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.

项目摘要 意义学习某些刺激或情况与危险或奖励有关的能力 结果通常是有利的。然而，这种学习也会导致自我强化的循环， 有害行为。因此，实现对调控网络机制的控制将是有用的。 习得和表达习得的情感行为。这就是我们在这里追求的目标。 背景基底外侧杏仁核（BLA）主要神经元的获取和表达是必不可少的， 条件性情绪行为然而，它们中很少有被情感刺激激活的。 这个悖论的解决方案在于伽马的同步影响。实际上，伽马射线 增加了同步放电，放大了BLA细胞对目标的影响。然而，它几乎没有改变BLA发射 rates.因此，我们将研究提升或抑制BLA伽马对情绪学习的影响。为此目的， 我们将联合收割机与可编程多通道信号处理器相结合，称为“现场编程"， 可编程门阵列（FPGA）。与计算机不同，FPGA允许几乎瞬时的信号分析和条件分析。 光刺激传递，在真实的时间内提供对快速神经元事件如伽马的前所未有的控制。 Approach.表达小清蛋白（PV）的中间神经元在γ的发生中起关键作用。因此，在本发明中， 通过注入病毒AAV 5-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，为了增强或抑制伽马， PV电池将被定时以分别与它们的优选或非优选伽马发射相位一致。 建议的工作：在目标#1中，我们将确定BLA中最强烈表达的伽马子带 以及与哪些事件（条件刺激或反应）有关。我们将记录单位和LFP活动， 学习不同条件刺激预测奖励传递（CS-R）或即将发生的足电击（CS-S）。我们 导频数据指示伽马功率的最大变化发生在中间伽马频带中， γ与不同的条件反应（CR）不同地相关。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中伽马是否有助于或损害 食欲和防御性CR的表达。最后，在目标3中，我们将测试是增强还是抑制BLA 训练后的γ促进或损害食欲和防御性CR的巩固。我确 先前发现，在情绪激动的学习经历后的30分钟内， BLA增加，这种增加的幅度与记忆中的个体差异有关 记得了在目标2-3中，对照组将包括随机组，其中将使用相同的光刺激序列。 不考虑正在进行的γ、无视蛋白组而递送，其中病毒将仅驱动报告基因表达， 和其他频率组来测试我们操作的频率特异性。