Biases in sharp wave-ripple content as a transdiagnostic cognitive process

项目总结 不同情绪障碍之间的共病，以及那些有其他症状的人，如 精神分裂症、创伤后应激障碍和强迫症提示有可能存在共同的潜在机制 可以为新疗法的开发提供信息。然而，在发现这种情况时，一个限速步骤 在实验室动物身上研究这些紊乱的机制仍然是困难的：它可能 永远不可能观察一只动物的行为并知道它正在经历一种情绪 无序。 为了回避这一根本挑战，我们采取了一种不同的方法：我们将建立一种神经 对带有负面偏见的思想的分析。许多情绪障碍的特点是信息有偏见。 处理，包括对负面过去事件的回忆偏差(在严重抑郁症中)和偏差 倾向于产生负面的未来情景(在广泛性焦虑障碍中)。认知过程 关于学习、记忆和决策的理论表明，这种有偏见的想法不仅可能 是情绪障碍的标志，但实际上是导致情绪障碍的原因。 这项工作将开发一种对小鼠负面偏见思维的神经分析，方法是将注意力集中在 波纹(SWR)：大脑内部产生的、同步的神经活动。 可以描绘过去或即将到来的经历的海马体。SWR是一种有吸引力的临床前研究 目标是因为(1)SWR在包括啮齿动物和人类在内的哺乳动物中高度保守， 使结果有可能被翻译，以及(2)SWR活动可以被解码以揭示其 内容，例如检索特定的先前经验。这意味着我们可以建立一个 对消极偏见思维的客观神经测试：给出一种积极和消极的经历， 这两种体验在下游是同样频繁、同样有效，还是存在偏见？ 目标1将优化行为任务和神经分析，以提供积极和消极的信息 可以在神经上区分的体验，对单个主体和个人都有好处 与积极事件相比，记录会话的SWR内容偏向负面事件。接下来，《目标2》将 给药可在啮齿动物体内产生情感偏向信息处理 (安非他命和普拉克索)，并确定它们对SWR偏差和行为的影响。 最后，我们将探讨SWR内容与激励/情感系统之间的联系机制 在AIM 3中，通过它们与多巴胺的相互作用，神经回路水平。 总而言之，拟议的工作有望将SWR内容确立为候选内容 与许多精神健康障碍具有广泛相关性的跨诊断过程。

PROJECT SUMMARY Comorbidities between different mood disorders, as well as those with other syndromes such as schizophrenia, PTSD, and OCD suggest the possibility of shared underlying mechanisms that could inform development of new treatments. However, a rate-limiting step in uncovering such mechanisms continues to be the difficulty of studying these disorders in laboratory animals: it may never be possible to look at the behavior of an animal and know that it is experiencing a mood disorder. To side-step this fundamental challenge, we take a different approach: we will establish a neural assay of negatively biased thought. Many mood disorders are characterized by biased information processing, including recall biases for negative past events (in major depression) and biases towards generating negative future scenarios (in generalized anxiety disorder). Cognitive process theories of learning, memory and decision-making indicate that such biased thought may not only be a signature of mood disorders, but in fact causally contribute to it. This work will develop a neural assay of negatively biased thought in mice by focusing on sharp wave-ripples (SWRs): bursts of internally generated, synchronous neural activity in the hippocampus that can depict past or upcoming experiences. SWRs are an attractive preclinical target because (1) SWRs are highly conserved across mammals including rodents and humans, making it likely that results will translate, and (2) SWR activity can be decoded to reveal their content, such as retrieval of specific prior experiences. This implies that we can establish an objective neural assay for negatively biased thought: given a positive and a negative experience, are both experiences retrieved equally often, equally effective downstream, or is there a bias? Aim 1 will optimize a behavioral task and neural assay to provide positive and negative experiences that can be neurally distinguished, yielding for individual subjects and individual recording sessions a SWR content bias for negative compared to positive events. Next, Aim 2 will administer drugs known to generate affectively biased information processing in rodents in humans (amphetamine and pramipexole) and determine their effects on SWR bias and behavior. Finally, we will probe the mechanisms that link SWR content to motivational/affective systems at the neural circuit level through their interaction with dopamine in Aim 3. Taken together, the proposed work is expected to establish SWR content as a candidate transdiagnostic process that is of broad relevance to a number of mental health disorders.