Dopamine and NMDA: role in novelty detection

多巴胺和 NMDA：在新颖性检测中的作用

• 批准号: 8074006
• 负责人: JOSEPH T. COYLE
• 金额: $ 25.28万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074006
• 关键词: Affect; Biophysics; Cells; Collaborations; Computer Simulation; Data; Defect; Dendritic Spines; Detection; Disease; Distal; Dopamine; Effectiveness; Event; Family; Glutamates; Hippocampus (Brain); In Vitro; Individual; Investigation; Laboratories; Lead; Mediating; Molecular; N-Methylaspartate; Neurons; Pathway interactions; Perforant Pathway; Photons; Principal Investigator; Process; Rattus; Role; Schizophrenia; Sensory; Signal Transduction; Site; Stimulus; Structure; Symptoms; Synapses; Synaptic Transmission; System; Testing; Time; Universities; Vertebral column; Whole-Cell Recordings; Work; cell type; dopamine system; entorhinal cortex; gamma-Aminobutyric Acid; in vivo; insight; member; novel; postsynaptic; prevent; programs; receptor; research study; response; transmission process; two-photon; visual stimulus

Both NMDA hypofunction and dopamine hyperfunction have been implicated in Schizophrenia. Moreover, the hippocampal region appears to be involved in the disease, perhaps because of aberrant novelty detection processes in the CA1 region. These novelty detection processes may depend on predictions arriving at CA1 from CAS via the Schaffer collaterals (SC) and sensory reality arriving directly from cortex via the perforant path (PP). It is therefore important to understand dopamine and NMDAR function in CA1, to elucidate the ways in which they contribute to pathway interactions, and to test the hypothesis that these pathway interactions indeed underlie a novelty detection process. Aim 1 seeks to understand the role of dopamine/NMDAR interactions at the SC and PP. Preliminary evidence indicates that D1 modulation can affect the NMDA conductance through a postsynaptic process, that the NMDA subunits are different in the two pathways and that D1 modulation may depend on NMDA subunit composition. This line of investigation will be continued and extended to D2 modulation. The ability to excite individual synapses using two-photon uncaging of glutamate will allow the first study of dopaminergic modulation at single dendritic spines. It will thus be possible to test whether this modulation is heterogeneous at the single spine level. Aim 2 utilizes both in vivo and in vitro approaches to test the hypothesis that pathway interactions perform a novelty detection process. Whole cell recording will be used to understand the biophysics of pathway interaction and the role of NMDAR and dopaminergic modulation in this process. Preliminary work suggests that pathway interactions can lead to supra-linear dendritic responses and that these are dependent on the NMDAR function. However, other work indicates that naturally occurring processes mediated by GABA conductances and lh can prevent (brake) the supralinearity. Experiments will be conducted to determine whether there are pathway timing conditions or neuromodulatory conditions in which the effectiveness of the brake is minimized. A supralinear response generated by an NMDA spike would be a candidate biophysical response to mediate novelty detection (a match signal). The role of dopamine in modulating these pathways (as studied in Aim 1) will also be examined. A critical need in understanding the pathway interactions studied in vitro is to obtain data about the CA1 computations that occur in vivo. In collaboration with the Center member, Howard Eichenbaum, recordings will be made from the CA1 region during the presentation of novel sequences. Multiple tetrodes will be used to test whether CA1 is a site of novelty detection, as proposed on theoretical grounds. Together these lines of investigation will help to integrate events spanning across multiple levels and elucidate how molecular defects in the NMDA and dopamine system could contribute to symptoms of schizophrenia.

NMDA 功能低下和多巴胺功能亢进都与精神分裂症有关。而且， 海马区似乎与这种疾病有关，也许是因为异常的新颖性 CA1 区域的检测过程。这些新颖性检测过程可能取决于预测 从 CAS 通过 Schaffer 络脉 (SC) 到达 CA1，而感觉现实通过直接从皮层到达 穿孔路径（PP）。因此，了解 CA1 中多巴胺和 NMDAR 的功能非常重要， 阐明它们对通路相互作用的贡献方式，并检验这些假设 通路相互作用确实是新颖性检测过程的基础。目标 1 旨在了解 SC 和 PP 处的多巴胺/NMDAR 相互作用。初步证据表明 D1 调制可以 通过突触后过程影响 NMDA 电导，NMDA 亚基在 两种途径，D1 调节可能取决于 NMDA 亚基组成。这条调查线 将继续并扩展到D2调制。使用双光子激发单个突触的能力 谷氨酸的解禁将允许首次研究单个树突棘的多巴胺能调节。它将 因此可以测试这种调制在单个脊柱水平上是否是异质的。目标2利用 体内和体外方法都可以检验通路相互作用具有新颖性的假设 检测过程。全细胞记录将用于了解通路相互作用的生物物理学和 NMDAR 和多巴胺能调节在此过程中的作用。初步工作表明该途径 相互作用可以导致超线性树突响应，并且这些响应取决于 NMDAR 功能。然而，其他研究表明，GABA 电导介导的自然发生过程 lh 可以防止（制动）超线性。将进行实验以确定是否存在 制动有效性的路径时序条件或神经调节条件 最小化。 NMDA 尖峰产生的超线性响应将是候选生物物理响应 调解新颖性检测（匹配信号）。多巴胺在调节这些途径中的作用（如 目标 1) 中研究的内容也将受到检查。迫切需要了解所研究的通路相互作用 体外的目的是获得有关体内发生的 CA1 计算的数据。与中心合作 成员 Howard Eichenbaum，在小说展示期间将在 CA1 区域进行录音 序列。将使用多个四极管来测试 CA1 是否是新颖性检测位点，如提议的 理论依据。这些调查线结合在一起将有助于整合跨领域的事件 多个层面并阐明 NMDA 和多巴胺系统中的分子缺陷如何导致 精神分裂症的症状。