Improving cortical function & cognition in schizophrenia by modulation of mGluR5

改善皮质功能

• 批准号: 8634609
• 负责人: JAMES M MCNALLY
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634609
• 关键词: Accounting; Acoustic Stimulation; Acute; Address; Affect; Age; Agonist; Animals; Antipsychotic Agents; Appearance; Area; Attention; Auditory; Autopsy; Behavior; Behavioral; Boston; Cells; Chronic; Clinical; Clinical Research; Cognition; Cognitive; Cognitive deficits; Communities; Data; Development; Disease; Doctor of Philosophy; Electroencephalography; Electrophysiology (science); Etiology; Functional disorder; Funding; Generations; Glutamates; Goals; Hallucinations; Head; Health Care Costs; Healthcare Systems; Impaired cognition; In Vitro; Individual; Interneurons; K-Series Research Career Programs; Ketamine; Knock-out; Knockout Mice; Label; Link; Maintenance; Mediating; Methods; Modeling; Molecular; Motivation; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neurons; Outcome; Patients; Pharmaceutical Preparations; Physiologic pulse; Physiological; Play; Population; Positioning Attribute; Postdoctoral Fellow; Prefrontal Cortex; Process; Property; Psyche structure; Psychotic Disorders; Pyramidal Cells; Research; Resources; Rodent; Role; Schizophrenia; Scientist; Short-Term Memory; Slice; Symptoms; Synapses; System; Testing; Therapeutic; Training; Veterans; Viral; Viral Proteins; Work; analog; cognitive function; disability; executive function; experience; extracellular; frontal lobe; improved; in vitro Model; in vivo; insight; interest; medical schools; metabotropic glutamate receptor 5; neocortical; neural circuit; neurotransmission; next generation; novel; novel strategies; novel therapeutics; optogenetics; postnatal; pre-clinical; preclinical study; protein expression; public health relevance; receptor; research study; risk variant; skills; stem; therapeutic target

Candidate Background: I (Dr. James McNally, Ph.D.) currently serve as a postdoctoral fellow with the preclinical schizophrenia (Sz) research group headed by Dr. Robert W. McCarley, at the VA Boston Healthcare System (VABHS), Brockton campus. I have held this position since 2008 (~4.5 years), following completion of my Ph.D. studies at the UMass Medical School. Since joining this group, my research has been focused on elucidating the molecular mechanisms behind the cognitive deficits associated with schizophrenia (Sz). Sz is a devastating psychiatric illness, which affects ~1% of individuals over the age of 18. This disease warrants increased interest in the VA research community, given the higher instance of Sz among the veteran population, treatment of which accounts for some 40% of VA mental healthcare costs nationally. Veterans with Sz experience high levels of disability and poor community outcome. While clinically identified by the appearance of positive symptoms (psychosis, hallucinations) and negative symptoms (flattened affect, deficits in attention/motivation), deficits in fundamental cognitive processes (working memory, executive function) serve as a major determinant of the long-term disability associated with this illness. Current therapeutic strategies (first and second generation antipsychotics) do not satisfactorily address Sz-related cognitive issues. Thus, development of novel Sz therapeutics which better alleviate all symptom classes associated with this disease represents important clinical need. While the mechanisms responsible for the cognitive deficiencies associated with Sz remain poorly understood, they have been linked to abnormalities in gamma band (30-80 Hz) oscillations (GBO). Clinical and postmortem studies suggest that these abnormalities stem from impaired cortical circuitry. Recently I have developed a novel in vitro model to allow analysis of GBO at the single-neuron level. This model employs acute slices of mouse prelimbic cortex, the rodent analogue of the dorsolateral prefrontal cortex, an area heavily implicated in Sz related cognitive deficits. Presently we are using this system to model Sz-related abnormalities in GBO, and are exploring developmental alterations in this activity (see: Preliminary data and Appendix). Further, I have centrally involved in the development of in vivo methods using either optogenetic or auditory stimulation to evoke GBO in freely moving mice. I believe the combination of our in vitro and in vivo GBO models provide a powerful means to allow detailed analysis of the underlying mechanisms behind the generation of GBO, and potentially provide a means to evaluate new pharmacological therapeutic strategies specifically addressing the cognitive impairments associated with Sz. Current Proposal: Recent studies suggest that positive modulators of the type 5 metabotropic glutamate receptor (mGluR5) represent a novel class of antipsychotics with cognitive enhancing properties. In this revised proposal we will directly examine the effects of mGluR5 on the development and maintenance of the neocortical circuitry responsible for the generation of GBO. The overall hypothesis to be tested posits that mGluR5 mediated enhancement of NMDAR activity is essential for the proper development and maintenance of the neural circuitry responsible for GBO. Further, positive modulation of mGluR5 can alleviate Sz-like NMDAR hypofunction, and restore abnormal GBO observed in in vitro and in vivo NMDAR antagonist models of Sz. As the effects of mGluR5 on GBO have yet to be explored, this work is novel, and will provide valuable insight for the development of agents improving cognitive function in Sz. Long-Term Goals: If funded this VA Career Development Award will provide me with training in a number of areas critical to successful completion of the research proposed above (ie. targeted viral protein expression, optogenetics, in vivo electrophysiology). This increased skill set and experience will provide me the resources needed for my progression as a successful independent scientist in the VA research community.

候选人背景：我（詹姆斯·麦克纳利博士，博士）目前担任博士后研究员 由 VA Boston Healthcare 的 Robert W. McCarley 博士领导的临床前精神分裂症 (Sz) 研究小组 系统（VABHS），布罗克顿校区。我自 2008 年（约 4.5 年）以来一直担任此职位，完成 我的博士学位在麻省大学医学院学习。自从加入这个小组以来，我的研究重点是 阐明与精神分裂症（Sz）相关的认知缺陷背后的分子机制。 Sz 是一个 毁灭性的精神疾病，影响约 1% 的 18 岁以上个体。这种疾病需要 鉴于 Sz 在 退伍军人群体，其治疗费用约占 VA 精神保健费用的 40% 全国范围内。患有 Sz 的退伍军人会经历严重的残疾和较差的社区成果。尽管 临床上通过阳性症状（精神病、幻觉）和阴性症状的出现来识别 （情感平淡、注意力/动机缺陷）、基本认知过程缺陷（工作 记忆、执行功能）是与此相关的长期残疾的主要决定因素 疾病。目前的治疗策略（第一代和第二代抗精神病药）不能令人满意地解决 与 Sz 相关的认知问题。因此，开发新的 Sz 疗法可以更好地缓解所有症状 与这种疾病相关的类别代表了重要的临床需求。 虽然与 Sz 相关的认知缺陷的机制仍然很差 据了解，它们与伽玛波段（30-80 Hz）振荡（GBO）异常有关。临床 尸检研究表明这些异常源于皮质回路受损。最近我有 开发了一种新颖的体外模型，可以在单神经元水平上分析 GBO。该模型采用急性 小鼠前边缘皮层切片，啮齿类动物的背外侧前额叶皮层的类似物，一个严重的区域 与 Sz 相关的认知缺陷有关。目前我们正在使用这个系统来模拟 Sz 相关的异常 在 GBO 中，并正在探索这项活动的发展变化（参见：初步数据和附录）。 此外，我主要参与了使用光遗传学或听觉的体内方法的开发 刺激可在自由活动的小鼠中诱发 GBO。我相信我们的体外和体内GBO的结合 模型提供了一种强大的手段来详细分析背后的潜在机制 GBO 的产生，并有可能提供一种评估新药理学治疗策略的方法 专门解决与 Sz 相关的认知障碍。 当前提案：最近的研究表明 5 型代谢型谷氨酸的正调节剂 受体（mGluR5）代表一类具有认知增强特性的新型抗精神病药。在这个 修订后的提案我们将直接检查 mGluR5 对发育和维持的影响 新皮质电路负责 GBO 的产生。要检验的总体假设表明 mGluR5 介导的 NMDAR 活性增强对于适当的发育和维持至关重要 负责 GBO 的神经回路。此外，mGluR5 的正向调节可以减轻 Sz 样 NMDAR 功能减退，并恢复在体外和体内 NMDAR 拮抗剂模型中观察到的异常 GBO 的 Sz。由于 mGluR5 对 GBO 的影响尚未被探索，这项工作是新颖的，并将提供有价值的 对开发改善 Sz 认知功能的药物的见解。 长期目标：如果获得资助，该 VA 职业发展奖将为我提供一系列培训 对成功完成上述研究至关重要的领域（即目标病毒蛋白表达， 光遗传学、体内电生理学）。这种增加的技能和经验将为我提供资源 我在退伍军人事务部研究界成为一名成功的独立科学家所需要的。