Brainstem-forebrain networks and threat computation

项目摘要 焦虑症的一个基本特征是对发出威胁信号的线索的夸大恐惧。普遍的观点认为 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 前脑威胁功能障碍会在焦虑症中引发夸大的恐惧。远远不止 整理恐惧输出，我的实验室正在展示脑干网络计算预测错误--一种学习 发出信号来驱使恐惧学习。此外，脑干网络发出威胁信号--据称这是一种特定于 前脑。这项提议将揭示脑干网络，这些网络发出威胁概率信号，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侧-腹侧脑干接受神经像素植入 轴心。在恐惧歧视期间，来自20多个脑干区域的数千个单一单位将被记录下来 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不同行为的跟踪超过了恐惧学习。目标2 将建立脑干预测误差动力学的框架。结束期内的射击分析 将脑干网络的触发动力学链接起来，用于预测恐惧学习出现之前的错误。目标 3将揭示影响脑干放电动力学和恐惧学习的前脑输入。大鼠将接受脑干移植 神经像素植入。脑干区域的aav2-retro和前脑区域的cre-casp3将用于 删除对脑干的特定输入(例如，投射到中脑导水管周围灰质的小脑皮质神经元)。 比较casp3和对照组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)影响前脑输入。目标4将通过化学遗传学操作脑干 射击是为了减少预测误差计算和害怕学习。大鼠将接受脑干神经像素 植入。其中一半将在中脑导水管周围灰质两侧区域接受兴奋性DREADD注射- 由激发抑制组织的音调预测误差的来源。致动器注射(JH60)，但不是生理盐水 注射后，会兴奋脑干放电--阻断紧张感预测误差网络。射击分析将揭示 网络中断对威胁、行为和预测误差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。这个 该提案将进一步揭示前脑输入如何塑造脑干放电动力学，从而发出威胁的信号，计算 预测错误并组织特定的恐惧行为。这方面的知识对于开发有效的 焦虑症的治疗旨在减少恐惧。

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.