Hippocampal memory circuits in delusions

摘要 海马体记忆回路与妄想症的形成和持续密切相关。在……里面 特别是，齿状回(DG)和CA1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；尸检证据表明抑制性输入和 神经发生。我们假设妄想症是由异常的联想记忆形成引起的 DG/CA3子场功能受损，并由于未能用新事件更新错误信念而持续存在 由于CA1中的助记预测错误信令减少和编码后减少而产生的信息 巩固新形成的记忆。因为抗精神病药物针对的是海马体记忆回路，所以 在未服用药物的受试者中研究这些回路很重要。我们建议应用三种基于任务的功能磁共振成像 检验早期助记联想加工、预测误差和电路可塑性的范例 与编码和提取相关的三个实验，每个实验包括50个第一集非情绪性 精神病(FEP)受试者和50名健康对照。药物天真的FEP受试者将被重新- 在抗精神病药物治疗8周后进行研究，以检查药物疗效与 妄想的严重性和对海马体记忆回路的影响。8周后，还将再次进行成像 健康对照以评估学习效果。第一个范例，行为模式分离任务，还没有 以前在药物治疗中研究过--幼稚的首发精神病。CA1的评估范式 预测误差期间的激活和海马腹侧亚区之间连接性的可塑性 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域 在健康受试者中的团队；我们已经证明了这些范例在精神分裂症受试者中的可行性。这个 拟议的项目将促进我们对错觉的回路及其药理的理解 响应，将为临床研究提供有效的成像生物标记物，并将确定新的靶点 治疗的发展。

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.