Hippocampal memory circuits in delusions

妄想中的海马记忆回路

• 批准号: 9447577
• 负责人: LILA DAVACHI
• 金额: $ 69.72万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-16 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447577
• 关键词: Adopted; Antipsychotic Agents; Autopsy; Behavior assessment; Behavioral; Belief; Brain; Clinical Research; Cognitive; Complex; Daphne plant; Delusions; Detection; Development; Dopamine; Equipment and supply inventories; Failure; Functional Magnetic Resonance Imaging; Future; Hip region structure; Hippocampus (Brain); Hypoxia; Image; Imaging Device; Impairment; Inflammation; Injury; Interneurons; Lateral; Learning; Measures; Memory; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Prefrontal Cortex; Process; Psychotic Disorders; Resolution; Retrieval; Risk Factors; Role; Schizophrenia; Severities; Shapes; Signal Transduction; Stimulus; Thinking; Update; Variant; Ventral Tegmental Area; base; dentate gyrus; dopaminergic neuron; expectation; experience; experimental study; first episode psychosis; high resolution imaging; imaging biomarker; memory consolidation; memory encoding; neurogenesis; novel; response; stressor; therapy development

SUMMARY Hippocampal memory circuits are strongly implicated in the formation and persistence of delusions. In particular, the dentate gyrus (DG) and the CA1 subfield are vulnerable to early developmental stressors that are risk factors for schizophrenia; postmortem evidence points to deficits in inhibitory input and in neurogenesis. We hypothesize that delusions result from aberrant associative memory formation due to impaired functioning of DG/CA3 subfields and persist due to a failure to update false beliefs with new episodic information due to reduced mnemonic prediction error signaling in CA1 and reduced post-encoding consolidation of newly formed memories. Because antipsychotics target hippocampal memory circuits, it is important to study these circuits in unmedicated subjects. We propose to apply three task-based fMRI paradigms to examine early mnemonic associative processing, prediction error, and plasticity of circuits associated with encoding and retrieval in three experiments, each including 50 first episode nonaffective psychosis (FEP) subjects and 50 healthy matched controls. The medication-naïve FEP subjects will be re- studied after 8 weeks of antipsychotic treatment to examine the relationship between medication effects on delusional severity and on hippocampal memory circuits. Imaging will also be repeated after 8 weeks in healthy controls to assess learning effects. The first paradigm, a behavioral pattern separation task, has not previously been studied in medication-naïve first episode psychosis. The paradigms for assessment of CA1 activation during prediction error and of plasticity of connectivity between hippocampal subfields, the ventral tegmental area dopamine neurons and cortical regions were recently developed and validated by Dr. Davachi's team in healthy subjects; we have demonstrated feasibility of these paradigms in schizophrenia subjects. The proposed project will advance our understanding of circuits involved in delusions and their pharmacologic response, will provide validated imaging biomarkers for clinical studies and will identify new targets for treatment development.

总结 海马体记忆回路与妄想的形成和持续密切相关。在 特别是，齿状回（DG）和CA 1亚区容易受到早期发育应激源的影响， 是精神分裂症的危险因素;死后证据表明抑制性输入和 神经发生我们假设错觉是由于联想记忆的形成异常而导致的， DG/CA 3子场功能受损，并且由于未能用新的事件更新错误信念而持续存在 由于在CA 1中减少的助记符预测误差信令和减少的后编码 巩固新形成的记忆。因为抗精神病药物的目标是海马记忆回路， 重要的是在未用药的受试者中研究这些回路。我们建议应用三个基于任务的功能磁共振成像 范式，以检查早期记忆联想处理，预测错误，和可塑性的电路 在三个实验中，每个实验包括50个第一次非情感性事件， 精神病（FEP）受试者和50名健康匹配的对照。未接受过药物治疗的FEP受试者将重新接受治疗。 在抗精神病药物治疗8周后进行研究，以检查药物作用与 妄想的严重程度和海马记忆回路。在8周后也将重复成像， 健康对照组来评估学习效果。第一个范例，一个行为模式分离任务， 以前曾在药物初治精神病首次发作中进行过研究。CA 1的评价范式 在预测错误和海马子场之间的连接可塑性，腹侧激活 达瓦奇博士最近开发并验证了被盖区多巴胺神经元和皮质区。 团队在健康受试者;我们已经证明了这些范式在精神分裂症受试者的可行性。的 拟议的项目将促进我们对妄想及其药理学回路的理解 反应，将提供有效的成像生物标志物的临床研究，并将确定新的目标， 治疗进展。