High-frequency stimulation of the subthalamic nucleus induces a sustained inhibition of serotonergic system via loss of cell phenotype

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a standard treatment for Parkinson’s disease (PD). However, in a considerable number of patients debilitating psychiatric side-effects occur. Recent research has revealed that external stimuli can alter the neurotransmitters’ h...

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Bibliographic Details
Published in:	Scientific reports Vol. 12; no. 1; p. 14011
Main Authors:	Alosaimi, Faisal, Temel, Yasin, Hescham, Sarah, Witzig, Victoria S., Almasabi, Faris, Tan, Sonny K. H., Jahanshahi, Ali
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 17-08-2022 Nature Publishing Group Nature Portfolio
Subjects:	631/378/1689 631/378/1697 631/378/3920 Calcium Deep brain stimulation Dorsal raphe nucleus Electrical stimuli External stimuli Genotype & phenotype Homeostasis Humanities and Social Sciences Movement disorders MPTP multidisciplinary Neurodegenerative diseases Neurotransmitters Parkinson's disease Phenotypes Photometry Raphe nuclei Science Science (multidisciplinary) Serotonin Solitary tract nucleus Subthalamic nucleus Transgenic mice Tryptophan Tryptophan hydroxylase
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Summary:	Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a standard treatment for Parkinson’s disease (PD). However, in a considerable number of patients debilitating psychiatric side-effects occur. Recent research has revealed that external stimuli can alter the neurotransmitters’ homeostasis in neurons, which is known as “neurotransmitter respecification”. Herein, we addressed if neurotransmitter respecification could be a mechanism by which DBS suppresses the serotonergic function in the dorsal raphe nucleus (DRN) leading to mood changes. We infused transgenic 5-HT-Cre (ePET-Cre) mice with AAV viruses to achieve targeted expression of eYFP and the genetically encoded calcium indicator GCaMP6s in the DRN prior to methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Mice received bilateral DBS electrodes in the STN and an optic fiber in the DRN for calcium photometry. MPTP-treated mice demonstrated behavioral and histological PD phenotype, whereas all STN-DBS animals exhibited an increased immobility time in the forced swim test, reduced calcium activity, and loss of tryptophan hydroxylase-2 expression in the DRN. Given the prominent role of calcium transients in mediating neurotransmitter respecification, these results suggest a loss of serotonergic phenotype in the DRN following STN-DBS. These findings indicate that loss of serotonergic cell phenotype may underlie the unwanted depressive symptoms following STN-DBS.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-022-18294-6