复发的能力，要么没有可靠地 就这么做吧。因此，确定防止恐惧在灭绝后复发的新策略对 心理健康。黑质纹状体多巴胺(NS DA)通路，由黑质中的DA神经元组成 致密部(SNC)投射到背侧内侧纹状体(DMS)，经典地被认为是在 运动行为，但越来越多的证据支持NS DA在情绪调节中的作用。进一步延长 在包括恐惧消退学习在内的NS DA功能范围内，我们观察到高频增加 病毒介导的化学发生技术在恐惧消退过程中NS-DA通路的(时相)活性 增强绝迹记忆，防止绝迹后恐惧重现。优先释放阶段性DA 信号通过低亲和力的D1R，我们的初步数据表明DMS中的D1R介导 观察NS-DA通路激活的作用。我们观察到：1)表达D1受体的神经元 DMS是在恐惧消退学习期间招募的，以及2)DMS D1受体的药理激活 恐惧消退强化恐惧消退记忆。这些数据表明，NS DA途径 代表了恐惧消退的一种以前未被识别的成分；激活它可能会强化消退。 对于雌性来说，在灭绝期间利用NS DA可能特别重要，因为她们的 焦虑的流行，以及当恐惧消退是分阶段学习时的恐惧消退恢复缺陷 雌激素水平较低时的发情周期。与NS DA阶段性活动增强复发的观点一致- 抵抗恐惧消退，我们观察到，自愿锻炼增加了DMS中DA的时相释放， 强化恐惧消退，减少男性恐惧复发。在女性中，锻炼拯救了恐惧的消退 在雌激素水平较低的发情期学习消退时，会出现检索缺陷。这样做的目的是 我们的初步数据支持这一假设，即NS DA代表了一种新的 男性和女性抗复发恐惧消退能力的增强。使用化学遗传学、神经化学 和药理学策略，我们的目的是确定NS DA途径和D1受体的激活 DS中的信号增强了抵抗复发的学习恐惧消退-2)是能力所必需的 剧烈运动以增强恐惧消退和防止复发。