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（博士詹姆斯麦克纳利，博士）目前担任博士后研究员与 临床前精神分裂症（Sz）研究小组领导的博士罗伯特W。McCarley在VA Boston Healthcare 系统（VABHS），布罗克顿校园。自2008年以来，我一直担任这一职务（约4.5年）， 我的博士在麻省大学医学院学习。自从加入这个小组以来，我的研究一直集中在 阐明与精神分裂症相关的认知缺陷背后的分子机制（Sz）。Sz是 毁灭性的精神疾病，影响到18岁以上人群的1%。这种疾病需要 增加了对VA研究社区的兴趣，因为Sz在 退伍军人群体，其治疗约占VA精神卫生保健费用的40% 全国范围内。患有Sz的退伍军人经历了高水平的残疾和不良的社区结果。而 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 （扁平化的影响、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。 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，更好地缓解所有症状的新型Sz疗法的开发 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， 尽管已经了解，但它们与伽马波段（30-80 Hz）振荡（GBO）的异常有关。临床 死后的研究表明这些异常源于受损的皮层回路。最近我 开发了一种新的体外模型，以允许在单神经元水平上分析GBO。该模型采用急性 小鼠前边缘皮层的切片，啮齿动物的背外侧前额叶皮层的类似物，一个区域严重 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与SZ相关的异常 在GBO，并正在探索在这一活动的发展变化（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， 刺激诱发自由活动小鼠中的GBO。我相信我们的体外和体内GBO的结合 模型提供了一个强大的手段，允许详细分析背后的机制， GBO的产生，并可能提供一种手段，以评估新的药理学治疗策略 专门针对与Sz相关的认知障碍。 目前的建议：最近的研究表明，5型代谢型谷氨酸的正调节剂 受体（mGluR 5）代表一类具有认知增强特性的新型抗精神病药。在这 修订后的建议，我们将直接检查mGluR 5对发展和维持的影响， 负责产生GBO的新皮层回路。待检验的总体假设假定， mGluR 5介导的NMDAR活性增强对于正常发育和维持是必需的 导致GBO的神经回路此外，mGluR 5的正调节可以减轻Sz样 在体外和体内NMDAR拮抗剂模型中观察到NMDAR功能减退，并恢复异常GBO 的SZ。由于mGluR 5对GBO的影响尚未被探索，因此这项工作是新颖的，并将提供有价值的 对改善Sz认知功能的药物开发的见解。 长期目标：如果资助这个VA职业发展奖将为我提供一些培训 成功完成上述建议的研究的关键领域（即，靶向病毒蛋白表达， 光遗传学、体内电生理学）。这些增加的技能和经验将为我提供资源 作为一名成功的独立科学家，我在VA研究界的进步所需要的。