State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, People's Republic of China.
State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, People's Republic of China
J Neurosci. 2023 May 17;43(20):3630-3646. doi: 10.1523/JNEUROSCI.1028-22.2023. Epub 2023 Apr 17.
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. 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.
压力对记忆的形成和表达的影响已经得到了充分的研究，尤其是对应激激素的贡献。但是，压力如何动态地影响大脑回路来调节记忆，这方面的了解还远远不够。在这里，我们使用雄性 C57BL6/J 小鼠的听觉恐惧条件反射作为模型系统来研究这个问题，并重点研究了压力对在概率性恐惧记忆中起重要作用的背内侧前额叶皮层 (dmPFC) 神经元的影响。我们发现，室旁丘脑 (PVT) 神经元在急性束缚应激下被强烈激活。在概率性恐惧记忆表达过程中，PVT 活动的升高增加了 dmPFC 生长抑素神经元的放电，进而抑制了 dmPFC 钙调蛋白结合蛋白（PV）神经元的放电，并使与概率性恐惧记忆相关的通常较低的恐惧反应恢复为较高的恐惧。这种动态和可逆的调节允许在记忆表达过程中保存和调节原始记忆。相比之下，在恐惧条件反射过程中，PVT 活动的升高会损害 dmPFC PV 神经元中的突触修饰，并消除概率性恐惧记忆的形成。因此，PVT 作为应激传感器，通过调节前额叶回路中的抑制功能，调节厌恶记忆的形成和表达。应激对认知功能的影响，如记忆和执行功能，已有充分的记录，尤其是应激激素的影响。然而，大脑回路的贡献还远未被理解。在这里，我们表明，基于回路的机制可以动态调节记忆的形成和表达，即，更高的应激诱导的室旁丘脑（PVT）活动通过提高生长抑素神经元的活性来抑制背内侧前额叶钙调蛋白结合蛋白（PV）神经元的放电，从而损害概率性恐惧记忆的形成和表达。这种通过前额叶抑制的动态调谐对记忆的应激影响保留了形成的记忆，但使记忆的动态表达成为可能。这些发现对更好的应激应对策略以及治疗选择具有重要意义，包括更好的药物靶点/机制。
