Network dysregulation in depression: A synthesis of HPA Axis, BDNF signaling, and neurotransmitter interactions across multidimensional systems.

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.