Maternal fasting during early gestation induces epigenetic alterations and schizophrenia-related phenotypes.

Major depressive disorder (MDD) is a highly prevalent and recurrent psychiatric condition and a leading contributor to global disability. According to the World Health Organization, depression ranks among the top causes of disease burden worldwide []. Despite extensive investigation, its pathophysiological basis remains incompletely resolved, limiting mechanistic stratification and precision therapeutic development. Recent studies have identified multiple biological processes contributing to the pathogenesis of depression, including, but not limited to, the following: Neuroinflammation: Converging clinical and experimental evidence indicates that subsets of patients exhibit elevated peripheral and central inflammatory markers [–]. Increased circulating concentrations of interleukin-6 (IL-6), tumor necrosis factor (TNF), and interleukin-1β (IL-1β) have been reported in meta-analyses. These inflammatory signals are associated with microglial activation, altered blood-brain barrier (BBB) integrity, and synaptic remodeling [, ]. However, inflammatory signatures are heterogeneous and appear most prominent in specific clinical subtypes (e.g., treatment-resistant or high-inflammatory phenotypes), rather than universally across all individuals with MDD. Neurotransmitter dysregulation: The monoamine hypothesis historically posited that reduced serotonergic, noradrenergic, and dopaminergic signaling underlies depressive symptomatology [, ]. Although monoaminergic modulation remains central to pharmacotherapy, this framework is now understood to be incomplete. Glutamatergic and γ-aminobutyric acid (GABA) signaling, synaptic plasticity, and neurotrophic mechanisms—particularly those involving brain-derived neurotrophic factor (BDNF)—have emerged as critical components of contemporary models. Brain-gut axis alterations: The brain–gut axis comprises bidirectional communication among the central nervous system (CNS), autonomic nervous system, immune pathways, and the intestinal microbiota. Reduced microbial diversity and altered metabolite profiles have been described in MDD cohorts [, ]. These alterations may influence mood-relevant circuitry through immune modulation, tryptophan metabolism, and synaptic plasticity pathways. Causal directionality, however, remains incompletely established. Within this evolving systems framework, exosomes—30–150 nm extracellular vesicles (EVs) generated through multivesicular body (MVB) pathways—have gained attention as potential mediators of intercellular communication. Exosomes transport diverse cargo, including proteins, lipids, messenger RNA, microRNAs (miRNAs), and other non-coding RNAs [–]. Because vesicular content reflects the physiological state of the originating cell, exosomes have been proposed as both mechanistic participants and peripheral readouts of CNS processes (Fig. ). Preclinical and clinical studies suggest that exosomal signaling may intersect with neuroinflammatory pathways, synaptic remodeling, and gut-brain communication. Nonetheless, much of the current human literature remains cross-sectional and associative. Sample sizes are typically modest, diagnostic stratification is variable, and methodological heterogeneity in isolation and characterization complicates reproducibility.