Hassell James E, Arellano Perez Angel D, Vasudevan Krithika, Ressler Reed L, Garcia Gabriela M, Parr Madison, Vierkant Valerie M, Bayer Hugo, Maren Stephen
Department of Psychological and Brain Sciences and Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA.
Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
Mol Psychiatry. 2025 May 24. doi: 10.1038/s41380-025-03064-3.
Extinction learning is central to behavioral therapies for post-traumatic stress disorder (PTSD), but relapse poses a major challenge to this approach. Recent work has revealed a critical role for the thalamic nucleus reuniens (RE) in the suppression of extinguished fear memories. Silencing the RE yields a relapse of extinguished fear (i.e., "circuit-induced relapse"). Considerable work suggests that RE may contribute to extinction by inhibiting the retrieval of hippocampal (HPC)-dependent fear memories. To test this hypothesis, we first examined whether undermining the formation of contextual fear memories in the HPC would prevent circuit-induced relapse. Intra-hippocampal infusions of the NMDA receptor antagonist, APV, prior to auditory fear conditioning eliminated contextual fear memory and prevented the subsequent relapse of extinguished fear to the auditory conditioned stimulus (CS). In a second experiment, we used an activity-dependent labeling system (AAV-cFos-tTA; AAV-TRE-hM3Dq-mCherry) to express excitatory DREADDs in HPC neurons during fear conditioning. Chemogenetic reactivation of these ensembles after extinction was sufficient to drive relapse of fear to the extinguished CS. Lastly, in a third experiment, we expressed excitatory DREADDs in HPC ensembles captured during extinction learning and found that chemogenetic reactivation of this ensemble was sufficient to inhibit circuit-induced relapse. These results reveal that HPC-dependent ensembles play a critical role in regulating the expression and relapse of extinguished fear.
消退学习是创伤后应激障碍（PTSD）行为疗法的核心，但复发对这种方法构成了重大挑战。最近的研究表明，丘脑 reunens 核（RE）在抑制消退的恐惧记忆方面起着关键作用。沉默 RE 会导致消退的恐惧复发（即“回路诱导的复发”）。大量研究表明，RE 可能通过抑制海马体（HPC）依赖性恐惧记忆的提取来促进消退。为了验证这一假设，我们首先研究了破坏 HPC 中情境恐惧记忆的形成是否能预防回路诱导的复发。在听觉恐惧条件反射之前，向海马体内注射 NMDA 受体拮抗剂 APV，消除了情境恐惧记忆，并防止了随后对听觉条件刺激（CS）消退的恐惧复发。在第二个实验中，我们使用了一种活动依赖性标记系统（AAV-cFos-tTA；AAV-TRE-hM3Dq-mCherry）在恐惧条件反射期间在 HPC 神经元中表达兴奋性 DREADDs。消退后对这些神经元群进行化学遗传再激活足以驱使对消退的 CS 的恐惧复发。最后，在第三个实验中，我们在消退学习期间捕获的 HPC 神经元群中表达兴奋性 DREADDs，发现对该神经元群进行化学遗传再激活足以抑制回路诱导的复发。这些结果表明，HPC 依赖性神经元群在调节消退恐惧的表达和复发中起着关键作用。
