Glucosylceramide regulates depression through activating peroxisome proliferator-activated receptor gamma in dorsal striatum

Sep 30, 2026

Depression is a heterogeneous brain disorder driven in part by cell type-specific transcriptional programs. Peroxisome proliferator-activated receptor gamma (PPARγ) is known to shape depression-related pathophysiology, yet its control of depression-responsive neuronal ensembles is unclear. Using chronic restraint stress mice and multi-omics plus functional assays, the study tests whether glucosylceramide (GlcCer) activates PPARγ signaling in dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs).

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Abstract

Rationale

Methods

Results

Conclusions

Introduction

Theranostics 2026, Vol. 16, Issue 6 2845 Ivyspring International Publisher Theranostics 2026; 16(6): 2845-2865. doi: 10.7150/thno.123178 Research Paper Glucosylceramide regulates depression through activating peroxisome proliferator-activated receptor gamma in dorsal striatum Linhong Jiang1†, Yuman He1†, Haxiaoyu Liu1, Dingwen Zhang1, Yanping Dai1, Qian Bu1, Quanshan Shi2, Huaichuan Duan3, Ying Zhao1, Shu Li1, Shuang Han1, Yuanyi Zhou1, Yue Zhao1, Feng Qin1, Yaxing Chen1, Liang Wang1, Hongchun Li1, Chunqi Liu1, Meng Qin1, Weihong Kuang4, Ni Zhang4, Yinglan Zhao1, Xiaobo Cen1􀀍 1. Mental Health Center and National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University; Chengdu, 610041, China. 2. Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University; Chengdu, 610106, China. 3. Institute for Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center; Chengdu, 610041, China. 4. Department of Psychiatry, West China Hospital, Sichuan University; Chengdu, 610041, China. †These authors contributed equally to this work. 􀀍 Corresponding author: Email: [xbcen@scu.edu.cn](xbcen@scu.edu.cn). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.08.06; Accepted: 2025.11.27; Published: 2026.01.01 Abstract Rationale: Depression is a heterogeneous disorder influenced by cell type-specific gene transcription in the brain. Peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in modulating the pathophysiology of depression. However, the role of PPARγ signaling in modulating depression-responsive neuronal ensembles remains largely unknown. Methods: We established a chronic restraint stress mouse model and integrated multi-omics and functional approaches to investigate the role of glucosylceramide (GlcCer)-PPARγ signaling in stress-induced depression. Conditional knockout mice targeting glucosylceramide synthase (GCS) or Pparg in dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) were generated using a Cre-loxP system, and molecular assays were used to characterize GlcCer as an endogenous activator of PPARγ-driven transcriptional programs. Results: GlcCer as a crucial native activator of PPARγ that specifically modulates depression by binding to the activation function 1 domain of PPARγ in D2-MSNs in the dorsal striatum. Genetic ablation of GCS in D2-MSNs disrupts PPARγ signaling and neuronal function, leading to depression-like behaviors in mice. Selective deletion of Pparg in D2-MSNs produces a similar effect through dopamine D2 receptor. Administration of GlcCer or the PPARγ agonist pioglitazone reverses stress-induced depression-like behaviors, combined GlcCer and pioglitazone exerts additive antidepressant effects. Conclusions: These findings demonstrate a pivotal role for GlcCer-PPARγ signaling in D2-MSNs in depression, highlighting the therapeutic potential of targeting PPARγ activity in depression. Keywords: depression; glucosylceramide; peroxisome proliferator-activated receptor gamma; dopamine 2 receptor-expressing medium spiny neurons; dorsal striatum Introduction Depression is one of the most heterogeneous and disabling neurological conditions worldwide, and stress is a major risk factor for depression [1, 2] . Dysregulated transcription factor-mediated gene expression is considered one of the molecular bases of depression [3-5] . Among transcription factors, peroxisome proliferator-activated receptor gam

FAQs

What role does PPARγ play in depression according to the document?

PPARγ is described as an important regulator of depression pathophysiology. The paper focuses on how PPARγ signaling influences depression-related neuronal ensembles.

How do the researchers test the involvement of GlcCer-PPARγ signaling?

The study uses a chronic restraint stress mouse model combined with multi-omics and functional approaches. Conditional knockout mice target glucosylceramide synthase (GCS) or Pparg in D2-MSNs using a Cre-loxP system.

What therapeutic effects are observed when GlcCer or pioglitazone is administered?

Administration of GlcCer or the PPARγ agonist pioglitazone reverses stress-induced depression-like behaviors. Combined treatment shows additive antidepressant effects.

Sep 30, 2026

Uploaded by Genevieve