Brainstem-forebrain networks and threat computation

脑干前脑网络和威胁计算

• 批准号: 10736117
• 负责人: MICHAEL A MCDANNALD
• 金额: $ 65.05万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736117
• 关键词: Amygdaloid structure; Anxiety Disorders; Area; Behavior; Behavioral; Brain; Brain Stem; Clinical; Cues; Data; Dependence; Discrimination; Disease; Dorsal; Equation; Female; Foundations; Freezing; Fright; Functional disorder; Implant; Infusion procedures; Injections; Interruption; Knowledge; Laboratories; Learning; Link; Locomotion; Mus; Neurons; Outcome; Output; Phase; Play; Probability; Procedures; Prosencephalon; Rattus; Role; Shapes; Shock; Signal Transduction; Source; Testing; Update; Virus; conditioned fear; density; designer receptors exclusively activated by designer drugs; effective therapy; fluorophore; genetic manipulation; innovation; learning network; male; midbrain central gray substance; neural; neural circuit; optogenetics; treatment of anxiety disorders

Project Summary A cardinal feature of anxiety disorders is exaggerated fear to cues signaling threat. The prevailing view of the neural circuit for fear learning is a division of labor in which the amygdala and associated forebrain regions signal threat probability, and brainstem regions organize fear output. This view is the intellectual foundation for proposals that forebrain threat dysfunction drives exaggerated fear in anxiety disorders. Much more than organizing fear output, my laboratory is showing brainstem networks compute prediction error – a learning signal to drive fear learning. Further, brainstem networks signal threat – a function purported to be specific to the forebrain. This proposal will reveal brainstem networks that signal threat probability, compute prediction error, and organize fear output. Aim 1 will detail the emergence of brainstem threat and behavior signaling dynamics. Female and male rats will receive Neuropixels implant through a complete dorsal-ventral brainstem axis. Thousands of single units will be recorded from 20+ brainstem regions during a fear discrimination procedure that produces selective learning to a threat cue. Firing analyses during the cue period will reveal the emergence of brainstem network threat signaling and tracking of diverse behaviors over fear learning. Aim 2 will establish a framework for brainstem prediction error dynamics. Firing analyses during the outcome period will link brainstem network firing dynamics for prediction error that precede the emergence of fear learning. Aim 3 will reveal forebrain inputs shaping brainstem firing dynamics and fear learning. Rats will receive brainstem Neuropixels implant. AAV2-retro in a brainstem region and cre-casp3 in a forebrain region will be used to delete specific inputs to the brainstem (e.g. prelimibic cortex neurons projecting to the periaqueductal gray). Firing analyses comparing casp3 and control rats will reveal the dependence of brainstem firing dynamics (threat, behavior, and prediction error) on forebrain inputs. Aim 4 will chemogenetically manipulate brainstem firing to diminish prediction error computation and fear learning. Rats will receive brainstem Neuropixels implant. Half will then receive excitatory DREADD infusions in regions flanking the periaqueductal gray – sources of a tonic prediction error organized by firing inhibition. Actuator injections (JH60), but not saline injection, will excite brainstem firing – blocking the tonic prediction error network. Firing analyses will reveal the effects of network interruption on brainstem firing dynamics for threat, behavior, and prediction error. This proposal will extend scientific knowledge by uncovering core threat functions of brainstem networks. The proposal will further reveal how forebrain inputs shape brainstem firing dynamics that signal threat, compute prediction error and organize specific fear behaviors. This knowledge is essential to developing effective anxiety disorder treatments aimed to reduce fear.

项目摘要 焦虑症的一个主要特征是对威胁信号的过度恐惧。普遍认为， 恐惧学习的神经回路是一种分工，其中杏仁核和相关的前脑区域 信号威胁概率和脑干区域组织恐惧输出。这一观点是知识基础， 前脑威胁功能障碍驱动焦虑症中的过度恐惧。远不止 组织恐惧输出，我的实验室正在展示脑干网络计算预测误差-一种学习 恐惧学习的信号。此外，脑干网络信号的威胁-一个功能，据称是特定的， 前脑这项提案将揭示脑干网络，信号威胁的可能性，计算预测， 错误，并组织恐惧输出。目标1将详细说明脑干威胁和行为信号的出现 动力学雌性和雄性大鼠将通过完整的背腹侧脑干接受Neuropixels植入 轴线在恐惧辨别期间，将从20多个脑干区域记录数千个单个单位 对威胁线索产生选择性学习的过程。在提示期间的射击分析将揭示 脑干网络威胁信号的出现和对恐惧学习的不同行为的跟踪。目的2 将建立一个脑干预测误差动力学的框架。结局期间的击发分析 将把脑干网络放电动力学与恐惧学习出现之前的预测错误联系起来。目的 3将揭示前脑输入塑造脑干放电动力学和恐惧学习。大鼠将接受脑干 神经像素植入物。将使用脑干区域中的AAV 2-retro和前脑区域中的cre-Casp 3来 删除脑干的特定输入（例如，投射到导水管周围灰质的前边缘皮层神经元）。 比较Casp 3和对照大鼠的放电分析将揭示脑干放电动力学的依赖性 （威胁，行为和预测错误）对前脑输入的影响。目标4将化学基因操纵脑干 射击以减少预测误差计算和恐惧学习。大鼠将接受脑干神经像素 植入然后，一半的人将在中脑导水管周围灰质两侧的区域接受兴奋性DREADD注射- 由放电抑制组织的主音预测误差的来源。致动器注射（JH 60），但不是生理盐水 注射，会激发脑干放电-阻断紧张性预测网络。射击分析将揭示 网络中断对威胁、行为和预测误差的脑干放电动力学的影响。这 该提案将通过揭示脑干网络的核心威胁功能来扩展科学知识。的 这项提案将进一步揭示前脑输入如何塑造脑干放电动力学，即发出威胁信号， 预测错误和组织特定的恐惧行为。这些知识对于开发有效的 焦虑症治疗旨在减少恐惧。