An axonal brake on striatal dopamine output by cholinergic interneurons

ABSTRACT

Depolarisation of distal axons is necessary for somatic action potentials to be translated into axonal neurotransmitter release. Here, we show that activation of striatal cholinergic interneurons (ChIs) and nicotinic receptors (nAChRs) on mouse DA axons transiently prevents the release of dopamine (DA) by subsequent stimuli for ~100 ms. Previous studies have shown that nAChRs on DA axons can drive ectopic action potentials in DA axons to trigger DA release. We demonstrate ex vivo that a lower level of activation of ChIs is needed to suppress DA release than to trigger it, an effect that is not due to DA depletion, but to restricted re-activation of DA axons. This axonal brake on DA output is stronger and more persistent in dorsal than ventral striatum.  In vivo, we reveal a predominant depression of DA release by endogenous acetylcholine, as antagonism of nAChRs in dorsal striatum conversely elevated tonic DA detected with optic-fibre photometry of GRABDA2m sensor and promoted conditioned place-preference. Our findings reveal that ChIs acting via nAChRs limit activation of DA axons by subsequent DA neuron activity, uncoupling DA axons from ascending action potentials and generating a dynamic inverse scaling of DA release according to ChI activity.

FILE DESCRIPTIONS

This repository contains the following files:

Key Resources Table (.xlsx) - Table containing details on key resources (antibodies, mouse lines, virus strains, and software), and the persistent identifiers for protocols and code used and generated in this study. 

Source Data Folder (.zip):

_README_Source_Data (.txt) with detailed information about each dataset.

Individual tabular datasets corresponding to panels shown in the Main Figures 1 to 5 (.csv).

Excel spreadsheet containing all tabular datasets plotted in Main Figures 1 to 5 (.xlsx)

Supplementary Data Folder (.zip):

_README_Supplementary_Data (.txt) with detailed information about each dataset.

Individual tabular datasets corresponding to panels shown in the Supplementary Figures 1 to 6 (.csv).

Excel spreadsheet containing all tabular datasets plotted in Supplementary Figures 1 to 6  (.xlsx)

【摘要】 躯体动作电位转化为轴突神经递质释放的必要前提是远端轴突发生去极化。本研究证实，激活小鼠多巴胺（DA，dopamine）轴突上的纹状体胆碱能中间神经元（striatal cholinergic interneurons, ChIs）与烟碱型乙酰胆碱受体（nicotinic receptors, nAChRs），可暂时阻断后续刺激诱导的多巴胺释放，时长约100毫秒。既往研究表明，多巴胺轴突上的烟碱型乙酰胆碱受体可触发轴突异位动作电位，进而诱发多巴胺释放。本研究通过离体实验证实，相较于诱发多巴胺释放，抑制多巴胺释放所需的胆碱能中间神经元激活水平更低；该效应并非源于多巴胺耗竭，而是由于多巴胺轴突的再激活受到限制。这种对多巴胺输出的轴突“刹车”效应，在背侧纹状体中强于腹侧纹状体，且持续时间更久。在体实验中，我们发现内源性乙酰胆碱主要抑制多巴胺释放：背侧纹状体的烟碱型乙酰胆碱受体拮抗作用，反而会升高通过GRABDA2m传感器光纤光度法检测到的基础多巴胺水平，并促进条件性位置偏好行为。本研究结果揭示：胆碱能中间神经元通过烟碱型乙酰胆碱受体，可限制后续多巴胺神经元活动对多巴胺轴突的激活，使多巴胺轴突与上行动作电位脱耦联，并根据胆碱能中间神经元的活动水平动态反向调节多巴胺释放量。

【文件说明】
本数据集仓库包含以下文件：
1. 关键资源表（.xlsx）：收录本研究所用关键实验材料的详细信息（包括抗体、小鼠品系、病毒毒株及软件），以及本研究中使用和生成的实验方案与代码的永久标识符。
2. 源数据文件夹（.zip）：
- README_Source_Data（.txt）：详细说明每个数据集的具体信息。
- 对应主图1至5各面板的独立表格数据集（.csv格式）。
- 汇总主图1至5所有绘图所用表格数据的Excel工作簿（.xlsx格式）。
3. 补充数据文件夹（.zip）：
- README_Supplementary_Data（.txt）：详细说明每个数据集的具体信息。
- 对应附图1至6各面板的独立表格数据集（.csv格式）。
- 汇总附图1至6所有绘图所用表格数据的Excel工作簿（.xlsx格式）。