The formation of memory for a novel experience is a critical cognitive capacity. The ability to form novel memories is sensitive to age-related pathologies and disease, to which prolonged metabolic stress is a major contributing factor. Presently, we describe a dopamine-dependent redox modulation pathway within the hippocampus of male mice that promotes memory consolidation. Namely, following novel information acquisition, quinone reductase 2 (QR2) is suppressed by miRNA-182 (miR-182) in the CA1 region of the hippocampus via dopamine D1 receptor (D1R) activation, a process largely facilitated by locus coeruleus activity. This pathway activation reduces ROS generated by QR2 enzymatic activity, a process that alters the intrinsic properties of CA1 interneurons 3 h following learning, in a form of oxidative eustress. Interestingly, novel experience decreases QR2 expression predominately in inhibitory interneurons. Additionally, we find that in aged animals this newly described QR2 pathway is chronically under activated, resulting in miR-182 underexpression and QR2 overexpression. This leads to accumulative oxidative stress, which can be seen in CA1 via increased levels of oxidized, inactivated potassium channel Kv2.1, which undergoes disulfide bridge oligomerization. This newly described interneuron-specific molecular pathway lies alongside the known mRNA translation-dependent processes necessary for long-term memory formation, entrained by dopamine in CA1. It is a process crucial for the distinguishing features of novel memory, and points to a promising new target for memory enhancement in aging and age-dependent diseases.

SIGNIFICANCE STATEMENT One way in which evolution dictates which sensory information will stabilize as an internal representation, relies on information novelty. Dopamine is a central neuromodulator involved in this process in the mammalian hippocampus. Here, we describe for the first time a dopamine D1 receptor-dependent quinone reductase 2 pathway in interneurons. This is a targeted redox event necessary to delineate a novel experience to a robust long-term internal representation. Activation of this pathway alone can explain the effect novelty has on "flashbulb" memories, and it can become dysfunctional with age and diseases, such as Alzheimer's disease.

对新体验的记忆形成是至关重要的认知能力。形成新的记忆的能力对与年龄有关的病理和疾病敏感，长期的代谢压力是与之相关的主要因素。目前，我们描述了雄性小鼠海马内多巴胺依赖性氧化还原调节途径，可促进记忆巩固。即，在获得新的信息后，通过多巴胺D1受体（D1R）激活，海马CA1区的miRNA-182（miR-182）抑制了醌还原酶2（QR2），该过程在很大程度上由位点蓝藻活性促进。该途径的激活减少了QR2酶促活性产生的ROS，QR2酶促活性是学习后3小时以氧化性应激的形式改变CA1神经元内在特性的过程。有趣的是 新颖的经验主要在抑制性中间神经元中降低QR2表达。此外，我们发现在成年动物中，这种新描述的QR2通路长期处于激活状态，导致miR-182表达不足和QR2过表达。这会导致累积的氧化应激，这可以在CA1中通过增加水平的氧化，灭活的钾离子通道Kv2.1进行观察，该通道经历了二硫键桥的低聚反应。这种新描述的神经元间特异的分子途径与长期记忆形成所必需的已知mRNA依赖翻译过程有关，该过程由CA1中的多巴胺携带。这是区分新型记忆特征的关键过程，并指出了在衰老和年龄依赖性疾病中增强记忆的新目标。

意义声明进化决定哪种感官信息将作为内部表征稳定的一种方式依赖于信息的新颖性。多巴胺是哺乳动物海马中参与该过程的中枢神经调节剂。在这里，我们第一次描述了interneurons中的多巴胺D1受体依赖性醌还原酶2途径。这是一个有针对性的氧化还原事件，对于将新颖的体验描述为强大的长期内部代表来说是必需的。单独激活该途径可以解释新颖性对“闪光灯”记忆的影响，并且随着年龄和疾病（例如阿尔茨海默氏病）的出现，功能可能会失调。