Local 5-HT Signaling Bi-directionally Regulates the Coincidence Time Window for Associative Learning

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2023 Jan 27

PMID 36706757

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

Affiliations

Soon will be listed here.

Abstract

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.

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References

Aso Y, Hattori D, Yu Y, Johnston R, Iyer N, Ngo T . The neuronal architecture of the mushroom body provides a logic for associative learning. Elife. 2014; 3:e04577. PMC: 4273437. DOI: 10.7554/eLife.04577. View

Takemura S, Aso Y, Hige T, Wong A, Lu Z, Xu C . A connectome of a learning and memory center in the adult brain. Elife. 2017; 6. PMC: 5550281. DOI: 10.7554/eLife.26975. View

Felsenberg J, Barnstedt O, Cognigni P, Lin S, Waddell S . Re-evaluation of learned information in Drosophila. Nature. 2017; 544(7649):240-244. PMC: 5392358. DOI: 10.1038/nature21716. View

Vogt K, Yarali A, Tanimoto H . Reversing Stimulus Timing in Visual Conditioning Leads to Memories with Opposite Valence in Drosophila. PLoS One. 2015; 10(10):e0139797. PMC: 4592196. DOI: 10.1371/journal.pone.0139797. View

Livingstone M, Sziber P, Quinn W . Loss of calcium/calmodulin responsiveness in adenylate cyclase of rutabaga, a Drosophila learning mutant. Cell. 1984; 37(1):205-15. DOI: 10.1016/0092-8674(84)90316-7. View

Davis R, Cherry J, Dauwalder B, Han P, Skoulakis E . The cyclic AMP system and Drosophila learning. Mol Cell Biochem. 1995; 149-150:271-8. DOI: 10.1007/978-1-4615-2015-3_31. View

Miyazaki K, Miyazaki K, Doya K . Activation of the central serotonergic system in response to delayed but not omitted rewards. Eur J Neurosci. 2010; 33(1):153-60. PMC: 3040841. DOI: 10.1111/j.1460-9568.2010.07480.x. View

Keene A, Stratmann M, Keller A, Perrat P, Vosshall L, Waddell S . Diverse odor-conditioned memories require uniquely timed dorsal paired medial neuron output. Neuron. 2004; 44(3):521-33. DOI: 10.1016/j.neuron.2004.10.006. View

Yamaguchi K, Maeda Y, Sawada T, Iino Y, Tajiri M, Nakazato R . A behavioural correlate of the synaptic eligibility trace in the nucleus accumbens. Sci Rep. 2022; 12(1):1921. PMC: 8817024. DOI: 10.1038/s41598-022-05637-6. View

10.

Ludke A, Raiser G, Nehrkorn J, Herz A, Galizia C, Szyszka P . Calcium in Kenyon Cell Somata as a Substrate for an Olfactory Sensory Memory in . Front Cell Neurosci. 2018; 12:128. PMC: 5960692. DOI: 10.3389/fncel.2018.00128. View

11.

Schwaerzel M, Monastirioti M, Scholz H, Friggi-Grelin F, Birman S, Heisenberg M . Dopamine and octopamine differentiate between aversive and appetitive olfactory memories in Drosophila. J Neurosci. 2003; 23(33):10495-502. PMC: 6740930. View

12.

Suzuki Y, Schenk J, Tan H, Gaudry Q . A Population of Interneurons Signals Changes in the Basal Concentration of Serotonin and Mediates Gain Control in the Drosophila Antennal Lobe. Curr Biol. 2020; 30(6):1110-1118.e4. PMC: 7133499. DOI: 10.1016/j.cub.2020.01.018. View

13.

Becnel J, Johnson O, Majeed Z, Tran V, Yu B, Roth B . DREADDs in Drosophila: a pharmacogenetic approach for controlling behavior, neuronal signaling, and physiology in the fly. Cell Rep. 2013; 4(5):1049-59. PMC: 3889141. DOI: 10.1016/j.celrep.2013.08.003. View

14.

Zhang Y, Lu H, Bargmann C . Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature. 2005; 438(7065):179-84. DOI: 10.1038/nature04216. View

15.

Qian Y, Cao Y, Deng B, Yang G, Li J, Xu R . Sleep homeostasis regulated by 5HT2b receptor in a small subset of neurons in the dorsal fan-shaped body of drosophila. Elife. 2017; 6. PMC: 5648528. DOI: 10.7554/eLife.26519. View

16.

Brzosko Z, Schultz W, Paulsen O . Retroactive modulation of spike timing-dependent plasticity by dopamine. Elife. 2015; 4. PMC: 4626806. DOI: 10.7554/eLife.09685. View

17.

Miyazaki K, Miyazaki K, Doya K . Activation of dorsal raphe serotonin neurons is necessary for waiting for delayed rewards. J Neurosci. 2012; 32(31):10451-7. PMC: 6621383. DOI: 10.1523/JNEUROSCI.0915-12.2012. View

18.

Lottem E, Banerjee D, Vertechi P, Sarra D, Oude Lohuis M, Mainen Z . Activation of serotonin neurons promotes active persistence in a probabilistic foraging task. Nat Commun. 2018; 9(1):1000. PMC: 5843608. DOI: 10.1038/s41467-018-03438-y. View

19.

Liu Z, Lin R, Luo M . Reward Contributions to Serotonergic Functions. Annu Rev Neurosci. 2020; 43:141-162. DOI: 10.1146/annurev-neuro-093019-112252. View

20.

Harvey J, GORMEZANO I, Schindler C . Effects of LSD on classical conditioning as a function of CS-UCS interval: relationship to reflex facilitation. Pharmacol Biochem Behav. 1988; 30(2):433-41. DOI: 10.1016/0091-3057(88)90477-7. View