Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
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
_version_ 1785107601699110912
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
work_keys_str_mv AT mcgregorjamesn tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT farrisclaytona tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT ensleysahara tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT schneideraidan tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT wangchao tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT liuyuqi tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT tujianhong tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT elmorehalla tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT ronaynekeenand tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT wesselralf tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT dyereval tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT bhaskarannairkiran tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT holtzmandavidm tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons
AT hengenkeithb tauopathyseverelydisruptshomeostaticsetpointsinemergentneuraldynamicsbutnotintheactivityofindividualneurons