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。在危险和安全方面，世界是多种多样的。虽然害怕是适应的，但当 面对一定的危险，同等程度的安全恐惧甚至不确定性是不适应的，对 健康。焦虑症患者对恐惧的精确控制被打乱，例如创伤后应激障碍患者 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。为了做到这一点，我们设计了一种新颖且具有挑战性的恐惧歧视程序。在恐惧中 辨别，有三种听觉提示与脚部电击的不同概率有关：危险(p=1.00)，不确定性 (P=0.25)和安全性(P=0.00)。线索呈现要么是随机的，要么是被阻止的。老鼠通常表现出对恐惧的精确控制，因为 表示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恐惧。在……里面 具体目标1，我们检验了这样的假设，即时相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中植入可驱动微电极束， 而RRF活动将在恐惧歧视期间被记录下来。对阶段活动的分析将集中在线索上 演示期。我们预测，大量的RRF神经元将阶段性地增加放电 安全评估：安全提示活动大幅增加，不确定性中等增加 以及对危险提示的低/不增加。对补药活性的分析将集中在试验之间的时间段。我们 预测大量的RRF神经元将根据当前的阻断改变紧张性放电水平： 在危险区块中观察到最高的强直RRF活性，在不确定区块中观察到中等的强直活性，以及 安全块中的补药活性最低。在特定目标2中，我们将使用光发生抑制和激发来提供 时相RRF活动的因果作用是以安全性估计为基础的，而紧张性RRF活动是以 危险。抑制将通过将含有卤视紫质的病毒载体导入RRF神经元来实现， 在上面植入光学套圈，并用绿光照射RFF。激励将使用相同的通用 战略，但将使用通道视紫红质与蓝光照明相结合。抑制RRF或 提示期的激发将与提示期以外的时期进行比较。我们预测阶段性抑制或 对RRF活动的紧张刺激将增加对所有线索的恐惧。相反，RRF的时相兴奋或紧张性抑制 活动将减少对所有线索的恐惧。累积起来，目标1和目标2将证明RRF活动在多个时间 刻度对于适当地表现恐惧是必不可少的。这项提议的结果将发现RRF是一个关键的大脑 允许精确控制恐惧的区域，以及功能障碍的场所和引人注目的药物疗法 精神障碍的目标，在这种精神障碍中，恐惧已经失去控制。