MODULATION OF EXCITATORY AND INHIBITORY COMPONENTS OF MNEMONIC CODING

助记符编码的兴奋性和抑制性成分的调节

• 批准号: 6204830
• 负责人: PATRICIA S GOLDMAN-RAKIC
• 金额: $ 30.43万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6204830
• 关键词: Macaca mulatta; NMDA receptors; antiadrenergic agents; antipsychotic agents; brain electrical activity; cognition; dopamine receptor; drug interactions; electrophysiology; glutamate receptor; interneurons; memory; neural information processing; neurochemistry; neuropsychology; neurotransmitter metabolism; neurotransmitters; nontherapeutic iontophoresis; prefrontal lobe /cortex; schizophrenia; serotonin; serotonin receptor; single cell analysis

The deficits in working memory evident in schizophrenia are hypothesized to arise from a dysfunction of prefrontal cortex. Neurons in this area of the primate display memory for the location and identity of salient stimuli in working memory tasks. The prefrontal cortex is dependent on adequate dopaminergic tone for its function, and atypical antipsychotics which influences serotonin receptors may also have an important influence at this cortical site. Previous studies in this laboratory have shown that both D1 and 5-HT2 receptors strongly influence this mnemonic coding. Both receptor subtypes have important facilitatory actions on glutamate receptor input to prefrontal neurons. Thus, in order to elucidate the mechanisms of neuromodulation in the working memory process, our first aim is to determine the relative contribution of NMDA and non-NMDA receptors in producing mnemonic activity. With this knowledge, the selective monoaminergic regulation of these excitatory inputs can be ascertained while neurons are active engaged in the working memory process. Moreover, 5-HT2 and other subtypes of dopamine and serotonin receptors also influence interneurons which regulate the mnemonic coding of pyramidal cells through local circuits. We therefore propose to distinguish direct actions of dopaminergic and serotonergic receptors on glutamate receptors input from indirect actions mediated by inhibitory interneurons. Knowledge of the effects of systemically applies therapeutic and psychotogenic agents on the mnemonic coding of prefrontal neurons is extremely limited. By comparing iontophoretic versus systemic actions of these drugs we intend to determine their effects at the level of the cortex and to identify which dopamine and serotonin receptors are involved. Most antipsychotic drugs elevate cortical dopamine levels, an effect which may be a primary route of their action on prefrontal neurons subserving cognitive processes. Thus, or final aim is to reveal electrochemically for the first time, the significance of cortical dopamine and serotonin levels in mnemonic coding, and the importance of alteration of these levels for drug action. This research will reveal the mechanisms by which dopamine and serotonin regulate the cellular basis of working memory and the involvement of these mechanisms in clinically- relevant drug events. By revealing key aspects of the neuromodulation of glutamatergic and inhibitory processes in mnemonic coding, this work will substantially enhance our knowledge of the neurobiology of cognition. Discerning essential sites for drug action, will advance our understanding of the neuropathology of schizophrenia and aid in the development of improved antipsychotic therapy.

工作记忆的缺陷在精神分裂症中很明显， 前额叶皮层功能障碍这个区域的神经元 灵长类动物对显著位置和身份的显示记忆 工作记忆任务中的刺激。前额叶皮层依赖于 足够的多巴胺能张力，其功能，和非典型抗精神病药 它影响血清素受体， 在这个皮质部位该实验室先前的研究表明， D1和5-HT 2受体都强烈地影响这种记忆编码。两 受体亚型对谷氨酸具有重要的易化作用 前额叶神经元的感受器输入。因此，为了阐明 工作记忆过程中的神经调节机制，我们的第一个目标 确定NMDA和非NMDA受体的相对贡献 产生记忆活动。有了这些知识， 可以确定这些兴奋性输入的单胺能调节 而神经元则活跃地参与工作记忆过程。此外，委员会认为， 5-HT 2和多巴胺和5-羟色胺受体的其他亚型也 影响调节锥体细胞记忆编码的中间神经元 通过本地电路。因此，我们建议区分直接 多巴胺能和多巴胺能受体对谷氨酸受体的作用 由抑制性中间神经元介导的间接作用的输入。 了解全身应用治疗药物的影响， 精神药物对前额叶神经元记忆编码的影响 极其有限。通过比较离子电渗与全身作用， 这些药物，我们打算确定其影响的水平， 大脑皮层，并确定哪些多巴胺和血清素受体 涉案大多数抗精神病药物会升高大脑皮层多巴胺水平， 这可能是它们作用于前额叶神经元的主要途径 有助于认知过程因此，或最终目的是揭示 电化学的第一次，皮层的意义， 多巴胺和5-羟色胺水平在记忆编码中的重要性， 改变这些水平的药物作用。这项研究将揭示 多巴胺和5-羟色胺调节细胞基础的 工作记忆和这些机制在临床上的参与- 相关药物事件。通过揭示神经调节的关键方面， 记忆编码中的抑制和抑制过程，这项工作将 大大增强了我们对认知神经生物学的了解。 识别药物作用的基本部位，将促进我们的理解 精神分裂症的神经病理学， 改善抗精神病药物治疗