Acetylcholine Waves and Dopamine Release in the Striatum: A Reaction-Diffusion Mechanism
Lior Matityahu¹, Naomi Gilin¹, Gideon A. Sarpong², Yara Atamna¹, Lior Tiroshi¹, Nicolas X. Tritsch³, Jeffery R. Wickens², Joshua A. Goldberg¹*
¹Department of Medical Neurobiology, Institute of Medical Research Israel-Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel ²Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan ³Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA
*Email: joshua.goldberg2@mail.huji.ac.il
Introduction
Striatal dopamine (DA) encodes reward and exhibits traveling waves across the mediolateral axis during behavior. However, the mechanism generating these patterns remains unknown. Cholinergic interneurons (CINs) modulate DA release through nicotinic acetylcholine receptors (nAChRs) on DA terminals. We hypothesized that reciprocal interactions between CINs and DA axons might underlie wave generation. Here, we investigated whether acetylcholine (ACh) exhibits wave-like activity, whether nAChRs extend DA release spatial scale, and whether a reaction-diffusion framework can explain these waves' emergence from local interactions.
Methods
We imaged ACh sensors (GRAB-ACh3.0, iAChSnFR) in the dorsal striatum of head-fixed mice through cranial windows and GRIN lenses. To test whether nAChRs extend DA release, we expressed GRAB-DA2m in striatal DA axons and measured electrically-evoked DA release at increasing distances with and without the nAChR antagonist mecamylamine. We combined patch-clamp recordings of individual CINs with two-photon imaging of GRAB-DA2m to test if single CINs trigger DA release. We developed and analyzed activator-inhibitor reaction-diffusion models of CIN-DA interactions, exploring how parameters influence wave behavior.
Results
We observed ACh waves propagating primarily lateral-to-medial at velocities of ±10 mm/s. Mecamylamine reduced DA release spatial scale by approximately 50% (from ~532 µm to ~264 µm). Action potentials in individual CINs induced local DA release. We will present novel in vivo data showing that chemogenetic silencing of CINs reduces the spatial scale of ongoing DA release events in awake mice, directly confirming CINs' role in extending DA release. Our modeling demonstrated that CIN-DA interactions form an activator-inhibitor system generating traveling waves. Phase-nullcline-flow analysis (Fig. 1) revealed that wave properties depend on system parameters, explaining directional biases in behavioral contexts.
Discussion
Our findings provide evidence for striatal ACh waves and establish that local CIN-DA fiber interactions drive endogenous traveling waves. The new in vivo data showing CINs extend DA release validates our model's core assumption. The reaction-diffusion framework explains how waves emerge from local axo-axonal interactions without external pacemakers. Our model predicts: strongly coupled DA-ACh waves, nAChR blockade compromising wave propagation, and interneuron activity influencing wave direction. This mechanism contributes to spatiotemporal coding in the striatum, with implications for reward processing, learning, and movement coordination.
Figure 1. Figure 1. Phase-nullcline-flow analysis of the activator-inhibitor model. (a) Nullclines and flow field showing fixed points. (b) The direction of wave propagation depends on the area between nullclines. β values control the coupling strength between CINs and DA axons, determining whether CIN waves advance (β=1.0) or recede (β=1.8).
Acknowledgements
This work was funded by a Research Grant from the Human Frontier Science Program (RGP0062/2019), an ERC Consolidator Grant (646886), and grants from the National Institutes of Health (DP2NS105553 and R01MH130658) and Dana and Whitehall Foundations.
References
[1] Hamid, A. A., et al. (2021). Wave-like dopamine dynamics as a mechanism for spatiotemporal credit assignment. Cell, 184, 2733-2749.
[2] Threlfell, S., et al. (2012). Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron, 75, 58-64.
[3] Matityahu, L., et al. (2023). Acetylcholine waves and dopamine release in the striatum. Nature Communications, 14, 6852.
[4] Liu, C., et al. (2022). An action potential initiation mechanism in distal axons for dopamine release control. Science, 375, 1378-1385.
