Hippocampal-dorsolateral prefrontal interactions and cognitive dysfunction in schizophrenia: A non-human primate model

博士项目战略主题：生物科学对健康的综合理解精神分裂症是一种毁灭性的精神疾病，没有治愈的方法。它影响约1%的人群，并与三个主要临床症状群相关：阳性症状（精神病和幻觉），阴性/情绪症状（情感迟钝，冷漠，快感缺乏和社会功能障碍）和认知症状（工作记忆，解决问题，视觉/语言学习和记忆，处理速度和注意力的缺陷）。虽然目前精神分裂症的药物治疗在治疗阳性症状方面是有效的，但它们在治疗阴性和认知症状群方面很差，甚至可能导致它们。由于这些症状深刻地影响生活质量，并对患者的恢复有重大影响，因此它们代表了一种重要的、未满足的临床需求。因此，需要新的方法来理解这些具体问题（标准4）.认识到这一需要，（测量和治疗研究，以提高认知精神分裂症）建议的动物模型的开发和验证：i）更好地模仿精神分裂症中明显的认知和消极障碍，ii）符合精神分裂症的病理生理学，和iii）可用于预测已知治疗剂的效果并促进新治疗的开发。然而，尽管有许多精神分裂症的啮齿动物模型，但由于啮齿动物和人类大脑之间的关键结构和功能差异，对神经功能障碍如何导致精神分裂症的负面/认知症状缺乏基本了解。认知症状尤其如此，它依赖于海马体，特别是前额叶皮层（PFC），这是一个从大鼠到猴子再到人类的大脑区域。因此，在猴子中进行的研究至关重要，因为PFC的结构组织与人类比啮齿动物更相似。该项目旨在通过在新世界的小型灵长类动物（绒猴）中开发新的精神分裂症翻译模型来解决这一问题-海马神经元周净降解和氯胺酮（一种已知的拟精神病药物）给药。这些模型将使我们能够了解功能障碍的海马体和PFC背外侧区（dlPFC）之间的通信如何导致工作记忆缺陷-精神分裂症最普遍和最令人衰弱的症状之一。针对dlPFC的神经化学研究也将旨在确定新疗法的新靶点，然后将其与现有抗精神病药物的效果进行比较。这种直接的比较将提高我们对如何改善精神分裂症dlPFC功能障碍和缓解工作记忆功能障碍症状的理解。

PhD project strategic theme: Biosciences for an integrated understanding of healthSchizophrenia is a devastating psychiatric disorder for which there is no cure. It affects ~1% of the population and is associated with three main clinical symptom clusters: positive symptoms (psychosis and hallucinations), negative/emotional symptoms (blunted affect, apathy, anhedonia and social dysfunction) and cognitive symptoms (deficits in working memory, problem solving, visual/verbal learning and memory, processing speed and attention). Although current pharmacotherapies for schizophrenia are effective in treating the positive symptoms, they are poor at treating the negative and cognitive symptom clusters, and may even contribute to them. As these symptoms profoundly impact quality of life and have a significant bearing on patient recovery, they represent a vital, unmet clinical need. Consequently new approaches to understanding these specific problems are required (criteria 4).In recognition of this need, the MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia) recommended the development and validation of animal models that: i) better mimic the cognitive and negative impairments apparent in schizophrenia, ii) conform to schizophrenia pathophysiology and iii) can be used to predict the effects of known therapeutics and encourage the development of novel treatments. However, although there are many rodent models of schizophrenia, a fundamental understanding of how neural dysfunction causes the negative/cognitive symptoms of schizophrenia is lacking because of key structural and functional differences between rodent and human brains. This is particularly the case for the cognitive symptoms, which are known to depend upon the hippocampus and particularly the prefrontal cortex (PFC), a region of the brain that has expanded greatly from rats to monkeys to humans. Studies performed in monkeys, where the structural organisation of the PFC is much more similar to humans than rodents, are therefore crucial.This project aims to address this problem by developing novel translational models of schizophrenia in a small, new world primate, the marmoset monkey - hippocampal perineuronal net degradation and administration of ketamine (a known psychotomimetic). These models will allow us to understand how communication between a dysfunctional hippocampus and the dorsolateral region of the PFC (dlPFC) contributes to deficits in working memory - one of the most pervasive and debilitating symptoms of schizophrenia. Targeted neurochemical investigations of the dlPFC will also aim to identify novel targets for new therapies that can then be compared to the effects of existing antipsychotic medications. Such direct comparisons will improve our understanding of how to ameliorate dlPFC dysfunction in schizophrenia and alleviate the symptoms of working memory dysfunction.