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Fueling the future: brain bioenergetics as a driver of neurodevelopment and mental health trajectories

Neuropsychopharmacology (2025)Cite this article

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While these cellular shifts are central to brain development, cerebral energy homeostasis is also influenced by systemic factors. Gut microbiota, neuroendocrine, and immune signaling coregulate brain metabolism through vagal pathways and microbial metabolites, with the enteric nervous system acting as a “second brain” within the brain–gut–immune axis, directly and indirectly, via control of appetite, satiety and overall metabolic processes (Fig. 1B) [3]. Specific metabolic byproducts acquired through diet and metabolic processes help fuel and support brain development. For example, the shuttling of lactate and pyruvate between astrocytes and neurons enables synaptic plasticity, essential for circuit formation [2]. In parallel, branched-chain amino acids (BCAAs) shape functional networks by fueling neurotransmitter synthesis (glutamate, GABA) and modulating synaptic activity and connectivity (Fig. 1C) [1, 3].

Disruptions in bioenergetic processes can therefore functionally derail neurodevelopment and heighten psychiatric vulnerability [1,2,3]. Many disorder-associated risk genes converge on mitochondrial and metabolic pathways, and altered brain energy metabolism, including reduced mitochondrial enzyme activity and impaired glucose utilization, characterize psychiatric disorders, including idiopathic autism spectrum disorder (ASD), bipolar disorder, and schizophrenia, sometimes preceding illness onset [2, 3].

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Fig. 1: Brain bioenergetics as a central regulator of neurodevelopment and psychiatric vulnerability.

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Authors and Affiliations

  1. Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia

    Susannah J. Tye

  2. Department of Psychiatry and Psychology, Mayo Clinic Depression Center, Mayo Clinic, Rochester, MN, USA

    Susannah J. Tye

  3. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

    Susannah J. Tye

  4. Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA

    Kathryn R. Cullen

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  1. Susannah J. Tye
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  2. Kathryn R. Cullen
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SJT conceived the manuscript concept and structure. SJT conducted the literature review and wrote the initial draft of the manuscript. KRC contributed to the refinement of the scientific content and provided critical feedback on structure, clarity, and interpretation. Both authors were involved in iterative revisions and approved the final manuscript. SJT led the integration of emerging literature and coordinated the alignment of the manuscript with the journal’s thematic focus. All authors contributed substantially to the intellectual content.

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Correspondence to Susannah J. Tye.

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Tye, S.J., Cullen, K.R. Fueling the future: brain bioenergetics as a driver of neurodevelopment and mental health trajectories. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02230-z

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