Harvard Medical School - New England Primate Research Center Southborough, MA, USA ; Department of Psychiatry, Beth Israel Deaconess Medical Center Boston, MA, USA.
Front Neural Circuits. 2014 Apr 23;8:38. doi: 10.3389/fncir.2014.00038. eCollection 2014.
Spike timing-dependent plasticity (STDP) of glutamatergic synapses is a Hebbian associative plasticity that may underlie certain forms of learning. A cardinal feature of STDP is its dependence on the temporal order of presynaptic and postsynaptic spikes during induction: pre-post (positive) pairings induce t-LTP (timing-dependent long-term potentiation) whereas post-pre (negative) pairings induce t-LTD (timing-dependent long-term depression). Dopamine (DA), a reward signal for behavioral learning, is believed to exert powerful modulations on synapse strength and plasticity, but its influence on STDP has remained incompletely understood. We previously showed that DA extends the temporal window of t-LTP in the prefrontal cortex (PFC) from +10 to +30 ms, gating Hebbian t-LTP. Here, we examined DA modulation of synaptic plasticity induced at negative timings in layer V pyramidal neurons on mouse medial PFC slices. Using a negative timing STDP protocol (60 post-pre pairings at 0.1 Hz, δt = -30 ms), we found that DA applied during post-pre pairings did not produce LTD, but instead enabled robust LTP. This anti-Hebbian t-LTP depended on GluN2B-containing NMDA receptors. Blocking D1- (D1Rs), but not D2- (D2Rs) class DA receptors or disrupting cAMP/PKA signaling in pyramidal neurons also abolished this atypical t-LTP, indicating that it was mediated by postsynaptic D1R-cAMP/PKA signaling in excitatory synapses. Unlike DA-enabled Hebbian t-LTP that requires suppression of GABAergic inhibition and cooperative actions of both D1Rs and D2Rs in separate PFC excitatory and inhibitory circuits, DA-enabled anti-Hebbian t-LTP occurred under intact inhibitory transmission and only required D1R activation in excitatory circuit. Our results establish DA as a potent modulator of coincidence detection during associative synaptic plasticity and suggest a mechanism by which DA facilitates input-target association during reward learning and top-down information processing in PFC circuits.
谷氨酸能突触的尖峰时间依赖性可塑性 (STDP) 是一种赫布型联想可塑性，可能是某些形式学习的基础。STDP 的一个主要特征是其在诱导过程中对突触前和突触后尖峰时间顺序的依赖性：前-后 (正) 配对诱导 t-LTP（时依赖长时程增强），而后-前 (负) 配对诱导 t-LTD（时依赖长时程抑制）。多巴胺 (DA) 被认为是行为学习的奖励信号，它对突触强度和可塑性施加强大的调制作用，但它对 STDP 的影响仍不完全清楚。我们之前的研究表明，DA 将前额叶皮层 (PFC) 中的 t-LTP 的时间窗口从 +10 延长至 +30 ms，从而门控赫布型 t-LTP。在这里，我们检查了 DA 对内侧 PFC 切片上 V 层锥体神经元负时间诱导的突触可塑性的调制作用。使用负时间 STDP 方案（60 个后-前配对，频率为 0.1 Hz，δt = -30 ms），我们发现 DA 在后-前配对期间施加不会产生 LTD，而是产生强大的 LTP。这种反赫布型 t-LTP 依赖于含有 GluN2B 的 NMDA 受体。阻断 D1-（D1Rs），而不是 D2-（D2Rs）类 DA 受体或在锥体神经元中破坏 cAMP/PKA 信号也消除了这种非典型的 t-LTP，表明它是由兴奋性突触中突触后 D1R-cAMP/PKA 信号介导的。与需要抑制 GABA 抑制和 D1R 和 D2R 在单独的 PFC 兴奋性和抑制性回路中的协同作用的 DA 启用赫布型 t-LTP 不同，DA 启用的反赫布型 t-LTP 在完整的抑制性传递下发生，仅需要兴奋性回路中 D1R 的激活。我们的结果确立了 DA 作为联想突触可塑性中巧合检测的强大调节剂，并提出了 DA 促进奖励学习期间输入-目标关联和 PFC 回路中自上而下信息处理的机制。
