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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...

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Autores principales: Mastwal, Surjeet, Li, Xinjian, Stowell, Rianne, Manion, Matthew, Zhang, Wenyu, Kim, Nam-Shik, Yoon, Ki-jun, Song, Hongjun, Ming, Guo-li, Wang, Kuan Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
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.
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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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