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Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons
The homeostatic regulation of neuronal activity is essential for robust computation; key set-points, such as firing rate, are actively stabilized to compensate for perturbations. From this perspective, the disruption of brain function central to neurodegenerative disease should reflect impairments o...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10508737/ https://www.ncbi.nlm.nih.gov/pubmed/37732214 http://dx.doi.org/10.1101/2023.09.01.555947 |
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author | McGregor, James N. Farris, Clayton A. Ensley, Sahara Schneider, Aidan Wang, Chao Liu, Yuqi Tu, Jianhong Elmore, Halla Ronayne, Keenan D. Wessel, Ralf Dyer, Eva L. Bhaskaran-Nair, Kiran Holtzman, David M. Hengen, Keith B. |
author_facet | McGregor, James N. Farris, Clayton A. Ensley, Sahara Schneider, Aidan Wang, Chao Liu, Yuqi Tu, Jianhong Elmore, Halla Ronayne, Keenan D. Wessel, Ralf Dyer, Eva L. Bhaskaran-Nair, Kiran Holtzman, David M. Hengen, Keith B. |
author_sort | McGregor, James N. |
collection | PubMed |
description | The homeostatic regulation of neuronal activity is essential for robust computation; key set-points, such as firing rate, are actively stabilized to compensate for perturbations. From this perspective, the disruption of brain function central to neurodegenerative disease should reflect impairments of computationally essential set-points. Despite connecting neurodegeneration to functional outcomes, the impact of disease on set-points in neuronal activity is unknown. Here we present a comprehensive, theory-driven investigation of the effects of tau-mediated neurodegeneration on homeostatic set-points in neuronal activity. In a mouse model of tauopathy, we examine 27,000 hours of hippocampal recordings during free behavior throughout disease progression. Contrary to our initial hypothesis that tauopathy would impact set-points in spike rate and variance, we found that cell-level set-points are resilient to even the latest stages of disease. Instead, we find that tauopathy disrupts neuronal activity at the network-level, which we quantify using both pairwise measures of neuron interactions as well as measurement of the network’s nearness to criticality, an ideal computational regime that is known to be a homeostatic set-point. We find that shifts in network criticality 1) track with symptoms, 2) predict underlying anatomical and molecular pathology, 3) occur in a sleep/wake dependent manner, and 4) can be used to reliably classify an animal’s genotype. Our data suggest that the critical set-point is intact, but that homeostatic machinery is progressively incapable of stabilizing hippocampal networks, particularly during waking. This work illustrates how neurodegenerative processes can impact the computational capacity of neurobiological systems, and suggest an important connection between molecular pathology, circuit function, and animal behavior. |
format | Online Article Text |
id | pubmed-10508737 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-105087372023-09-20 Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons McGregor, James N. Farris, Clayton A. Ensley, Sahara Schneider, Aidan Wang, Chao Liu, Yuqi Tu, Jianhong Elmore, Halla Ronayne, Keenan D. Wessel, Ralf Dyer, Eva L. Bhaskaran-Nair, Kiran Holtzman, David M. Hengen, Keith B. bioRxiv Article The homeostatic regulation of neuronal activity is essential for robust computation; key set-points, such as firing rate, are actively stabilized to compensate for perturbations. From this perspective, the disruption of brain function central to neurodegenerative disease should reflect impairments of computationally essential set-points. Despite connecting neurodegeneration to functional outcomes, the impact of disease on set-points in neuronal activity is unknown. Here we present a comprehensive, theory-driven investigation of the effects of tau-mediated neurodegeneration on homeostatic set-points in neuronal activity. In a mouse model of tauopathy, we examine 27,000 hours of hippocampal recordings during free behavior throughout disease progression. Contrary to our initial hypothesis that tauopathy would impact set-points in spike rate and variance, we found that cell-level set-points are resilient to even the latest stages of disease. Instead, we find that tauopathy disrupts neuronal activity at the network-level, which we quantify using both pairwise measures of neuron interactions as well as measurement of the network’s nearness to criticality, an ideal computational regime that is known to be a homeostatic set-point. We find that shifts in network criticality 1) track with symptoms, 2) predict underlying anatomical and molecular pathology, 3) occur in a sleep/wake dependent manner, and 4) can be used to reliably classify an animal’s genotype. Our data suggest that the critical set-point is intact, but that homeostatic machinery is progressively incapable of stabilizing hippocampal networks, particularly during waking. This work illustrates how neurodegenerative processes can impact the computational capacity of neurobiological systems, and suggest an important connection between molecular pathology, circuit function, and animal behavior. Cold Spring Harbor Laboratory 2023-09-06 /pmc/articles/PMC10508737/ /pubmed/37732214 http://dx.doi.org/10.1101/2023.09.01.555947 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article McGregor, James N. Farris, Clayton A. Ensley, Sahara Schneider, Aidan Wang, Chao Liu, Yuqi Tu, Jianhong Elmore, Halla Ronayne, Keenan D. Wessel, Ralf Dyer, Eva L. Bhaskaran-Nair, Kiran Holtzman, David M. Hengen, Keith B. Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons |
title | Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons |
title_full | Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons |
title_fullStr | Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons |
title_full_unstemmed | Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons |
title_short | Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons |
title_sort | tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10508737/ https://www.ncbi.nlm.nih.gov/pubmed/37732214 http://dx.doi.org/10.1101/2023.09.01.555947 |
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