Cellular Energetics and Metabolic Infrastructure for Neural Activity

Open Scientific Question

What is the metabolic infrastructure (oxygen, glucose, lactate, ATP, mitochondrial function) that sustains neural firing in adult cortex under chronic stimulation, and how does this infrastructure remodel under perturbation, age, and disease? The framing is that myelin, oligodendrocytes, mural cells, and the cerebrovasculature collectively constitute a metabolic plasticity machinery for the cortex, and that the failures observed around chronic implants and in neurological disease share a common metabolic substrate. This thrust integrates the lab's work on myelin biology (Thrust 1), mural cell function (Thrust 2), and parametric stimulation mechanism (Thrust 4) into a unified mechanistic framework.

Anchor Papers from the Lab

•         Kozai TDY, Jaquins-Gerstl AS, Vazquez AL, Michael AC, Cui XT. Brain tissue responses to neural implants impact signal sensitivity and intervention strategies. ACS Chemical Neuroscience, 2015. The metabolic stress framework, ACS Chem Neurosci Most-Cited 2015, 744+ citations. Established oxygen depletion and metabolic stress as central mechanisms in chronic interface failure.

•         Wellman SM, Forrest AM, Douglas MM, Subbaraman A, Zhang G, Kozai TDY. Dynamic changes in the structure and function of brain mural cells around chronically implanted microelectrodes. Biomaterials, 2025, 315, 122963. Mural cells as metabolic infrastructure, with longitudinal characterization of vascular remodeling that determines local metabolic supply.

•         Wellman SM, Coyne T, Douglas MM, Kozai TDY. Aberrant accumulation of age- and disease-associated factors at the neural electrode interface. Journal of Neural Engineering, 2023, 20(4), 046044. Age-associated factors, including those tied to metabolic infrastructure, accumulate at the chronic interface.

Disease and Translational Connections

•         Multiple sclerosis. Myelin as metabolic plasticity reframes MS as both a demyelinating disease and a metabolic infrastructure failure, with implications for therapeutic strategies that target the metabolic dimension.

•         Alzheimer's disease. Recent work on oligodendrocyte vulnerability in AD (including the lab's Tung et al. bioRxiv 2025) intersects with the broader metabolic decline characteristic of AD. Mathys et al. Nature 2024 single-cell transcriptomics identifies metabolic and resilience signatures in OL populations.

•         Stroke and TBI white matter recovery. Metabolic infrastructure recovery is a determinant of long-term outcome in both conditions.

•         Deep brain stimulation for depression. The companion COBE with Mayberg and Rozell frames DBS as a white matter therapy with metabolic infrastructure as the proximate mechanism. Mayberg's recent mitochondria and glucose funding directly supports this thesis.

•         Engineering implication. Stimulation parameters that respect metabolic infrastructure constraints (oxygen consumption, ATP supply, lactate transport) are likely to outperform parameters optimized empirically without mechanistic awareness.

Skills Developed by Trainees on This Thrust

•         Two-photon imaging of metabolic and hemodynamic readouts (oxygen, blood flow, calcium, glutamate, lactate sensors)

•         Mitochondrial and metabolic readouts in vivo and in fixed tissue

•         Biophysical modeling of metabolic supply and demand under stimulation

•         Cross-cell-type analysis integrating neuronal activity, glial dynamics, and vascular function

•         Pharmacological and genetic perturbation of metabolic pathways, with longitudinal in vivo readout