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

作为跨诊断认知过程的尖锐波波纹内容的偏差

• 批准号: 10624939
• 负责人: Matthijs van der Meer
• 金额: $ 32.8万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624939
• 关键词: Address; Affect; Affective; Amphetamines; Animal Behavior; Animals; Behavior; Behavioral; Belief; Biological Assay; Decision Making; Development; Dextroamphetamine; Diagnostic; Disease; Dopamine; Dopaminergic Agents; Equilibrium; Event; Failure; Future; Generalized Anxiety Disorder; Generations; Hippocampus; Human; Individual; Laboratory Animals; Learning; Link; Major Depressive Disorder; Mammals; Mediating; Memory; Mental disorders; Mood Disorders; Moods; Motivation; Mus; Outcome; Pharmaceutical Preparations; Pharmacological Treatment; Post-Traumatic Stress Disorders; Process; Proliferating; Retrieval; Rewards; Rodent; Schizophrenia; Signal Transduction; Syndrome; System; Testing; Translating; Validation; Ventral Striatum; Work; clinical translation; cognitive process; comorbidity; expectation; experience; experimental study; information processing; memory retrieval; neural; neural circuit; pharmacologic; pramipexol; pre-clinical; response; success; theories; translational potential

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.

项目摘要 不同情绪障碍之间的共病，以及与其他综合征，如 精神分裂症、创伤后应激障碍和强迫症表明， 可以为新疗法的发展提供信息。然而，在揭示这种情况中的速率限制步骤 机制仍然是在实验室动物中研究这些疾病的困难：它可能 永远不可能看到一只动物的行为，并知道它正在经历一种情绪， disorder. 为了避开这一根本性的挑战，我们采取了不同的方法：我们将建立一个神经网络。 消极偏见思想的分析。许多情绪障碍的特点是有偏见的信息 处理，包括对负面过去事件的回忆偏见（在重度抑郁症中）和偏见 产生消极的未来情景（广泛性焦虑症）。认知过程 学习、记忆和决策的理论表明，这种有偏见的想法不仅 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神经测定的负偏见的想法在小鼠通过集中在夏普 波纹（Wave-ripple，SWRs）：大脑中内部产生的同步神经活动的爆发。 海马体可以描绘过去或即将到来的经历。SWR是有吸引力的临床前 靶向是因为（1）SWR在包括啮齿动物和人类在内的哺乳动物中高度保守， 使其有可能的结果将翻译，和（2）SWR活动可以解码，以揭示他们的 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 负性偏见思维的客观神经测定：给定一个积极和消极的经历， 这两种经验是否同样频繁地被检索，同样有效地下游，或者是否存在偏见？ 目标1将优化行为任务和神经测定，以提供阳性和阴性结果。 经验，可以神经区分，产生个别科目和个人 记录会话，与积极事件相比，负面事件的SWR内容偏差。接下来，Aim 2将 在啮齿类动物中施用已知会产生情感偏见信息处理的药物， 人类（安非他明和普拉克索）并确定它们对SWR偏见和行为的影响。 最后，我们将探讨将SWR内容与动机/情感系统联系起来的机制， 在目标3中，通过与多巴胺的相互作用，神经回路水平。 总之，预计拟议的工作将确立SWR内容作为候选内容 这是一个跨诊断过程，与许多精神健康障碍有着广泛的相关性。