Preface to the Special Issue “Nutritional Neurochemistry”

Abstract

Nutrition not only constitutes a source of energy and structural building blocks for the brain, it shapes brain development, cellular metabolism, neurotransmission and behavior. The brain itself continuously senses and integrates peripheral metabolic information to regulate feeding and whole-body homeostasis. This Journal of Neurochemistry special issue on Nutritional Neurochemistry brings together a collection of original research and reviews that explore the intricate relationship between diet, metabolism, and brain function.

A recurring theme throughout this collection is that the consequences of nutrition depend strongly on when an exposure occurs. Early life represents a particularly sensitive period during which nutritional signals can leave persistent molecular and functional imprints on the brain. Fernández et al. demonstrate that neonatal overnutrition produces long-lasting epigenetic modifications in hypothalamic pathways regulating energy balance, namely reducing pro-opiomelanocortin (Pomc) expression in the arcuate nucleus, which is likely to result from hypermethylation of the Pomc promoter and was found to shape the responses to obesogenic stimuli in adulthood (Fernández et al. 2026). Schmitt et al. review evidence linking maternal obesity with gestational reprogramming of the fetal immune, metabolic, endocrine, and neurological systems, which influence the metabolism and mental health of the offspring (Schmitt et al. 2025). Fortunato et al. further extend this principle of gestational reprogramming to the maternal gut–brain axis, showing that maternal tryptophan supplementation in the diet can alter offspring microbiota, neurochemistry and behavior in a sex-dependent manner (Fortunato et al. 2025). In particular, the female offspring exhibited disrupted microbiota diversity, reduced brain tryptophan and serotonin levels, and behavior alterations indicative of anxiety (Fortunato et al. 2025). Together, these studies emphasize that nutrition is a neurochemical modulator influencing brain function through mechanisms that depend on developmental stage, subsequent dietary patterns in adulthood and biological sex. Zanesco and Velloso further review the role of hypothalamic BDNF in sexually dimorphic metabolic regulation, emphasizing that sex is a biological variable fundamental to understanding systemic metabolic control by the brain (Zanesco and Velloso 2025).

The diversity of mechanisms through which the brain detects and responds to metabolic information has been addressed in the special issue “Nutritional Neurochemistry”. At the cellular level, Baumart et al. examine how LDL cholesterol modifies astrocyte metabolism, lipid handling and morphology, highlighting astrocytes as active metabolic sensors and responders to systemic lipid homeostasis (Baumart et al. 2026). This is of particular importance in the context of the role of obesity and associated metabolic disorders in driving progression of neurodegenerative diseases (de Bem et al. 2021). In this special issue, Kaya and Stranahan review how peripheral metabolic disturbances associated with obesity impact transport across the blood–brain and blood-cerebrospinal fluid barriers, proposing a model of metabolic-immune-vascular dysfunction in chronic overnutrition and obesity (Kaya and Stranahan 2025). The work by Kostrikov et al. in this special issue suggests that dietary iron deficiency can modify blood–brain-barrier physiology, more specifically by modifying transferrin receptor-mediated trafficking (Kostrikov et al. 2025). These contributions reinforce the emerging view that the blood–brain barrier and glial cells are not passive elements of systemic metabolic homeostasis, but dynamic mediators between nutritional cues and neural function.

Several contributions to the special issue “Nutritional Neurochemistry” focus on the neural circuits that transform metabolic information into feeding behavior. Volcko et al. exploit the genetically encoded HisLightG sensor to reveal rapid and region-specific histamine dynamics during individual ingestive episodes in the paraventricular and ventromedial hypothalamus, providing a new window into neuromodulatory control of appetite (Volcko et al. 2025). Dib et al. review how the lateral septum can integrate a number of neurochemical signals, propose it as a node connecting homeostatic and hedonic control of feeding, and discuss the emerging importance of GLP-1 receptor signaling within this circuitry (Dib et al. 2025). Pérez-Kast and colleagues review molecular and cellular plasticity of mesocorticolimbic circuits and dopaminergic activity in the context of intermittent fasting, discussing how changes in feeding patterns may influence hypothalamic homeostatic mechanisms and dopaminergic reward (Pérez-Kast et al. 2025).

Linking the central role of dopaminergic signaling in the motivational and reward components of feeding (Pérez-Kast et al. 2025), and the potential epigenetic control over cerebral responses to nutritional cues (Fernández et al. 2026), Olivares-Costa et al. explore crosstalk between dopaminergic signaling and the epigenetic enzyme LSD1/KDM1A in the response to amphetamine (Olivares-Costa et al. 2025). These findings highlight molecular mechanisms of dopaminergic plasticity that are relevant to understanding reward-related behaviors, including in the context of feeding and appetite regulation.

Emerging evidence positions the gut microbiota and its metabolites as powerful modulators of emotional, cognitive, and stress-related behaviors. Studies in this Special issue examine how specific dietary components (tryptophan, prebiotic fibers, polyphenols, etc.) influence microbial composition, short-chain fatty acid (SCFA) production, and neurogenesis, ultimately shaping behavioral resilience or vulnerability. Tanabe et al. show that the prebiotic 1-kestose modifies gut microbial composition and SCFA production in association with protection against behavioral alterations triggered by social isolation (Tanabe et al. 2025). D'Andrea et al. demonstrate that nutritional supplementation with hydroxytyrosol, a phenolic compound present in olive oil, mitigates anxiety-like behavior following traumatic experience in aged mice in parallel with increased hippocampal neurogenesis and preservation of the gut microbiota (D'Andrea et al. 2026). These studies point to dietary modulation of microbiota and microbial metabolites as neurochemical modulators.

Following up on abundant evidence for the neuroprotective effect of dietary taurine supplementation (Rafiee et al. 2022), Zhang et al. investigate relationships between mid-life dietary taurine intake, circulating taurine and subsequent dementia risk (Zhang et al. 2025). Despite the negative findings, such studies are particularly valuable because associations between nutrients and brain function in experimental models do not necessarily translate straightforwardly to human populations. Integrating neurochemistry research with nutritional epidemiology is increasingly important for identifying the genuine potential to promote brain health with diet interventions.

Taken together, this Special Issue portrays examples of how dietary patterns and nutritional signals modulate the brain, and highlight the need for further neurochemical research that integrates whole-body physiology and the metabolic environment, and accounts for development, aging, and biological sex. This complexity also points to an important direction for the field: understanding how nutrition influences the brain will require moving beyond isolated nutrients, specific pathways, or single cell types toward approaches that integrate metabolism across biological scales and across the lifespan. Such knowledge will be essential for determining how nutritional and metabolic health contribute to resilience or vulnerability to neuropsychiatric and neurodegenerative disorders.

João M. N. Duarte: writing – review and editing, writing – original draft. Andreza F. de Bem: writing – review and editing.

The authors have nothing to report.

João M. N. Duarte and Andreza F. de Bem are Handling Editors for the Journal of Neurochemistry.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.