PDF(Pubmed)
Abstract：
Recent work demonstrated that activation of spinal D1 and D5 dopamine receptors (D1/D5Rs) facilitates non-Hebbian long-term potentiation (LTP) at primary afferent synapses onto spinal projection neurons. However, the cellular localization of the D1/D5Rs driving non-Hebbian LTP in spinal nociceptive circuits remains unknown, and it is also unclear whether D1/D5R signaling must occur concurrently with sensory input in order to promote non-Hebbian LTP at these synapses. Here we investigate these issues using cell-type-selective knockdown of D1Rs or D5Rs from lamina I spinoparabrachial neurons, dorsal root ganglion (DRG) neurons, or astrocytes in adult mice of either sex using Cre recombinase-based genetic strategies. The LTP evoked by low-frequency stimulation of primary afferents in the presence of the selective D1/D5R agonist SKF82958 persisted following the knockdown of D1R or D5R in spinoparabrachial neurons, suggesting that postsynaptic D1/D5R signaling was dispensable for non-Hebbian plasticity at sensory synapses onto these key output neurons of the superficial dorsal horn (SDH). Similarly, the knockdown of D1Rs or D5Rs in DRG neurons failed to influence SKF82958-enabled LTP in lamina I projection neurons. In contrast, SKF82958-induced LTP was suppressed by the knockdown of D1R or D5R in spinal astrocytes. Furthermore, the data indicate that the activation of D1R/D5Rs in spinal astrocytes can either retroactively or proactively drive non-Hebbian LTP in spinoparabrachial neurons. Collectively, these results suggest that dopaminergic signaling in astrocytes can strongly promote activity-dependent LTP in the SDH, which is predicted to significantly enhance the amplification of ascending nociceptive transmission from the spinal cord to the brain.
摘要：
最近的工作表明，脊髓D1和D5多巴胺受体（D1/D5Rs）的激活可促进非Hebbian长期增强（LTP）在脊髓投射神经元的初级传入突触上。然而,在脊髓伤害性回路中驱动非HebbianLTP的D1/D5R的细胞定位仍然未知，也不清楚D1/D5R信号是否必须与感觉输入同时发生，以促进这些突触的非HebbianLTP。在这里，我们使用来自I层脊髓臂神经元的D1R或D5Rs的细胞类型选择性敲除来研究这些问题，使用基于Cre重组酶的遗传策略，任何性别的成年小鼠的背根神经节（DRG）神经元或星形胶质细胞。在选择性D1/D5R激动剂SKF82958的存在下，初级传入神经的低频刺激引起的LTP在脊髓臂神经元中D1R或D5R敲低后持续存在，这表明突触后D1/D5R信号对于感觉突触的非Hebbian可塑性是不必要的，这些关键输出神经元的浅层背角（SDH）。同样，DRG神经元中D1Rs或D5Rs的敲除未能影响I层投射神经元中SKF82958启用的LTP.相比之下,SKF82958诱导的LTP被脊髓星形胶质细胞中D1R或D5R的敲低所抑制。此外，数据表明，脊髓星形胶质细胞中D1R/D5Rs的激活可以逆转录或主动驱动脊髓臂神经元中的非HebbianLTP。总的来说，这些结果表明，星形胶质细胞中的多巴胺能信号可以强烈促进SDH中的活性依赖性LTP，这被预测会显著增强从脊髓到大脑的上升伤害性传递的放大。意义陈述感觉突触对层I投射神经元的长期增强（LTP）代表了一种关键机制，通过这种机制，脊髓浅层背角（SDH）可以增强对大脑的上升伤害性传递。在这里，我们证明了在脊髓星形胶质细胞中表达的D1或D5多巴胺受体的激活在小鼠脊髓背臂神经元的初级传入输入时促进了非HebbianLTP。此外，星形胶质细胞D1/D5R信号不仅能逆转最近活跃的感觉突触，而且在随后的刺激后，还主动启动突触以进行LTP。这些结果确定了星形胶质细胞上的多巴胺能信号作为SDH中突触化可塑性的关键调节剂，并表明星形胶质细胞D1/D5Rs可以作为增益控制，使脊髓伤害性传递过度放大。
