Transcriptional signatures in prefrontal cortex confer vulnerability versus resilience to food and cocaine addiction-like behavior

Mohit Navandar,Susanne Gerber,Rafael Maldonado,Elena Martín-García,Beat Lutz,Inigo Ruiz De Azua

doi:10.1038/s41598-021-88363-9

Abstract

Addiction is a chronic relapsing brain disease characterized by compulsive reward-seeking despite harmful consequences. The mechanisms underlying addiction are orchestrated by transcriptional reprogramming in the reward system of vulnerable subjects. This study aims at revealing gene expression alterations across different types of addiction. We analyzed publicly available transcriptome datasets of the prefrontal cortex (PFC) from a palatable food and a cocaine addiction study. We found 56 common genes upregulated in the PFC of addicted mice in these two studies, whereas most of the differentially expressed genes were exclusively linked to either palatable food or cocaine addiction. Gene ontology analysis of shared genes revealed that these genes contribute to learning and memory, dopaminergic synaptic transmission, and histone phosphorylation. Network analysis of shared genes revealed a protein–protein interaction node among the G protein-coupled receptors (Drd2, Drd1, Adora2a, Gpr6, Gpr88) and downstream targets of the cAMP signaling pathway (Ppp1rb1, Rgs9, Pde10a) as a core network in addiction. Upon extending the analysis to a cell-type specific level, some of these common molecular players were selectively expressed in excitatory neurons, oligodendrocytes, and endothelial cells. Overall, computational analysis of publicly available whole transcriptome datasets provides new insights into the molecular basis of addiction-like behaviors in PFC.

Highlights

Addiction is a chronic relapsing brain disease characterized by compulsive reward-seeking despite harmful consequences
Gene expression signature in prefrontal cortex (PFC) of addiction‐like behaviors associated with palatable food and cocaine addiction
We performed a computational analysis of whole transcriptomic data of PFC from palatable food addiction-like behavior[5] and cocaine addiction[9] studies from NCBI-GEO (Fig. 1a)

Summary

Introduction

Addiction is a chronic relapsing brain disease characterized by compulsive reward-seeking despite harmful consequences. We analyzed publicly available transcriptome datasets of the prefrontal cortex (PFC) from a palatable food and a cocaine addiction study. We performed a computational analysis of the publicly available whole transcriptome datasets of the PFC from two independent self-administration studies in mice using palatable food and cocaine as reinforcers, respectively[5, 9]. In both studies, mice were scored with addiction criteria-index based on their operant behavior, which allowed to classify them as addicted (vulnerable) and non-addicted (resilient) mice. Using single-cell RNA-seq data from a publicly available s tudy[14], we could allocate the shared molecular players in a cell-type-specific manner

Objectives

Methods

Results

Conclusion