MODULATION OF EXCITATORY AND INHIBITORY COMPONENTS OF MNEMONIC CODING

精神分裂症患者明显的工作记忆缺陷是假设的 由前额叶皮质功能障碍引起。这一区域的神经元 灵长类动物对突出物的位置和身份的显示记忆 工作记忆任务中的刺激。前额叶皮质依赖于 充分发挥其功能的多巴胺能药和非典型的抗精神病药物 影响5-羟色胺受体的因素可能也有重要影响 在这个大脑皮层部位。这个实验室以前的研究表明， D1和5-HT2受体都强烈地影响着这种助记编码。两者都有 受体亚型对谷氨酸有重要的促进作用 前额叶神经元的受体输入。因此，为了阐明 工作记忆过程中的神经调节机制，我们的首要目标 是确定NMDA和非NMDA受体的相对贡献 在产生助记活动方面。有了这些知识，有选择性的 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， 5-HT2和其他亚型的多巴胺和5-羟色胺受体也 影响调节锥体助记编码的中间神经元 细胞通过本地电路。因此，我们建议直接区分 多巴胺能和5-羟色胺能受体对谷氨酸受体的作用 来自抑制性中间神经元介导的间接动作的输入。 了解系统应用治疗性和非接触性药物的效果 精神诱因对前额神经元记忆编码的影响 非常有限。通过比较离子导入和全身性作用 这些药物我们打算确定它们的效果在 并确定哪些多巴胺和5-羟色胺受体是 牵涉其中。大多数抗精神病药物会提高皮质多巴胺水平，并 这可能是它们对前额叶神经元作用的主要途径 从属于认知过程。因此，或者说最终的目的是揭示 首次从电化学的角度，揭示了大脑皮质的意义 记忆编码中的多巴胺和5-羟色胺水平，以及 为了药物作用而改变这些水平。这项研究将揭示 多巴胺和5-羟色胺调节细胞基础的机制 工作记忆和这些机制在临床上的参与- 相关毒品事件。通过揭示神经调节的关键方面 记忆编码中的谷氨酸能和抑制过程，这项工作将 大大提高了我们对认知的神经生物学的了解。 辨别毒品作用的关键部位，将促进我们的理解 精神分裂症的神经病理学和在精神分裂症的发展中的帮助 改进的抗精神病药物治疗。

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.