The impact of stress on the formation and expression of memory is well studied, especially on the contributions of stress hormones. But how stress affects brain circuitry dynamically to modulate memory is far less understood. Here, we used male C57BL6/J mice in an auditory fear conditioning as a model system to examine this question and focused on the impact of stress on dorsomedial prefrontal cortex (dmPFC) neurons which play an important role in probabilistic fear memory. We found that paraventricular thalamus (PVT) neurons are robustly activated by acute restraining stress. Elevated PVT activity during probabilistic fear memory expression increases spiking in the dmPFC somatostatin neurons which in turn suppresses spiking of dmPFC parvalbumin (PV) neurons, and reverts the usual low fear responses associated with probabilistic fear memory to high fear. This dynamic and reversible modulation allows the original memory to be preserved and modulated during memory expression. In contrast, elevated PVT activity during fear conditioning impairs synaptic modifications in the dmPFC PV-neurons and abolishes the formation of probabilistic fear memory. Thus, PVT functions as a stress sensor to modulate the formation and expression of aversive memory by tuning inhibitory functions in the prefrontal circuitry.

SIGNIFICANCE STATEMENT The impact of stress on cognitive functions, such as memory and executive functions, are well documented especially on the impact by stress hormone. However, the contributions of brain circuitry are far less understood. Here, we show that a circuitry-based mechanism can dynamically modulate memory formation and expression, namely, higher stress-induced activity in paraventricular thalamus (PVT) impairs the formation and expression of probabilistic fear memory by elevating the activity of somatostatin-neurons to suppress spiking in dorsomedial prefrontal parvalbumin (PV) neurons. This stress impact on memory via dynamic tuning of prefrontal inhibition preserves the formed memory but enables a dynamic expression of memory. These findings have implications for better stress coping strategies as well as treatment options including better drug targets/mechanisms.

压力对记忆形成和表达的影响已得到充分研究，特别是压力激素的贡献。但压力如何动态影响大脑回路来调节记忆，人们却知之甚少。在这里，我们使用雄性 C57BL6/J 小鼠进行听觉恐惧调节作为模型系统来研究这个问题，并重点研究压力对背内侧前额叶皮层 (dmPFC) 神经元的影响，这些神经元在概率恐惧记忆中发挥重要作用。我们发现室旁丘脑（PVT）神经元被急性抑制应激强烈激活。概率性恐惧记忆表达期间PVT活性升高会增加dmPFC生长抑素神经元的尖峰，进而抑制dmPFC小白蛋白（PV）神经元的尖峰，并将与概率恐惧记忆相关的通常低恐惧反应恢复为高恐惧。这种动态且可逆的调制允许在记忆表达过程中保留和调制原始记忆。相反，恐惧调节过程中PVT活性升高会损害dmPFC PV神经元的突触修饰，并消除概率恐惧记忆的形成。因此，PVT 充当压力传感器，通过调节前额叶电路中的抑制功能来调节厌恶记忆的形成和表达。

意义陈述压力对认知功能（例如记忆和执行功能）的影响已有充分记录，尤其是压力激素的影响。然而，人们对大脑回路的贡献知之甚少。在这里，我们证明基于电路的机制可以动态调节记忆的形成和表达，即室旁丘脑（PVT）中较高的应激诱导活动通过提高生长抑素神经元的活性来抑制概率恐惧记忆的形成和表达背内侧前额叶小白蛋白（PV）神经元中的尖峰。这种压力通过前额叶抑制的动态调节对记忆产生影响，保留了已形成的记忆，但实现了记忆的动态表达。这些发现对更好的压力应对策略以及治疗选择（包括更好的药物靶点/机制）具有影响。