Soheil Saghafi, Timothy Rumbell, Viatcheslav Gurev, James Kozloski, Francesco Tamagnini, Kyle C A Wedgwood, Casey O Diekman
{"title":"利用生物物理建模和深度学习推断阿尔茨海默病小鼠模型中锥体神经元兴奋性的参数","authors":"Soheil Saghafi, Timothy Rumbell, Viatcheslav Gurev, James Kozloski, Francesco Tamagnini, Kyle C A Wedgwood, Casey O Diekman","doi":"10.1007/s11538-024-01273-5","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's disease (AD) is believed to occur when abnormal amounts of the proteins amyloid beta and tau aggregate in the brain, resulting in a progressive loss of neuronal function. Hippocampal neurons in transgenic mice with amyloidopathy or tauopathy exhibit altered intrinsic excitability properties. We used deep hybrid modeling (DeepHM), a recently developed parameter inference technique that combines deep learning with biophysical modeling, to map experimental data recorded from hippocampal CA1 neurons in transgenic AD mice and age-matched wildtype littermate controls to the parameter space of a conductance-based CA1 model. Although mechanistic modeling and machine learning methods are by themselves powerful tools for approximating biological systems and making accurate predictions from data, when used in isolation these approaches suffer from distinct shortcomings: model and parameter uncertainty limit mechanistic modeling, whereas machine learning methods disregard the underlying biophysical mechanisms. DeepHM addresses these shortcomings by using conditional generative adversarial networks to provide an inverse mapping of data to mechanistic models that identifies the distributions of mechanistic modeling parameters coherent to the data. Here, we demonstrated that DeepHM accurately infers parameter distributions of the conductance-based model on several test cases using synthetic data generated with complex underlying parameter structures. We then used DeepHM to estimate parameter distributions corresponding to the experimental data and infer which ion channels are altered in the Alzheimer's mouse models compared to their wildtype controls at 12 and 24 months. We found that the conductances most disrupted by tauopathy, amyloidopathy, and aging are delayed rectifier potassium, transient sodium, and hyperpolarization-activated potassium, respectively.</p>","PeriodicalId":9372,"journal":{"name":"Bulletin of Mathematical Biology","volume":"86 5","pages":"46"},"PeriodicalIF":2.0000,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10963524/pdf/","citationCount":"0","resultStr":"{\"title\":\"Inferring Parameters of Pyramidal Neuron Excitability in Mouse Models of Alzheimer's Disease Using Biophysical Modeling and Deep Learning.\",\"authors\":\"Soheil Saghafi, Timothy Rumbell, Viatcheslav Gurev, James Kozloski, Francesco Tamagnini, Kyle C A Wedgwood, Casey O Diekman\",\"doi\":\"10.1007/s11538-024-01273-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Alzheimer's disease (AD) is believed to occur when abnormal amounts of the proteins amyloid beta and tau aggregate in the brain, resulting in a progressive loss of neuronal function. Hippocampal neurons in transgenic mice with amyloidopathy or tauopathy exhibit altered intrinsic excitability properties. We used deep hybrid modeling (DeepHM), a recently developed parameter inference technique that combines deep learning with biophysical modeling, to map experimental data recorded from hippocampal CA1 neurons in transgenic AD mice and age-matched wildtype littermate controls to the parameter space of a conductance-based CA1 model. Although mechanistic modeling and machine learning methods are by themselves powerful tools for approximating biological systems and making accurate predictions from data, when used in isolation these approaches suffer from distinct shortcomings: model and parameter uncertainty limit mechanistic modeling, whereas machine learning methods disregard the underlying biophysical mechanisms. DeepHM addresses these shortcomings by using conditional generative adversarial networks to provide an inverse mapping of data to mechanistic models that identifies the distributions of mechanistic modeling parameters coherent to the data. Here, we demonstrated that DeepHM accurately infers parameter distributions of the conductance-based model on several test cases using synthetic data generated with complex underlying parameter structures. We then used DeepHM to estimate parameter distributions corresponding to the experimental data and infer which ion channels are altered in the Alzheimer's mouse models compared to their wildtype controls at 12 and 24 months. We found that the conductances most disrupted by tauopathy, amyloidopathy, and aging are delayed rectifier potassium, transient sodium, and hyperpolarization-activated potassium, respectively.</p>\",\"PeriodicalId\":9372,\"journal\":{\"name\":\"Bulletin of Mathematical Biology\",\"volume\":\"86 5\",\"pages\":\"46\"},\"PeriodicalIF\":2.0000,\"publicationDate\":\"2024-03-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10963524/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bulletin of Mathematical Biology\",\"FirstCategoryId\":\"100\",\"ListUrlMain\":\"https://doi.org/10.1007/s11538-024-01273-5\",\"RegionNum\":4,\"RegionCategory\":\"数学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bulletin of Mathematical Biology","FirstCategoryId":"100","ListUrlMain":"https://doi.org/10.1007/s11538-024-01273-5","RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOLOGY","Score":null,"Total":0}
Inferring Parameters of Pyramidal Neuron Excitability in Mouse Models of Alzheimer's Disease Using Biophysical Modeling and Deep Learning.
Alzheimer's disease (AD) is believed to occur when abnormal amounts of the proteins amyloid beta and tau aggregate in the brain, resulting in a progressive loss of neuronal function. Hippocampal neurons in transgenic mice with amyloidopathy or tauopathy exhibit altered intrinsic excitability properties. We used deep hybrid modeling (DeepHM), a recently developed parameter inference technique that combines deep learning with biophysical modeling, to map experimental data recorded from hippocampal CA1 neurons in transgenic AD mice and age-matched wildtype littermate controls to the parameter space of a conductance-based CA1 model. Although mechanistic modeling and machine learning methods are by themselves powerful tools for approximating biological systems and making accurate predictions from data, when used in isolation these approaches suffer from distinct shortcomings: model and parameter uncertainty limit mechanistic modeling, whereas machine learning methods disregard the underlying biophysical mechanisms. DeepHM addresses these shortcomings by using conditional generative adversarial networks to provide an inverse mapping of data to mechanistic models that identifies the distributions of mechanistic modeling parameters coherent to the data. Here, we demonstrated that DeepHM accurately infers parameter distributions of the conductance-based model on several test cases using synthetic data generated with complex underlying parameter structures. We then used DeepHM to estimate parameter distributions corresponding to the experimental data and infer which ion channels are altered in the Alzheimer's mouse models compared to their wildtype controls at 12 and 24 months. We found that the conductances most disrupted by tauopathy, amyloidopathy, and aging are delayed rectifier potassium, transient sodium, and hyperpolarization-activated potassium, respectively.
期刊介绍:
The Bulletin of Mathematical Biology, the official journal of the Society for Mathematical Biology, disseminates original research findings and other information relevant to the interface of biology and the mathematical sciences. Contributions should have relevance to both fields. In order to accommodate the broad scope of new developments, the journal accepts a variety of contributions, including:
Original research articles focused on new biological insights gained with the help of tools from the mathematical sciences or new mathematical tools and methods with demonstrated applicability to biological investigations
Research in mathematical biology education
Reviews
Commentaries
Perspectives, and contributions that discuss issues important to the profession
All contributions are peer-reviewed.