Characterizing Genetic, Neurotransmitter receptors and Macroscopic Brain Interactions via Multi-scale Analytical Modeling

点击翻译按钮获取中文摘要

Amongst the multiple challenges that we are faced when trying to understand the brain, our current inability at integrating multiscale data (molecular, neuroimaging, cognitive, behavioral) into a unified generative model stands out. To solve this problem requires the development of novel mathematical, neuroscience and computational techniques, which form the basis of this proposal. From the molecular (e.g. genes, neurotransmitter receptors) to the macroscopic (e.g. neuroimaging) scales, the brain constitutes a complex dynamic system. It is known that each cognitive/behavioral state is the result of concurrent causal interactions between the multiple biological scales. However, most generative models of brain dynamics only focus on macroscopic functional brain signals, not characterizing the molecular basis underlying brain multifactorial dynamics and, importantly, failing to consider other crucial biological factors (e.g. cerebrovascular flow, metabolism, neuronal tissue density). This research aims to: i)Construct an integrative mathematical model to consider the spatiotemporal multiscale and multifactorial interactions between genes, neurotransmitter receptors, multifactorial macroscopic brain factors (neuronal activity integrity, glucose metabolism, vascular flow, gray matter density) and individual cognitive/behavioral properties. We will use dynamic system equations to define a unifying formulation capturing the direct interactions among across-scales biological factors and cognitive/behavioral states. Data from large-scale databases (e.g. Allen Brain Atlas, receptors atlases from Research Center Julich, Gene Expression Omnibus) will be used for developing the model and validating its applicability. We hypothesize that the post-hoc analysis of personalized transcriptomic-receptor-imaging model parameters will reveal essential biological mechanisms. ii)Use the defined molecular-neuroimaging-cognitive brain framework to characterize the molecular and macroscopic impact of different demographic (sex, gender, educational level), life style (diet, physical exercise, sleep habits) and environmental conditions (geographic location, social and community context) on each individual's brain and cognition/behavior. We hypothesize that post-hoc analysis of model parameters will clarify the biological impact of different demographic, lifestyle and environmental conditions. iii)Share all resulting analytic tools with the research community via an already developed open-access user-friendly software. Sharing the integrated molecular-neuroimaging-cognitive brain framework will accelerate its validation and international use. This program will train 4 HQPs (2 MAs and 2 PhDs) and enhance our understanding of the spatiotemporal multiscale brain interactions underlying human cognition and behavior; thus, establishing the critical foundation for understanding and modulating multifactorial brain states from a mechanistic perspective.