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Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function
Dopamine system dysfunction is commonly implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive to such pharmacological treatments and novel research paradigms investigating the circuit substra...
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/PMC9915739/ https://www.ncbi.nlm.nih.gov/pubmed/36778456 http://dx.doi.org/10.1101/2023.02.03.526987 |
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author | Mastwal, Surjeet Li, Xinjian Stowell, Rianne Manion, Matthew Zhang, Wenyu Kim, Nam-Shik Yoon, Ki-jun Song, Hongjun Ming, Guo-li Wang, Kuan Hong |
author_facet | Mastwal, Surjeet Li, Xinjian Stowell, Rianne Manion, Matthew Zhang, Wenyu Kim, Nam-Shik Yoon, Ki-jun Song, Hongjun Ming, Guo-li Wang, Kuan Hong |
author_sort | Mastwal, Surjeet |
collection | PubMed |
description | Dopamine system dysfunction is commonly implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive to such pharmacological treatments and novel research paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in the Arc or DISC1 genes to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but not Arc mutant mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits in DISC1 mutant mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders. |
format | Online Article Text |
id | pubmed-9915739 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-99157392023-02-11 Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function Mastwal, Surjeet Li, Xinjian Stowell, Rianne Manion, Matthew Zhang, Wenyu Kim, Nam-Shik Yoon, Ki-jun Song, Hongjun Ming, Guo-li Wang, Kuan Hong bioRxiv Article Dopamine system dysfunction is commonly implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive to such pharmacological treatments and novel research paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in the Arc or DISC1 genes to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but not Arc mutant mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits in DISC1 mutant mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders. Cold Spring Harbor Laboratory 2023-07-12 /pmc/articles/PMC9915739/ /pubmed/36778456 http://dx.doi.org/10.1101/2023.02.03.526987 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. |
spellingShingle | Article Mastwal, Surjeet Li, Xinjian Stowell, Rianne Manion, Matthew Zhang, Wenyu Kim, Nam-Shik Yoon, Ki-jun Song, Hongjun Ming, Guo-li Wang, Kuan Hong Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function |
title | Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function |
title_full | Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function |
title_fullStr | Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function |
title_full_unstemmed | Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function |
title_short | Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function |
title_sort | adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915739/ https://www.ncbi.nlm.nih.gov/pubmed/36778456 http://dx.doi.org/10.1101/2023.02.03.526987 |
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