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: 7858385
• 负责人: JOSEPH T. COYLE
• 金额: $ 25.68万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7858385
• 关键词: Affect; Biophysics; Cells; Collaborations; Computer Simulation; Data; Defect; Dendritic Spines; Detection; Disease; Distal; Dopamine; Effectiveness; Event; Family; Functional disorder; 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功能减退和多巴胺功能亢进都与精神分裂症有关。此外，委员会认为， 海马区似乎与这种疾病有关，也许是因为异常的新奇， 在CA 1区的检测过程。这些新奇检测过程可能取决于预测 从CAS经由Schaffer侧支（SC）到达CA 1，以及从皮层经由SC直接到达感觉现实。 穿孔路径（PP）。因此，了解多巴胺和NMDAR在CA 1中的功能， 阐明它们促进途径相互作用的方式，并检验这些相互作用的假设。 途径相互作用确实是新奇检测过程的基础。目标1旨在了解 在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亚基在突触后不同， 两种途径，D1的调节可能取决于NMDA亚基的组成。这条调查线 将继续并扩展到D2调制。利用双光子激发单个突触的能力 谷氨酸盐的释放将允许在单个树突棘上的多巴胺能调节的首次研究。它将 因此可以测试这种调制在单个脊柱水平是否是异质的。目标2利用 在体内和体外的方法来测试的假设，途径相互作用执行的新奇性 检测过程。全细胞记录将用于理解通路相互作用的生物物理学， NMDAR和多巴胺能调节在这一过程中的作用。初步研究表明， 相互作用可以导致超线性树突状反应，这些都依赖于NMDAR 功能然而，其他工作表明，由GABA电导介导的自然发生的过程 并且LH可以防止（制动）超线性。将进行实验以确定是否存在 通路定时条件或神经调节条件，其中制动器的有效性是 最小化由NMDA尖峰产生的超线性响应将是候选生物物理响应 以调节新奇检测（匹配信号）。多巴胺在调节这些通路中的作用（如 （1）也将进行研究。理解研究中的途径相互作用的关键需要 体外的目的是获得关于体内发生的CA 1计算的数据。与中心合作 成员，霍华德Eichenbaum，录音将从CA 1地区在介绍小说 序列的将使用多个四极管来测试CA 1是否是新奇检测位点，如 理论基础。这些调查线将有助于整合跨越 多个水平，并阐明如何在NMDA和多巴胺系统的分子缺陷可能有助于 精神分裂症的症状。