Retrorubral field control of fear

恐惧的红后场控制

• 批准号: 9297784
• 负责人: MICHAEL A MCDANNALD
• 金额: $ 23.48万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-05 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297784
• 关键词: Adult; Affect; Amygdaloid structure; Anxiety Disorders; Auditory; Behavioral Sciences; Brain; Brain region; Cues; Data; Discrimination; Dopamine; Female; Fright; Functional disorder; Funding; Glutamates; Goals; Halorhodopsins; Health; Human; Immunohistochemistry; Implant; Laboratories; Light; Lighting; Measures; Mental Health; Mental disorders; Microelectrodes; National Institute of Mental Health; Negative Valence; Neurons; Optics; Phase; Population; Post-Traumatic Stress Disorders; Probability; Procedures; Prosencephalon; PubMed; Rattus; Research; Role; Safety; Shock; Source; Synapsins; Testing; Time; Tyrosine 3-Monooxygenase; Uncertainty; Viral; design; experimental study; foot; innovation; male; novel; optogenetics; promoter; relating to nervous system; virtual

Project Summary. The world is heterogeneous with respect to danger and safety. While it is adaptive to be afraid when confronted with certain danger, an equivalent level of fear in safety or even uncertainty is maladaptive and detrimental to health. Precise control of fear is disrupted in anxiety disorders, such as post-traumatic stress disorder, with those affected displaying exaggerated fear to safety cues. The goal of this project is to uncover how RRF neural activity permits precise control of fear. To do this, we have designed a novel and challenging fear discrimination procedure. In fear discrimination, three auditory cues are associated with different probabilities of foot shock: danger (p=1.00), uncertainty (p=0.25), and safety (p=0.00). Cue presentation is either random or blocked. Rats normally show precise control of fear as indicated by high fear to the danger cue, intermediate fear to the uncertainty cue, and low fear to the safety cue. In Specific Aim 1, we test the hypothesis that phasic RRF activity reflects an estimate of safety while tonic RRF activity reflects an estimate of danger. We will implant drivable microelectrode bundles in the RRF of adult male and female rats, and RRF activity will be recorded during fear discrimination. Analysis of phasic activity will focus on the cue presentation period. We predict that a significant population of RRF neurons will phasically increase firing in accordance with an estimate of safety: large phasic increases in activity to the safety cue, intermediate increases to the uncertainty cue, and low/no increases to the danger cue. Analysis of tonic activity will focus on the time period between trials. We predict that a significant population of RRF neurons will alter tonic firing levels in accordance with the current block: highest tonic RRF activity will be observed in the danger block, intermediate tonic activity in the uncertainty block, and lowest tonic activity in the safety block. In Specific Aim 2, we will use optogenetic inhibition and excitation to provide causal roles for phasic RRF activity underlying an estimate of safety and tonic RRF activity underlying an estimate of danger. Inhibition will be achieved by transfecting RRF neurons with viral constructs containing halorhodopsin, implanting optical ferrules above, and illuminating the RFF with green light. Excitation will employ the same general strategy, but will use channelrhodopsin in combination with blue-light illumination. Effects of RRF inhibition or excitation in the cue period will be compared to periods outside of cue presentation. We predict that phasic inhibition or tonic excitation of RRF activity will increase fear to all cues. By contrast, phasic excitation or tonic inhibition of RRF activity will decrease fear to all cues. Cumulatively, Aims 1 and 2 will demonstrate that RRF activity on multiple time scales is essential to the appropriate display of fear. The results of this proposal will uncover the RRF as a key brain region permitting the precise control of fear, as well as a locus of dysfunction and a compelling pharmacotherapeutic target for psychiatric disorders in which control of fear has been lost.

项目摘要。世界在危险和安全方面是多种多样的。虽然害怕是适应性的 面对某种危险，对安全甚至不确定性的同等程度的恐惧是不适应的，并且有害 健康。焦虑症（例如创伤后应激障碍）患者对恐惧的精确控制会受到干扰 对安全提示表现出过度的恐惧。该项目的目标是揭示 RRF 神经活动如何实现精确的 控制恐惧。为此，我们设计了一种新颖且具有挑战性的恐惧歧视程序。处于恐惧之中 歧视，三种听觉线索与不同的足部震动概率相关：危险 (p=1.00)、不确定性 （p=0.25）和安全性（p=0.00）。提示呈现是随机的或块状的。老鼠通常表现出对恐惧的精确控制 对危险提示的高度恐惧，对不确定性提示的中度恐惧，以及对安全提示的低度恐惧。在 具体目标 1，我们测试以下假设：阶段性 RRF 活动反映了安全性估计，而强直性 RRF 活动 反映了对危险的估计。我们将在成年雄性和雌性大鼠的 RRF 中植入可驱动的微电极束， 恐惧歧视期间将记录 RRF 活动。阶段性活动的分析将集中于提示 演示期。我们预测大量的 RRF 神经元将根据 安全性估计：安全线索活动的大幅阶段性增加，不确定性的中间增加 提示，并且危险提示低/无增加。强直活动的分析将集中于试验之间的时间段。我们 预测大量 RRF 神经元将根据当前块改变强直放电水平： 最高的强直 RRF 活动将在危险块中观察到，中间强直活动将在不确定块中观察到，并且 安全区中最低的补品活动。在具体目标 2 中，我们将使用光遗传学抑制和激发来提供 阶段性 RRF 活动的因果作用是安全性估计的基础，强直性 RRF 活动是估计的基础 危险。通过用含有盐视紫红质的病毒构建体转染 RRF 神经元来实现抑制， 在上方植入光插芯，并用绿光照射RFF。激励将采用相同的一般 策略，但将使用视紫红质通道与蓝光照明相结合。 RRF 抑制的影响或 提示期间的兴奋将与提示呈现之外的时期进行比较。我们预测相抑制或 RRF 活动的强直性兴奋会增加对所有线索的恐惧。相比之下，RRF 的相性兴奋或强直性抑制 活动会减少对所有暗示的恐惧。总的来说，目标 1 和 2 将证明 RRF 活动在多个时间 尺度对于适当地表达恐惧至关重要。该提案的结果将揭示 RRF 作为关键大脑的作用 允许精确控制恐惧的区域，以及功能障碍和令人信服的药物治疗的场所 目标是失去对恐惧的控制的精神疾病。