The metabolic costs of cognition

Trends in Cognitive Sciences, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(10)

Опубликована: Март 3, 2025

Understanding the key drivers of brain aging is essential for effective prevention and treatment neurodegenerative diseases. Here, we integrate human physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that networks not only destabilize throughout lifetime but do so along a nonlinear trajectory, with consistent temporal "landmarks" starting in midlife (40s). Comparison metabolic, vascular, inflammatory biomarkers implicate dysregulated glucose homeostasis as driver mechanism these transitions. Correlation between brain's regionally heterogeneous patterns gene expression further supports findings, selectively implicating GLUT4 (insulin-dependent transporter) APOE (lipid transport protein). Notably, MCT2 (a neuronal, glial, ketone emerges potential counteracting factor by facilitating neurons' energy uptake independently insulin. Consistent results, an interventional study 101 participants shows ketones exhibit robust effects restabilizing networks, maximized from ages 40 60, suggesting "critical window" early metabolic intervention.

Язык: Английский

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D-ꞵ-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance

PNAS Nexus, Год журнала: 2024, Номер 3(5)

Опубликована: Апрель 30, 2024

The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely transporter 4 (GLUT4) or insulin, has shown promising clinical applicability in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, specific mechanisms by interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 investigate exogenous D-ꞵ-hydroxybutyrate (D-ꞵHb) mouse metabolism during acute insulin resistance (AIR). We found that both AIR D-ꞵHb had distinct impacts across compartments: decreased synaptic activity long-term potentiation (LTP) impaired axonal conduction, synchronization, action potential properties, while rescued associated LTP.

Язык: Английский

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Challenges and Frontiers in Computational Metabolic Psychiatry

Опубликована: Авг. 13, 2024

One of the primary challenges in metabolic psychiatry is that disrupted brain functions underlie psychiatric conditions arise from a complex set downstream and feedback processes spanning across multiple spatiotemporal scales. Importantly, same circuit can have points failure, each which results different type dysregulation, thus elicits distinct cascades produce divergent signs symptoms. Here, we illustrate this challenge by examining how subtle differences perturbations lead to clinical outcomes. We also discuss computational models perform spatially heterogenous integration bridge vitro vivo paradigms. By leveraging recent methodological advances tools, integrate relevant scales (e.g., TCA-cycle, ion channel, neural microassembly, whole-brain macro-circuit) physiological systems neural, endocrine, immune, vascular), providing framework unite these mechanistic manner goes beyond conceptual descriptive, quantitative generative. These hold potential sharpen our intuitions towards circuit-based for personalized diagnostics treatment.

Язык: Английский

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Challenges and Frontiers in Computational Metabolic Psychiatry

Biological Psychiatry Cognitive Neuroscience and Neuroimaging, Год журнала: 2024, Номер 10(3), С. 258 - 266

Опубликована: Окт. 30, 2024

Язык: Английский

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