Dopamine and NMDA: role in novelty detection

NMDA功能低下和多巴胺功能亢进都与精神分裂症有关。此外， 海马区似乎与这种疾病有关，可能是因为异常的新颖性。 CA1区的检测过程。这些新颖性检测过程可能依赖于预测 通过Schaffer络脉(SC)从CAS到达CA1，以及通过 穿孔剂路径(PP)。因此，了解多巴胺和NMDAR在CA1中的功能是很重要的 阐明它们对途径相互作用的贡献方式，并检验以下假设 途径的相互作用确实是新颖性检测过程的基础。目标1试图了解 多巴胺/NMDAR在SC和PP的相互作用。初步证据表明，D1的调制可以 通过突触后过程影响NMDA的电导，NMDA亚单位在 两条途径和D1的调制可能依赖于NMDA亚基的组成。这条调查路线 将继续并扩展到D2调制。使用双光子激发单个突触的能力 谷氨酸的去化将使第一次研究单个树突棘上的多巴胺能调节。会的 因此，可以测试该调制是否在单个脊椎水平上是异质的。AIM 2利用 体内和体外两种方法来检验通路相互作用发挥新颖性的假说 检测过程。全细胞记录将被用于理解途径相互作用的生物物理和 NMDAR和多巴胺能调节在这一过程中的作用。初步研究表明，这条路径 相互作用可导致超线性树突反应，这些反应依赖于NMDAR 功能。然而，其他研究表明，由GABA电导调节的自然发生的过程 而黄体生成素能预防(制动)超线性。将进行实验，以确定是否有 刹车有效的路径定时条件或神经调节条件 最小化。由NMDA尖峰产生的超线性响应将是候选的生物物理响应 以调解新颖性检测(匹配信号)。多巴胺在调节这些通路(AS)中的作用 在目标1)中学习过的学生也将参加考试。了解中研究的途径相互作用的关键需要 体外实验是为了获得发生在体内的CA1计算的数据。与该中心合作 成员Howard Eichenbaum将在小说展示期间从CA1区进行录音 序列。将使用多个四极管来测试CA1是否为新颖性检测地点，如 理论依据。这些调查线索结合在一起将有助于整合横跨 并阐明NMDA和多巴胺系统中的分子缺陷是如何导致 精神分裂症的症状。

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.