Biology subjects

Buxton, R. B.

Publications and source records attributed to Buxton, R. B..

6 recordsLinked to original sources

bioRxiv2023

Metabolic energetics underlying attractors in neural models

Neural population modeling, including the role of neural attractors, is a promising tool for understanding many aspects of brain function. We propose a modeling framework to connect the abstract variables used in modeling to recent cellular level estimates of the bioenergetic costs of different aspects of neural activity, measured in ATP consumed per second per neuron. Based on recent work, an empirical reference for brain ATP use for the awake resting brain was estimated as [~]2x109 ATP/s-neuron across several mammalian species. The energetics framework was applied to the Wilson-Cowan (WC) model of two interacting populations of neurons, one excitatory (E) and one inhibitory (I). Attractors were considered exhibiting steady-state behavior and limit cycle behavior, both of which end when the excitatory stimulus ends, and sustained activity that persists after the stimulus ends. The general finding was that the energy cost essentially follows the firing rate (average spikes/s) of the E-population, and firing rates of 8-10 spikes/s are in good agreement with the empirical reference value of ATP use. Self-sustained firing driven by recurrent excitation, though, involves higher firing rates and a higher energy cost. By considering a network in which each node is a WC model, we found that a combination of three nodes can serve as a circuit element that turns on when input passes a threshold and then persists after the input ends (an on-switch), with moderate overall ATP use. The proposed framework can serve as a guide for anchoring neural population models to plausible bioenergetics requirements.

neuroscience↗

bioRxiv2023

Thermodynamic limitations on brain oxygen metabolism: physiological implications

A recent hypothesis is that maintaining the brain tissue ratio of O2 to CO2 is critical for preserving the entropy increase available from oxidative metabolism of glucose, with a fall of that available entropy leading to a reduction of the phosphorylation potential and impairment of brain energy metabolism. The hypothesis suggests that physiological responses under different conditions can be understood as preserving tissue O2/CO2. To test this idea, a mathematical model of O2 and CO2 transport was used to calculate how well different physiological responses maintain tissue O2/CO2, showing good agreement with reported experimental measurements for increased neural activity, hypercapnia and hypoxia. The results highlight the importance of thinking about brain blood flow as a way to modulate tissue O2/CO2, rather than simply in terms of O2 delivery to the capillary bed. The hypoxia modeling focused on humans at high altitude, including acclimatized lowlanders and adapted populations, with a primary finding that decreasing CO2 by increasing ventilation rate is much more effective for preserving tissue O2/CO2 than increasing blood hemoglobin content. The modeling provides a new framework and perspective for understanding how blood flow and other physiological factors support energy metabolism in the brain under a wide range of conditions. Key points summaryO_LIRecent thermodynamic modeling suggests that preserving the O2/CO2 ratio in brain tissue is critical for preserving the entropy change available from the oxidative metabolism of glucose and the phosphorylation potential underlying energy metabolism. C_LIO_LIThe hypothesis tested is that normal physiological responses (notably blood flow changes) often act to preserve this ratio under changing conditions. C_LIO_LIUsing a detailed model to calculate tissue O2/CO2 we found good agreement with the predictions of the hypothesis and reported experimental results during hypoxia, hypercapnia and increased oxygen metabolic rate in response to increased neural activity. C_LIO_LIFor the hypoxia modeling we considered high altitude acclimatization and adaptation in humans, showing the critical role of reducing CO2 in preserving tissue O2/CO2. C_LIO_LIThe tissue O2/CO2 hypothesis provides a useful perspective for understanding the function of observed physiological responses under different conditions in terms of preserving brain energy metabolism, although the mechanisms underlying these functions are not well understood. C_LI

neuroscience↗

bioRxiv2021

Microscopic Quantification of Oxygen Consumption across Cortical Layers

The cerebral cortex is organized in cortical layers that differ in their cellular density, composition, and wiring. Cortical laminar architecture is also readily revealed by staining for cytochrome oxidase - the last enzyme in the respiratory electron transport chain located in the inner mitochondrial membrane. It has been hypothesized that a high-density band of cytochrome oxidase in cortical layer IV reflects higher oxygen consumption under baseline (unstimulated) conditions. Here, we tested the above hypothesis using direct measurements of the partial pressure of O2 (pO2) in cortical tissue by means of 2-photon phosphorescence lifetime microscopy (2PLM). We revisited our previously developed method for extraction of the cerebral metabolic rate of O2 (CMRO2) based on 2-photon pO2 measurements around diving arterioles and applied this method to estimate baseline CMRO2 in awake mice across cortical layers. To our surprise, our results revealed a decrease in baseline CMRO2 from layer I to layer IV. This decrease of CMRO2 with cortical depth was paralleled by an increase in tissue oxygenation. Higher baseline oxygenation and cytochrome density in layer IV may serve as an O2 reserve during surges of neuronal activity or certain metabolically active brain states rather than baseline energy needs. Our study provides the first quantification of microscopically resolved CMRO2 across cortical layers as a step towards informed interpretation and modeling of cortical-layer-specific Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) signals.

neuroscience↗

bioRxiv2019

Resolving intrinsic ambiguities of the fMRI signal in the human brain

Functional magnetic resonance imaging (fMRI) using the blood oxygenation level dependent (BOLD) signal is a standard tool in human neuroscience studies. However, the BOLD signal is physiologically complex, depending on the baseline state of the brain and the balance of changes in blood flow and oxygen metabolism in response to a change in neural activity. Interpretation of the magnitude of the BOLD response is thus problematic; specifically, group differences of the BOLD response to a standard task or stimulus, or a change after administration of a drug, could be due to a change in the neural response, neurovascular coupling, or the baseline state. While changes in oxygen metabolism can serve as a biomarker of neural activity change, reflecting the energy cost of activity, oxygen metabolism cannot be estimated from BOLD measurements alone. Here we used the effects of caffeine as a test case to show that a suite of additional noninvasive measurements, requiring no manipulation of inhaled gases, makes it possible to untangle the underlying effects of caffeine on blood flow and oxygen metabolism. After caffeine administration, the BOLD response to a standard motor task was reduced, but oxygen metabolism was not reduced; rather, caffeine reduced the balance of blood flow relative to oxygen metabolism, both in the baseline state and in response to the task. The MRI methods used required only an additional 12 minutes of scanning, can be implemented on any MRI system, and painted a more complete picture of the physiological effects of caffeine. In addition to the assessment of drug effects in the human brain, these methods make it possible to resolve ambiguities of the BOLD signal in studies of development, aging, and disease. (Duplicated from first paragraph of manuscript)

neuroscience↗

bioRxiv2019

The thermodynamics of thinking: connections between neural activity, energy metabolism and blood flow

Several current functional neuroimaging methods are sensitive to cerebral metabolism and cerebral blood flow (CBF) rather than the underlying neural activity itself. Empirically, the connections between metabolism, flow and neural activity are complex and somewhat counterintuitive: CBF and glycolysis increase more than seems to be needed to provide oxygen and pyruvate for oxidative metabolism, and the oxygen extraction fraction is relatively low in the brain and decreases when oxygen metabolism increases. This work lays a foundation for the idea that this unexpected pattern of physiological changes is consistent with basic thermodynamic considerations related to metabolism. In the context of this thermodynamic framework, the apparent mismatches in metabolic rates and CBF are related to preserving the entropy change of oxidative metabolism, specifically the O2/CO2 ratio in the mitochondria. However, the mechanism supporting this CBF response is likely not due to feedback from a hypothetical O2 sensor in tissue, but rather is consistent with feed-forward control by signals from both excitatory and inhibitory neural activity. Quantitative predictions of the thermodynamic framework, based on models of O2 and CO2 transport and possible neural drivers of CBF control, are in good agreement with a wide range of experimental data, including responses to neural activation, hypercapnia, hypoxia and high-altitude acclimatization.

neuroscience↗

bioRxiv2019

The potential for gas-free measurements of absolute oxygen metabolism during both baseline and activation states in the human brain

Quantitative functional magnetic resonance imaging methods make it possible to measure cerebral oxygen metabolism (CMRO2) in the human brain. Current methods require the subject to breathe special gas mixtures (hypercapnia and hyperoxia). We tested a noninvasive suite of methods to measure absolute CMRO2 in both baseline and dynamic activation states without the use of special gases: arterial spin labeling (ASL) to measure baseline and activation cerebral blood flow (CBF), with concurrent measurement of the blood oxygenation level dependent (BOLD) signal as a dynamic change in tissue R2*; VSEAN to estimate baseline O2 extraction fraction (OEF) from a measurement of venous blood R2, which in combination with the baseline CBF measurement yields an estimate of baseline CMRO2; and FLAIR-GESSE to measure tissue R2' to estimate the scaling parameter needed for calculating the change in CMRO2 in response to a stimulus with the calibrated BOLD method. Here we describe results for a study sample of 17 subjects (8 female, mean age=25.3 years, range 21-31 years). The primary findings were that OEF values measured with the VSEAN method were in good agreement with previous PET findings, while estimates of the dynamic change in CMRO2 in response to a visual stimulus were in good agreement between the traditional hypercapnia calibration and calibration based on R2'. These results support the potential of gas-free methods for quantitative physiological measurements.\n\nSynopsisWe tested noninvasive methods to measure absolute oxygen metabolism (CMRO2) in both baseline and activation states without the use of special gases: VSEAN to measure baseline O2 extraction fraction (OEF), and FLAIR-GESSE to measure R2' to estimate the scaling parameter M. Primary findings were: CMRO2 changes to visual stimulation derived from R2' were similar to estimates based on hypercapnia-derived M; OEF values were in good agreement with previous PET findings; and, variation of baseline CBF/CMRO2 coupling across subjects does not follow activation coupling, suggesting different mechanisms may be involved. These results support the potential of gas-free methods for quantitative physiological measurements.\n\nPurposeTo demonstrate the potential for two non-invasive techniques, VSEAN and FLAIR-GESSE, for absolute measurements of CMRO2 during both baseline and activation states.

neuroscience↗