Salk Institute for Biological Studies, La Jolla, CA, USA.
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nature. 2022 Aug;608(7923):586-592. doi: 10.1038/s41586-022-04964-y. Epub 2022 Jul 20.
The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different projections from the basolateral amygdala (BLA) are potentiated following reward or punishment learning. However, we do not yet understand how valence-specific information is routed to the BLA neurons with the appropriate downstream projections, nor do we understand how to reconcile the sub-second timescales of synaptic plasticity with the longer timescales separating the predictive cues from their outcomes. Here we demonstrate that neurotensin (NT)-expressing neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting NT concentration-dependent modulation in BLA during associative learning. We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, whereas PVT-BLA projection-specific knockout of the NT gene (Nts) augments punishment learning. Using genetically encoded calcium and NT sensors, we further revealed that both calcium dynamics within the PVT-BLA:NT projection and NT concentrations in the BLA are enhanced after reward learning and reduced after punishment learning. Finally, we showed that CRISPR-mediated knockout of the Nts gene in the PVT-BLA pathway blunts BLA neural dynamics and attenuates the preference for active behavioural strategies to reward and punishment predictive cues. In sum, we have identified NT as a neuropeptide that signals valence in the BLA, and showed that NT is a critical neuromodulator that orchestrates positive and negative valence assignment in amygdala neurons by extending valence-specific plasticity to behaviourally relevant timescales.
将时间上分隔的信息关联起来，并为环境线索赋予积极或消极的效价，这对于生存至关重要。研究表明，在进行奖励或惩罚学习后，来自基底外侧杏仁核（BLA）的不同投射会被增强。然而，我们尚不清楚如何将具有适当下游投射的特定效价信息路由到 BLA 神经元，也不清楚如何调和突触可塑性的亚秒级时间尺度与预测线索与其结果之间的更长时间尺度。在这里，我们证明丘脑室旁核（PVT）中表达神经降压素（NT）的神经元（PVT-BLA:NT）通过在关联学习期间对 BLA 施加 NT 浓度依赖性调制来介导效价分配。我们发现，PVT-BLA:NT 投射的光遗传学激活促进了奖励学习，而 PVT-BLA 投射特异性敲除 NT 基因（Nts）则增强了惩罚学习。使用遗传编码的钙和 NT 传感器，我们进一步揭示了 PVT-BLA:NT 投射内的钙动力学和 BLA 中的 NT 浓度在奖励学习后增强，在惩罚学习后降低。最后，我们表明，PVT-BLA 通路中 CRISPR 介导的 Nts 基因敲除会削弱 BLA 神经动力学，并减弱对积极行为策略的偏好，以奖励和惩罚预测线索。总之，我们已经确定 NT 作为一种神经肽，在 BLA 中发出效价信号，并表明 NT 是一种关键的神经调质，通过将特定效价的可塑性扩展到与行为相关的时间尺度，协调杏仁核神经元的积极和消极效价分配。
