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功能障碍和多巴胺超功能都与精神分裂症有关。而且， 海马区似乎参与了该疾病，也许是由于异常新颖的新颖性 CA1区域的检测过程。这些新颖的检测过程可能取决于预测 通过Schaffer侧支（SC）从CAS到达CA1，并直接从Cortex到达CA1 穿孔路径（PP）。因此，重要的是要了解CA1中的多巴胺和NMDAR功能 阐明它们为途径相互作用做出贡献的方式，并检验这些假设 途径相互作用确实是新颖性检测过程的基础。 AIM 1试图了解 SC和PP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 两种途径和D1调制可能取决于NMDA亚基组成。这条调查线 将继续并扩展到D2调制。使用两光子激发单个突触的能力 谷氨酸的渗透将允许在单一树突状棘上首次研究多巴胺能调节。会 因此，可以测试该调节在单个脊柱水平上是否是异质的。 AIM 2使用 体内和体外方法测试了途径相互作用的假设 检测过程。全细胞记录将用于了解途径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。初步工作表明途径 相互作用可以导致超线性树突状反应，并且这些反应取决于NMDAR 功能。但是，其他工作表明GABA电导介导的自然发生的过程 LH可以防止（制动）上线性。将进行实验以确定是否存在 途径的时序条件或刹车有效性的神经调节条件 最小化。 NMDA尖峰产生的上线性反应将是候选生物物理反应 介导新颖性检测（匹配信号）。多巴胺在调节这些途径中的作用（AS 在AIM 1）也将进行研究。了解在了解中所研究的路径相互作用的关键需求 体外是要获得有关体内发生的CA1计算的数据。与中心合作 成员霍华德·艾金鲍姆（Howard Eichenbaum 序列。如在上面提议的 理论上的理由。这些调查方案将有助于整合跨越的事件 多个水平，并阐明NMDA和多巴胺系统中的分子缺陷如何有助于 精神分裂症的症状。