Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need

Drugs of abuse are thought to promote addiction in part by \"hijacking\" brain reward systems, but the underlying mechanisms remain undefined. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we found that drugs of abuse augment dopaminoceptive ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell-type-specific manner. Combining FOS-Seq, CRISPR-perturbation, and snRNAseq, we identified Rheb as a molecular substrate that regulates cell-type-specific signal transduction in NAc while enabling drugs to suppress natural reward consumption. Mapping NAc-projecting regions activated by drugs of abuse revealed input-specific effects on natural reward consumption. These findings characterize the dynamic molecular and circuit basis of a common reward pathway, wherein drugs of abuse interfere with the fulfillment of innate needs.
, , , # Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need

[https://doi.org/10.5061/dryad.qrfj6q5nx](https://doi.org/10.5061/dryad.qrfj6q5nx)

A detailed description of methodology and analysis that were followed in order to generate and process all included files can be found in the associated publication \"Materials and Methods\" section ([https://pubmed.ncbi.nlm.nih.gov/38669575/]()).

#### **1. Dataset: Fos-Seq**

* **Description:** This dataset contains the results of a computational correlation analysis between brain-wide FOS expression (measured via whole-brain clearing) and the Allen Institute’s *in situ* hybridization (ISH) gene expression atlas.
* **Methodology:** Custom code was used to correlate spatial FOS patterns across experimental conditions with the expression patterns of specific genes to identify genetic markers associated with neuronal activation.

#### **2. Dataset: snRNA-seq**

* **Description:** Single-nucleus RNA sequencing (snRNA-seq) data from..., , **Changes after Jan 27, 2026:** Adding FOS expression from individual samples

人们普遍认为，成瘾性药物（Drugs of abuse）部分通过"劫持"大脑奖赏系统来促进成瘾，但背后的具体分子机制仍未明确。本研究通过全脑FOS作图（whole-brain FOS mapping）与活体单神经元钙成像（in vivo single-neuron calcium imaging），发现成瘾性药物可增强伏隔核（nucleus accumbens, NAc）内的多巴胺受体神经元集群活动，并以细胞类型特异性方式破坏天然奖赏的重叠集群响应。本研究结合FOS测序（FOS-Seq）、CRISPR扰动（CRISPR-perturbation）与单细胞核RNA测序（single-nucleus RNA sequencing, snRNAseq），鉴定出Rheb作为分子底物，可调控伏隔核内的细胞类型特异性信号转导，并介导成瘾性药物对天然奖赏摄入的抑制作用。对成瘾性药物激活的伏隔核投射脑区进行作图分析，揭示了其对天然奖赏摄入的输入特异性调控效应。本研究的发现阐明了经典奖赏通路的动态分子与环路机制，即成瘾性药物会干扰机体先天需求的满足过程。

# 成瘾性药物劫持处理内稳态需求的中脑边缘通路

[https://doi.org/10.5061/dryad.qrfj6q5nx](https://doi.org/10.5061/dryad.qrfj6q5nx)

生成并处理所有纳入文件所采用的方法学与分析流程的详细说明，可查阅相关论文的"材料与方法"部分（[https://pubmed.ncbi.nlm.nih.gov/38669575/]()）。

#### **1. 数据集：Fos测序（Fos-Seq）**
* **描述：** 本数据集包含全脑FOS表达（通过全脑透明化技术检测）与艾伦脑科学研究所（Allen Institute）的原位杂交（*in situ* hybridization, ISH）基因表达图谱之间的计算相关性分析结果。
* **方法学：** 本研究使用自定义代码，将不同实验条件下的空间FOS表达模式与特定基因的表达模式进行相关性分析，以鉴定与神经元激活相关的遗传标记物。

#### **2. 数据集：单细胞核RNA测序（snRNA-seq）**
* **描述：** 来自……的单细胞核RNA测序（snRNA-seq）数据，**2026年1月27日后更新：** 新增来自单个样本的FOS表达数据。