Network dysregulation in depression: A synthesis of HPA Axis, BDNF signaling, and neurotransmitter interactions across multidimensional systems.
Mengyang He, Zhifei Shi, Ruijie Zhan, Zhidong Zhuang, Xinyue Li, Wenrui Xue
Pharmacology, biochemistry, and behavior August 1, 2026 Peer reviewed DOI: 10.1016/j.pbb.2026.174215 via PubMed
Summary
Depression involves multiple dysfunctions across brain systems, including emotional-cognitive circuits, stress hormone regulation, neurotransmitter systems, and neuroplasticity. This review argues that the BDNF/CREB signaling pathway acts as a central hub connecting these systems. It explains how genetic variations, stress-related epigenetic changes, and microRNA regulation affect this pathway, which in turn influences brain plasticity, stress toxicity, and neurotransmitter balance. The review also describes how antidepressants like ketamine, rTMS, and SSRIs work by activating this pathway, supporting its potential as a biomarker and treatment target. Limitations and future directions integrating multiomics and neuroimaging are discussed, reconceptualizing depression as a network disorder centered on BDNF/CREB signaling.
Study at a glance
| Design | review |
|---|---|
| Key finding | The BDNF/CREB signaling pathway serves as a core hub mediating multisystem network dysfunction in depression, integrating emotional-cognitive circuits, HPA axis activity, neurotransmitter systems, and neuroplasticity. |
Abstract
Depression is a complex mental disorder threatening global public health. Its pathophysiological mechanisms involve multidimensional dysfunctions including the emotional-cognitive circuit, Hypothalamic-Pituitary-Adrenal (HPA) axis, neurotransmitter systems and neuroplasticity. Current studies mostly analyze each system in isolation, lacking a unified integrated framework. This review proposes that the Brain-Derived Neurotrophic Factor/cAMP-responsive Element Binding Protein (BDNF/CREB) signaling pathway serves as the core hub mediating multisystem network dysfunction in depression. It systematically elucidates the multilevel molecular mechanisms of this pathway, such as genetic polymorphisms, stress-induced epigenetic modifications, and post-transcriptional regulation by microRNAs (miRNAs); clarifies its bidirectional regulatory effects on the plasticity of the prefrontolimbic emotional-cognitive circuit, neurotoxic effects of the HPA axis, and imbalance of monoaminergic/amino acid neurotransmitter systems; summarizes the targeted activation mechanisms of antidepressant interventions (e.g., ketamine, repetitive Transcranial Magnetic Stimulation (rTMS), Selective Serotonin Reuptake Inhibitors (SSRIs)) on this pathway, and verifies its value as a disease biomarker and therapeutic target combined with clinical evidence. This review points out the limitations of current research and prospects the precision research direction integrating multiomics and neuroimaging, reconceptualizing depression as a network disorder centered on the abnormality of the BDNF/CREB signaling hub, so as to provide theoretical support for elucidating the pathological mechanism of depression and developing precision diagnosis and treatment strategies.