Local 5-HT signaling bi-directionally regulates the coincidence time window for associative learning

• DOI: 10.1016/j.neuron.2022.12.034
• Publication Date: 2023-01-26T15:55:16Z
• Authors: Jianzhi Zeng; Xuelin Li; Renzimo Zhang; Mingyue Lv; Yipan Wang; Ke Tan; Xiju Xia; Jinxia Wan; Miao Jing; Xiuning Zhang; Yu Li; Yang Yang; Liang Wang; Jun Chu; Yan Li; Yulong Li
• Keywords: Mushroom bodies; Associative learning; Stimulus (psychology); Neuromodulation

The coincidence between conditioned stimulus (CS) and unconditioned stimulus (US) is essential for associative learning; however, the mechanism regulating the duration of this temporal window remains unclear. Here, we found that serotonin (5-HT) bi-directionally regulates the coincidence time window of olfactory learning in Drosophila and affects synaptic plasticity of Kenyon cells (KCs) in the mushroom body (MB). Utilizing GPCR-activation-based (GRAB) neurotransmitter sensors, we found that KC-released acetylcholine (ACh) activates a serotonergic dorsal paired medial (DPM) neuron, which in turn provides inhibitory feedback to KCs. Physiological stimuli induce spatially heterogeneous 5-HT signals, which proportionally gate the intrinsic coincidence time windows of different MB compartments. Artificially reducing or increasing the DPM neuron-released 5-HT shortens or prolongs the coincidence window, respectively. In a sequential trace conditioning paradigm, this serotonergic neuromodulation helps to bridge the CS-US temporal gap. Altogether, we report a model circuitry for perceiving the temporal coincidence and determining the causal relationship between environmental events.