NCS-FR: Protecting the Aging Brain: Self-Organizing Networks and Multi-Scale Dynamics under Energy Constraints

NCS-FR：保护衰老的大脑：能量约束下的自组织网络和多尺度动力学

• 批准号: 1926781
• 负责人: Lilianne Mujica-Parodi
• 金额: $ 250万
• 依托单位: SUNY at Stony Brook
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1926781&HistoricalAwards=false
• 关键词: NCS; FR; Protecting; Aging; Brain

The brain's ability to use energy has been strongly implicated in age-based cognitive impairment, which will dramatically affect a disproportionally aging demographic. Globally, the number of adults aged 65 or older is estimated to more than double by 2030, with dementia rates exponentially increasing from 1-2% of the population for those age 65, to 58% for those age 94. This project probes the hypothesis that age-based cognitive impairment reflects insulin resistance (Type 2 diabetes) within the brain, limiting neurons' access to blood sugar, and tests whether one can reverse aging effects through the use of an alternative brain fuel: ketones. This project addresses individuality and variation, leveraging the interdisciplinary team's expertise in neuroscience, statistical physics, and machine learning, to tackle one of neurobiology's most fundamental unanswered questions: what are the "rules" by which the brain self-organizes in response to resource constraints? Unifying the project across scales and disciplines is a computational model designed to predict single-subject network trajectories in response to tightening and releasing of energy constraints, a first step towards understanding individuality and variation in brain aging. The project team have previously shown that aging is associated with destabilization of brain networks, an effect that the team's preliminary results suggest can be modulated by switching neuro-metabolism from glucose to ketones. Others have shown that age-based cognitive deterioration accelerates with insulin resistance. Thus, the team hypothesizes that network destabilization may result from reorganization as the brain attempts to optimize networks to conserve energy in response to neuron insulin-resistance. Using insulin resistance to tighten energy constraints and ketones to release them, the team plans to use animal (DREADD/patch-clamp/calcium imaging) and human (31P/1H-MRS, 7T fMRI) data to characterize changes in excitatory/inhibitory neuron firing dynamics and their implications for connectivity. Techniques adapted from "optimization under constraint" problems in statistical physics (e.g., Maximum Caliber) will then be applied to these data to identify cellular automaton-like "rules" that neurons might follow in guiding emergent self-organization. In so doing, the project considers optimization based upon biological principles as well as developing generative techniques for identifying constraints unbiased by the a priori hypotheses. Using an iterative approach, in which each individual subject's network trajectory provides feedback, informing the models, which then make predictions that are tested against the next individual's data, models will eventually converge in predicting human network trajectories based upon individually variable parameters. These would provide first steps towards personalized neurology, by being able to simulate - for a single individual - the potential consequences of different initial conditions and/or clinical interventions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

大脑使用能量的能力与基于年龄的认知障碍密切相关，这将极大地影响到人口老龄化。在全球范围内，到2030年，65岁或以上的成年人数量估计将增加一倍以上，痴呆症发病率从65岁人群的1-2%呈指数级增长，到94岁人群的58%。 该项目探讨了基于年龄的认知障碍反映大脑内胰岛素抵抗（2型糖尿病）的假设，限制了神经元对血糖的获取，并测试了是否可以通过使用替代大脑燃料来逆转衰老效应：酮。 该项目解决了个体性和变化，利用跨学科团队在神经科学，统计物理学和机器学习方面的专业知识，解决神经生物学最基本的未回答的问题之一：大脑自组织响应资源限制的“规则”是什么？统一跨尺度和学科的项目是一个计算模型，旨在预测单一受试者网络轨迹，以响应能量约束的收紧和释放，这是理解大脑衰老的个性和变化的第一步。该项目团队先前已经表明，衰老与大脑网络的不稳定有关，该团队的初步结果表明，这种效应可以通过将神经代谢从葡萄糖转换为酮来调节。其他人已经表明，基于年龄的认知恶化会随着胰岛素抵抗而加速。因此，研究小组假设，网络不稳定可能是由于大脑试图优化网络以保存能量以应对神经元胰岛素抵抗而导致的重组。利用胰岛素抵抗来收紧能量限制和酮来释放它们，该团队计划使用动物（DREADD/膜片钳/钙成像）和人类（31 P/1H-MRS，7 T fMRI）数据来表征兴奋性/抑制性神经元放电动力学的变化及其对连接的影响。从统计物理学中的“约束下的优化”问题改编的技术（例如，最大口径），然后将应用于这些数据，以确定细胞自动机一样的“规则”，神经元可能遵循指导紧急自我组织。在这样做时，该项目考虑基于生物学原理的优化，以及开发生成技术，用于识别先验假设无偏的约束。使用迭代方法，其中每个个体受试者的网络轨迹提供反馈，通知模型，然后根据下一个个体的数据进行预测，模型最终将收敛于基于个体可变参数预测人类网络轨迹。 这些将提供个性化神经病学的第一步，通过能够模拟-为一个人-不同的初始条件和/或临床干预的潜在后果。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

项目成果

Metabolism modulates network synchrony in the aging brain

• DOI: 10.1073/pnas.2025727118
• 发表时间: 2021-09
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Corey Weistuch;L. Mujica-Parodi;Rostam M. Razban;Botond B Antal;Helena van Nieuwenhuizen;Anar Amgalan;K. Dill

Acute administration of ketone beta-hydroxybutyrate downregulates 7T proton magnetic resonance spectroscopy-derived levels of anterior and posterior cingulate GABA and glutamate in healthy adults

酮 β-羟基丁酸酯的急性给药下调健康成人中 7T 质子磁共振波谱衍生的前扣带回和后扣带回 GABA 和谷氨酸水平

• DOI: 10.1038/s41386-022-01364-8
• 发表时间: 2022
• 期刊: Neuropsychopharmacology
• 影响因子: 7.6
• 作者: Hone-Blanchet, Antoine;Antal, Botond;McMahon, Liam;Lithen, Andrew;Smith, Nathan A.;Stufflebeam, Steven;Yen, Yi-Fen;Lin, Alexander;Jenkins, Bruce G.;Mujica-Parodi, Lilianne R.
• 通讯作者: Mujica-Parodi, Lilianne R.

Fast Spatial Autocorrelation

快速空间自相关

• DOI: 10.1109/icdm50108.2020.00010
• 发表时间: 2020
• 期刊: 2020 IEEE International Conference on Data Mining (ICDM
• 作者: Amgalan, Anar;Mujica-Parodi, LR;Skiena, Steven S.
• 通讯作者: Skiena, Steven S.

The Refractory Period Matters: Unifying Mechanisms of Macroscopic Brain Waves

不应期很重要：宏观脑电波的统一机制

• DOI: 10.1162/neco_a_01371
• 发表时间: 2021
• 期刊: Neural Computation
• 影响因子: 2.9
• 作者: Weistuch, Corey;Mujica-Parodi, Lilianne R.;Dill, Ken
• 通讯作者: Dill, Ken

Ion gradient-driven bifurcations of a multi-scale neuronal model

多尺度神经元模型的离子梯度驱动分叉

• DOI: 10.1016/j.chaos.2023.113120
• 发表时间: 2023
• 期刊: Solitons & Fractals
• 作者: Chesebro, Anthony G.;Mujica-Parodi, Lilianne R.;Weistuch, Corey
• 通讯作者: Weistuch, Corey