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<p>Striatal cholinergic interneurons (CINs) can drive local dopamine release via nicotinic acetylcholine receptors (nAChRs) expressed on dopaminergic axons, but their role in modulating serotonin (5-HT) signaling is poorly understood. Here, we show that synchronous activation of CINs directly triggers local 5-HT release in the dorsal striatum via nAChRs expressed on serotonergic axons. This CIN–5-HT coupling is not detectable in the ventral striatum, despite its substantially denser serotonergic innervation. The nAChR-dependent release not only increases 5-HT levels in the dorsal striatum, but also expands the spatial footprint of serotonergic signaling. In <i>Sapap3</i><sup><i>-/-</i></sup> mice, a model of obsessive-compulsive disorder (OCD)-like behavior, this mechanism is exaggerated due to a hypercholinergic state, selectively amplifying the nAChR-dependent component of monoamine release. These findings demonstrate a regionally confined form of acetylcholine–5-HT crosstalk in the striatum and identify CINs as regulators of 5-HT dynamics in both healthy and pathological states.</p>

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Synchronous activation of striatal cholinergic interneurons induces local serotonin release

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月16日

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  • Lior Matityahu,
  • Zachary B. Hobel,
  • Noa Berkowitz,
  • Jeffrey M. Malgady,
  • Naomi Gilin,
  • Joshua L. Plotkin,
  • Joshua A. Goldberg

摘要

Striatal cholinergic interneurons (CINs) can drive local dopamine release via nicotinic acetylcholine receptors (nAChRs) expressed on dopaminergic axons, but their role in modulating serotonin (5-HT) signaling is poorly understood. Here, we show that synchronous activation of CINs directly triggers local 5-HT release in the dorsal striatum via nAChRs expressed on serotonergic axons. This CIN–5-HT coupling is not detectable in the ventral striatum, despite its substantially denser serotonergic innervation. The nAChR-dependent release not only increases 5-HT levels in the dorsal striatum, but also expands the spatial footprint of serotonergic signaling. In Sapap3-/- mice, a model of obsessive-compulsive disorder (OCD)-like behavior, this mechanism is exaggerated due to a hypercholinergic state, selectively amplifying the nAChR-dependent component of monoamine release. These findings demonstrate a regionally confined form of acetylcholine–5-HT crosstalk in the striatum and identify CINs as regulators of 5-HT dynamics in both healthy and pathological states.