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 动画障碍的基本特征夸大了提示信号威胁的恐惧。盛行的视图 恐惧学习的神经回路是杏仁核和相关前脑区域的劳动分工 信号威胁概率，脑干地区组织恐惧输出。这种观点是智力基础 提议前脑威胁功能障碍引起了焦虑症的恐惧。不仅仅是 组织恐惧输出，我的实验室正在显示脑干网络计算预测错误 - 学习 信号推动恐惧学习。此外，脑干网络信号威胁 - 据称特定于 前脑。该建议将揭示信号威胁概率，计算预测的脑干网络 错误并组织恐惧输出。 AIM 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脑干接收神经质子植入物 轴。在恐惧歧视期间，将从20多个脑干地区记录成千上万的单元 产生选择性学习的过程。提示期间的解雇分析将揭示 脑干网络威胁信号的出现和潜水员行为对恐惧学习的影响。目标2 将建立脑干预测错误动态的框架。在结果期间进行分析 将把脑干网络射击动态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发射动力和恐惧学习。老鼠会接受脑干 Neuropixels植入物。脑干区域中的AAV2- retro和前脑区域中的CRE-CASP3将用于 删除对脑干的特定输入（例如，投射到周长灰色的前皮层神经元）。 比较CASP3和控制大鼠的射击分析将揭示脑干射击动态的依赖性 （威胁，行为和预测错误）在前脑输入上。 AIM 4会在化学上操纵脑干 发射以减少预测错误计算和恐惧学习。大鼠将接受脑干神经固定 注入。然后，一半将在周围灰色的区域中收到兴奋的恐惧症状的输注 - 通过抑制来组织的补品预测误差的来源。执行器注射（JH60），但没有盐水 注射会激发脑干的激发 - 阻止补品预测错误网络。解雇分析将揭示 网络中断对威胁，行为和预测错误的脑干发射动态的影响。这 建议将通过发现脑干网络的核心威胁功能来扩展科学知识。这 提案将进一步揭示前脑输入如何形成脑干发射动态，以发出威胁，计算 预测错误并组织特定的恐惧行为。这种知识对于发展有效至关重要 旨在减少恐惧的焦虑症治疗。