Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Front Neural Circuits. 2023 Apr 27;17:1167825. doi: 10.3389/fncir.2023.1167825. eCollection 2023.
Threatening environmental cues often generate enduring fear memories, but how these are formed and stored remains actively investigated. Recall of a recent fear memory is thought to reflect reactivation of neurons, in multiple brain regions, activated during memory formation, indicating that anatomically distributed and interconnected neuronal ensembles comprise fear memory engrams. The extent to which anatomically specific activation-reactivation engrams persist during long-term fear memory recall, however, remains largely unexplored. We hypothesized that principal neurons in the anterior basolateral amygdala (aBLA), which encode negative valence, acutely reactivate during remote fear memory recall to drive fear behavior.
Using adult offspring of TRAP2 and Ai14 mice, persistent tdTomato expression was used to "TRAP" aBLA neurons that underwent Fos-activation during contextual fear conditioning (electric shocks) or context only conditioning (no shocks) ( = 5/group). Three weeks later, mice were re-exposed to the same context cues for remote memory recall, then sacrificed for Fos immunohistochemistry.
TRAPed (tdTomato +), Fos +, and reactivated (double-labeled) neuronal ensembles were larger in fear- than context-conditioned mice, with the middle sub-region and middle/caudal dorsomedial quadrants of aBLA displaying the greatest densities of all three ensemble populations. Whereas tdTomato + ensembles were dominantly glutamatergic in context and fear groups, freezing behavior during remote memory recall was not correlated with ensemble sizes in either group.
We conclude that although an aBLA-inclusive fear memory engram forms and persists at a remote time point, plasticity impacting electrophysiological responses of engram neurons, not their population size, encodes fear memory and drives behavioral manifestations of long-term fear memory recall.
威胁性环境线索通常会产生持久的恐惧记忆，但这些记忆是如何形成和存储的仍在积极研究中。最近的恐惧记忆的回忆被认为反映了在记忆形成过程中激活的多个大脑区域的神经元的再激活，这表明解剖上分布和相互连接的神经元集合构成了恐惧记忆的印痕。然而，在长期恐惧记忆回忆期间，解剖上特定的激活-再激活印痕的持续程度在很大程度上仍未得到探索。我们假设，编码负价的前外侧杏仁核（aBLA）中的主要神经元在远程恐惧记忆回忆期间会急性再激活，以驱动恐惧行为。
使用 TRAP2 和 Ai14 小鼠的成年后代，持续的 tdTomato 表达被用来“TRAP”在前外侧杏仁核（aBLA）中经历了上下文恐惧条件反射（电击）或仅上下文条件反射（无电击）期间 Fos 激活的神经元（= 5/组）。三周后，将小鼠重新暴露于相同的上下文线索以进行远程记忆回忆，然后进行 Fos 免疫组织化学分析。
在恐惧条件反射的小鼠中，TRAP 化（tdTomato +）、Fos +和再激活（双标记）神经元集合比在上下文条件反射的小鼠中更大，aBLA 的中间亚区和中间/尾侧背内侧象限显示出所有三种集合群体的最大密度。虽然在上下文和恐惧组中，tdTomato +集合主要是谷氨酸能的，但在远程记忆回忆期间的冻结行为与两个组中的集合大小均无相关性。
我们的结论是，尽管包括杏仁核前外侧在内的恐惧记忆印痕在远程时间点形成并持续存在，但影响印痕神经元电生理反应的可塑性，而不是其群体大小，编码了恐惧记忆并驱动了长期恐惧记忆回忆的行为表现。
