James Clark Center, Stanford University, Stanford, CA, USA.
Department of Biology, Stanford University, Stanford, CA, USA.
Nature. 2024 Oct;634(8036):1141-1149. doi: 10.1038/s41586-024-07819-w. Epub 2024 Jul 22.
In dynamic environments, animals make behavioural decisions on the basis of the innate valences of sensory cues and information learnt about these cues across multiple timescales. However, it remains unclear how the innate valence of a sensory stimulus affects the acquisition of learnt valence information and subsequent memory dynamics. Here we show that in the Drosophila brain, interconnected short- and long-term memory units of the mushroom body jointly regulate memory through dopamine signals that encode innate and learnt sensory valences. By performing time-lapse in vivo voltage-imaging studies of neural spiking in more than 500 flies undergoing olfactory associative conditioning, we found that protocerebral posterior lateral 1 dopamine neurons (PPL1-DANs) heterogeneously and bidirectionally encode innate and learnt valences of punishment, reward and odour cues. During learning, these valence signals regulate memory storage and extinction in mushroom body output neurons (MBONs). During initial conditioning bouts, PPL1-γ1pedc and PPL1-γ2α'1 neurons control short-term memory formation, which weakens inhibitory feedback from MBON-γ1pedc>α/β to PPL1-α'2α2 and PPL1-α3. During further conditioning, this diminished feedback allows these two PPL1-DANs to encode the net innate plus learnt valence of the conditioned odour cue, which gates long-term memory formation. A computational model constrained by the fly connectome and our spiking data explains how dopamine signals mediate the circuit interactions between short- and long-term memory traces, yielding predictions that our experiments confirmed. Overall, the mushroom body achieves flexible learning through the integration of innate and learnt valences in parallel learning units sharing feedback interconnections. This hybrid physiological-anatomical mechanism may be a general means by which dopamine regulates memory dynamics in other species and brain structures, including the vertebrate basal ganglia.
在动态环境中，动物基于感觉线索的固有效价和跨多个时间尺度学习到的这些线索的信息做出行为决策。然而，目前尚不清楚感觉刺激的固有效价如何影响习得效价信息的获取以及随后的记忆动态。在这里，我们展示了在果蝇大脑中，蘑菇体的相互连接的短期和长期记忆单元通过多巴胺信号共同调节记忆，多巴胺信号编码了先天和习得的感觉效价。通过对 500 多只经历嗅觉联想条件作用的果蝇进行活体电压成像研究的延时研究，我们发现，脑前外侧 1 多巴胺神经元（PPL1-DANs）异质且双向编码惩罚、奖励和气味线索的先天和习得效价。在学习过程中，这些效价信号调节蘑菇体输出神经元（MBONs）中的记忆存储和遗忘。在初始条件作用期间，PPL1-γ1pedc 和 PPL1-γ2α'1 神经元控制短期记忆形成，这削弱了 MBON-γ1pedc>α/β 对 PPL1-α'2α2 和 PPL1-α3 的抑制性反馈。在进一步的条件作用过程中，这种减弱的反馈允许这两个 PPL1-DAN 编码条件气味线索的净先天加习得效价，从而门控长期记忆形成。受果蝇连接组和我们的尖峰数据约束的计算模型解释了多巴胺信号如何介导短期和长期记忆痕迹之间的电路相互作用，产生了我们的实验证实的预测。总体而言，蘑菇体通过共享反馈相互连接的并行学习单元整合先天和习得效价来实现灵活的学习。这种混合的生理-解剖学机制可能是多巴胺调节其他物种和大脑结构（包括脊椎动物基底神经节）记忆动态的一般手段。
