Trans-synaptic modulation of cholinergic circuits tunes opioid reinforcement

• 成果类型: Article
• 署名作者: Zucca, Stefano; Brunori, Gloria; Dunn, Henry A.; Lankford, Colten K.; Sutton, Laurie P.; Flores, Beatriz Algibez; Maza, Nycole A.; Sial, Omar; Crynen, Gogce; Lujan, Rafael; Martemyanov, Kirill A.
• 署名单位: State University System of Florida; University of Florida; State University System of Florida; University of Florida; Universidad de Castilla-La Mancha; University of Manitoba; University of Manitoba; Children's Hospital Research Institute of Manitoba; University of Manitoba; Saint Boniface Hospital; University System of Maryland; University of Maryland Baltimore County
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9455
• DOI: 10.1073/pnas.2409325122
• 发表日期: 2025-03-25
• 关键词: tonically active neurons; metabotropic glutamate receptors; cell-adhesion molecules; nucleus-accumbens; synaptic plasticity; striatal interneurons; messenger-rna; basal ganglia; dopamine; reward

摘要

Opioids trigger structural and functional neural adaptations of the reward circuit that lead to dependence. Synaptic cell adhesion molecules (CAMs) play a pivotal role in circuit organization and present prime candidates for orchestrating remodeling of neural connections in response to drug exposure. However, the contribution of CAMs to opioid-induced rewiring of the reward circuit has not been explored. Here, we used unbiased molecular profiling to identify CAMs in the nucleus accumbens (NAc) modulated by morphine administration. We found that opioid exposure induces the expression of ELFN1, a CAM selectively expressed in cholinergic interneurons in the NAc. We determined that ELFN1 acts trans-synaptically to modulate the strength and plasticity of the glutamatergic inputs onto cholinergic neurons via the recruitment of presynaptic metabotropic glutamate receptor 4 (mGlu4). Disruption of Elfn1 diminished morphine reward and intake in self-administering mice. Together, our findings identify a key molecular factor responsible for adjusting the strength of opioid effects by modulating the configuration of striatal circuitry in an experience-dependent fashion and unveil potential therapeutic target for combating opioid abuse.