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。就危险和安全而言，世界是多样化的。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，是有害的。 健康在焦虑症中，如创伤后应激障碍，对恐惧的精确控制被破坏， 对安全提示表现出夸张的恐惧这个项目的目标是揭示RRF神经活动如何允许精确的 控制恐惧。为此，我们设计了一个新颖而具有挑战性的恐惧辨别程序。在恐惧中 三个听觉线索与不同的足部电击概率相关：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阻塞的。老鼠通常表现出对恐惧的精确控制， 表现为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，我们检验了以下假设：阶段性RRF活动反映了安全性的估计，而紧张性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， 在恐惧辨别期间记录RRF活动。阶段性活动的分析将集中在线索上 演示期间。我们预测，RRF神经元的显著群体将根据RRF神经元的活动而阶段性地增加放电。 安全性估计：安全提示活动的大阶段性增加，不确定性的中间增加 提示，以及危险提示的低/无增加。紧张性活动的分析将集中在试验之间的时间段。我们 预测RRF神经元的显著群体将根据当前块改变紧张性放电水平： 在危险区块中将观察到最高紧张性RRF活动，在不确定区块中观察到中等紧张性活动，并且 最低的紧张性活动在安全区。在具体目标2中，我们将使用光遗传学抑制和激发来提供 作为安全性估计基础的阶段性RRF活动和作为安全性估计基础的强直性RRF活动的因果作用 危险抑制将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， 在上面植入光学套管，并用绿色光照射RFF。激励将采用相同的一般 策略，但将使用通道视紫红质结合蓝光照明。RRF抑制或 提示时段中的激励将与提示呈现之外的时段进行比较。我们预测相位抑制或 RRF活动的紧张性兴奋将增加对所有线索的恐惧。相反，RRF的相位性兴奋或紧张性抑制 活动将减少对所有线索的恐惧。累积而言，目标1和2将证明RRF在多个时间点的活性 尺度对于适当地表现恐惧是必不可少的。这项提案的结果将揭示RRF作为一个关键的大脑 一个允许精确控制恐惧的区域，也是一个功能障碍和令人信服的药理学的所在地 恐惧失控的精神疾病的治疗目标。