Closed-loop optogenetic control of gamma oscillations and emotional learning

伽玛振荡和情绪学习的闭环光遗传学控制

• 批准号: 10401814
• 负责人: DENIS PARE
• 金额: $ 38.75万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401814
• 关键词: Affective; Amygdaloid structure; Anxiety; Anxiety Disorders; Behavior; Behavioral; Cells; Cognitive; Computers; Conditioned Reflex; Control Groups; Dangerousness; Data; Desire for food; Drops; Electrophysiology (science); Emotional; Event; Frequencies; Funding Opportunities; Health; Impairment; Implant; Individual; Interneurons; Lead; Learning; Light; Memory; Neurons; Neurosciences; Opsin; Outcome; Parvalbumins; Pattern; Performance; Pharmaceutical Preparations; Phase; Play; Property; Rattus; Regimen; Reporter; Request for Applications; Rewards; Risk; Role; Signal Transduction; Specificity; Stimulus; Testing; Time; Training; Virus; Work; addiction; avoidance behavior; base; behavioral response; conditioning; emotional behavior; experience; improved; individual variation; memory consolidation; memory recall; novel; optogenetics; programs; response; showing emotion; social; social relationships; substance use

Project Summary Significance. The ability to learn that some stimuli or situations are associated with dangerous or rewarding outcomes is generally advantageous. However, such learning can also lead to a self-reinforcing cycle of harmful behaviors. Thus, it would be useful to achieve control over the network mechanisms that regulate the acquisition and expression of learned emotional behaviors. This is the objective we pursue here. Background. Principal basolateral amygdala (BLA) neurons are essential for the acquisition and expression of conditioned emotional behaviors. Yet, remarkably few of them are activated by emotionally-valenced stimuli. The solution to this paradox resides in the synchronizing influence of gamma. Indeed, gamma drastically increases firing synchrony, amplifying the impact of BLA cells on their targets. Yet, it barely alters BLA firing rates. Thus, we will study the impact of boosting or dampening BLA gamma on emotional learning. To this end, we will combine optogenetics with programmable multi-channel signal processors, known as “field programma- ble gate arrays” (FPGAs). Unlike computers, FPGAs allow nearly instantaneous signal analysis and conditional light stimulus delivery, providing unprecedented control over fast neuronal events like gamma, in real time. Approach. Parvalbumin (PV)-expressing interneurons play a critical role in the genesis of gamma. Thus, expression of the excitatory opsin Chronos will be restricted to PV cells, by infusing the virus AAV5-hSyn- FLEX-Chronos-GFP in the BLA of PV-cre rat. Then, to boost or dampen gamma, the optogenetic excitation of PV cells will be timed to coincide with their preferred or non-preferred gamma firing phase, respectively. Proposed work: In Aim #1, we will determine what gamma sub-band is most strongly expressed in the BLA and in relation to what events (conditioned stimuli or responses). We will record unit and LFP activity while rats learn that different conditioned stimuli predict reward delivery (CS-R) or an impending footshock (CS-S). Our pilot data indicates that the largest changes in gamma power occur in the mid-gamma band and that mid- gamma is differentially related to distinct conditioned responses (CRs). Based on these results, in Aim #2, we will test whether enhancing or dampening BLA mid-gamma during the CS-R or CS-S facilitates or impairs the expression of appetitive and defensive CRs. Last, in Aim 3, we will test whether enhancing or dampening BLA gamma after training facilitates or impairs the consolidation of appetitive and defensive CRs. Indeed, we previously found that in the 30 min following an emotionally arousing learning experience, mid-gamma power increases in the BLA and that the magnitude of this increase correlates with individual variations in memory recall. In Aims 2-3, control groups will include random groups where the same trains of light stimuli will be delivered irrespective of ongoing gamma, no-opsin groups where the virus will only drive reporter expression, and other frequency groups to test the frequency specificity of our manipulations.

项目概要 意义：了解某些刺激或情况与危险或有益相关的能力。 然而，这种学习也可以导致自我强化的循环。 因此，实现对调节网络机制的控制将是有用的。 习得的情感行为的获取和表达是我们追求的目标。 背景：主要基底外侧杏仁核（BLA）神经元对于获得和表达 然而，其中极少数是由情绪刺激所激活的。 这个悖论的解决方案在于伽玛的同步影响，事实上，伽玛的影响非常大。 增加发射同步性，放大 BLA 细胞对其目标的影响，但它几乎不会改变 BLA 发射。 因此，我们将研究增强或抑制 BLA 伽玛对情绪学习的影响。 我们将把光遗传学与可编程多通道信号处理器结合起来，称为“现场编程” 与计算机不同，FPGA 可以实现近乎瞬时的信号分析和条件分析。 光刺激传递，对伽玛等快速神经事件提供前所未有的实时控制。 表达小清蛋白 (PV) 的中间神经元在 γ 的发生中发挥着关键作用。 通过注入病毒 AAV5-hSyn-，兴奋性视蛋白 Chronos 的表达将仅限于 PV 细胞 PV-cre 大鼠 BLA 中的 FLEX-Chronos-GFP 然后，增强或抑制 γ 的光遗传学激发。 PV电池将被定时以分别与其优选或非优选的伽马发射阶段一致。 建议的工作：在目标 1 中，我们将确定 BLA 中表达最强烈的伽马子带 以及与什么事件（条件刺激或反应）相关，我们将记录大鼠的单位和 LFP 活动。 了解不同的条件刺激可预测奖励交付 (CS-R) 或即将发生的足部电击 (CS-S)。 导频数据表明，伽马功率的最大变化发生在中伽马带，并且中伽马带发生了变化。 伽玛与不同的条件反应（CR）有不同的相关性，基于这些结果，在目标#2中，我们。 将测试在 CS-R 或 CS-S 期间增强或抑制 BLA mid-gamma 是否会促进或削弱 最后，在目标 3 中，我们将测试是否增强或抑制 BLA。 训练后的伽玛促进或损害食欲和防御性 CR 的巩固。 先前发现，在情绪激动的学习经历后的 30 分钟内，中伽玛功率 BLA 增加，并且这种增加的幅度与记忆的个体差异相关 在目标 2-3 中，对照组将包括随机组，其中将有相同的光刺激序列。 无论正在进行的伽马、无视蛋白组，病毒只会驱动报告基因表达， 和其他频率组来测试我们操作的频率特异性。