Biochemical and Synaptic Mechanisms in Prefrontal Cortex and Vulnerability for Cognitive Deficits

前额皮质的生化和突触机制以及认知缺陷的脆弱性

• 批准号: 9888424
• 负责人: JOHN D ELSWORTH
• 金额: $ 62.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888424
• 关键词: Acute; Address; Adult; Affect; Antipsychotic Agents; Autopsy; Behavior; Behavioral; Belief; Biochemical; Brain; Brain-Derived Neurotrophic Factor; Cognition; Cognitive; Cognitive deficits; Data; Dendrites; Development; Disease; Disease remission; Dopamine; Drug resistance; Economics; Emotional; Estradiol; Exhibits; Face; Female; Functional disorder; Glutamates; Goals; Healthcare; Healthcare Systems; Impaired cognition; Impairment; Impulsivity; Intervention; Knowledge; Lead; Link; Mediating; Mental disorders; Methodology; Mission; Modeling; Monkeys; Neurons; New Agents; Occupational; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phencyclidine; Population; Prefrontal Cortex; Primates; Process; Psyche structure; Public Health; Recovery; Regulation; Research; Resistance; Risk; Rodent; Role; Schizophrenia; Serotonin; Sex Bias; Short-Term Memory; Symptoms; Synapses; Testing; United States National Institutes of Health; Vertebral column; Work; atypical antipsychotic; base; brain abnormalities; cognitive function; cognitive performance; combat; design; disability; executive function; family burden; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; improved; innovation; insight; male; mature animal; nonhuman primate; novel; novel therapeutics; overexpression; partial recovery; periadolescent; prevent; psychotic symptoms; public health relevance; resilience; restoration; selective attention; social; theories

 DESCRIPTION (provided by applicant): Cognitive deficits are an intrinsic part of schizophrenia, occurring independently of positive symptoms, and often persisting even when psychotic symptoms of schizophrenia have been successfully treated. Cognitive functioning is moderately to severely impaired in patients with schizophrenia and is typically present even in the prodromal phase of the disorder, in young drug-naïve patients. The deficits are in the domain of executive function largely controlled by the prefrontal cortex (PFC). However, there is only a fragmentary understanding of biochemical dysfunctions in brain that leads to cognitive impairment in schizophrenia. Furthermore, even though atypical antipsychotic drugs can improve certain aspects of cognition, many patients do not achieve remission. Therefore, the development of new therapeutic drugs for cognitive impairment remains imperative. However, the design of new agents for treating cognitive deficits in schizophrenia is hampered by not knowing how the more successful antipsychotic drugs exert their benefit on cognitive function. The goals of the application are to understand the biochemical and synaptic changes in PFC that underlie schizophrenia-like cognitive deficits and identify the beneficial alterations produce by drugs that have demonstrated efficacy in combating these symptoms. These goals will be addressed using non-human primate models that have face, construct and predictive validity for the cognitive deficits of schizophrenia, together with the sex bias that characterizes the risk for schizophrenia. Our hypothesis is that dopamine, brain derived neurotrophic factor (BDNF) and estradiol are important factors that interact in the PFC to modify excitatory spine synapses on dendrites of pyramidal neurons, which in turn critically modulates executive function. This project will use a novel developmental phencyclidine (PCP) model and an adult primate PCP model that have resonance to the dopamine, glutamate and GABA hypotheses of schizophrenia, in addition to being relevant to the theories of developmental origins for the illness. The application has 3 specific aims: 1) Identify to what extent estradiol contributes to resilience of the peri-adolescent monkey PFC to the detrimental biochemical, synaptic and cognitive effects of PCP, 2) Identify the potential of local over-expression of BDNF to initiate recovery of excitatory spine synapses from the impact of PCP on primate PFC, and 3) Identify biochemical, synaptic and cognitive consequences of acute and repeated novel atypical antipsychotic drug administration in PFC of PCP-exposed monkeys. This current project contains refinement of previous theoretical concepts and approaches, and tests the impact of new interventions, utilizing improvements in current methodology. This work is expected to lead to new strategies in treating cognitive deficits in schizophrenia, which is the prime driver of significant disabilities in occupational, social, and economic functioning in patients, and imposes a heavy emotional burden on the family and an economic toll on the healthcare system.

 描述（由申请人提供）：认知缺陷是精神分裂症的固有部分，独立于阳性症状发生，即使精神分裂症的精神病性症状已被成功治疗，也经常持续存在。精神分裂症患者的认知功能中度至重度受损，即使在年轻的药物初治患者中，也通常存在于疾病的前驱期。这些缺陷主要是由前额叶皮层（PFC）控制的执行功能领域。然而，对于导致精神分裂症认知障碍的脑生化功能障碍的认识却很不完整。此外，即使非典型抗精神病药物可以改善认知的某些方面，许多患者并没有达到缓解。因此，开发新的认知障碍治疗药物仍然势在必行。然而，由于不知道更成功的抗精神病药物如何对认知功能发挥作用，因此设计治疗精神分裂症认知缺陷的新药受到阻碍。 该应用程序的目标是了解PFC中的生化和突触变化，这些变化是精神分裂症样认知缺陷的基础，并确定已证明有效对抗这些症状的药物产生的有益改变。这些目标将使用非人灵长类动物模型来解决，这些模型具有精神分裂症认知缺陷的面孔，结构和预测有效性，以及表征精神分裂症风险的性别偏见。 精神分裂症我们的假设是，多巴胺，脑源性神经营养因子（BDNF）和雌二醇是在PFC中相互作用的重要因素，以修改锥体神经元树突上的兴奋性棘突触，这反过来又严重调节执行功能。 该项目将使用一种新的发育苯环利定（PCP）模型和一种成年灵长类PCP模型，这些模型与精神分裂症的多巴胺，谷氨酸和GABA假设有共鸣，此外还与疾病的发育起源理论有关。该申请有三个具体目标：1）确定雌二醇在多大程度上有助于青春期前后猴PFC对PCP的有害生物化学、突触和认知效应的恢复，2）确定BDNF的局部过表达启动兴奋性棘突触从PCP对灵长类PFC的影响中恢复的潜力，以及3）确定生物化学，PCP暴露猴PFC中急性和重复新型非典型抗精神病药物给药的突触和认知后果 目前的项目包含以前的理论概念和方法的完善，并测试新的干预措施的影响，利用目前的方法的改进。这项工作预计将导致治疗精神分裂症认知缺陷的新策略，这是患者职业，社会和经济功能显着残疾的主要驱动力， 对家庭造成沉重的情感负担，对医疗保健系统造成经济损失。