Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease

Aside from the classical motor symptoms, Parkinson’s disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson’s. In this study, we hypothesize...

Full description

Bibliographic Details
Main Authors: Milos Stanojlovic, Jean Pierre Pallais, Catherine M. Kotz
Format: Article
Language:English
Published: MDPI AG 2021-01-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/22/2/795
_version_ 1797411469013286912
author Milos Stanojlovic
Jean Pierre Pallais
Catherine M. Kotz
author_facet Milos Stanojlovic
Jean Pierre Pallais
Catherine M. Kotz
author_sort Milos Stanojlovic
collection DOAJ
description Aside from the classical motor symptoms, Parkinson’s disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson’s. In this study, we hypothesized that Parkinson’s-disease-associated pathology affects orexin neurons and therefore impairs functions they regulate. To test this, we used a transgenic animal model of Parkinson’s, the A53T mouse. We measured body composition, exploratory locomotion, spontaneous physical activity, and energy expenditure. Further, we assessed alpha-synuclein accumulation, inflammation, and astrogliosis. Finally, we hypothesized that chemogenetic inhibition of orexin neurons would ameliorate observed impairments in the A53T mice. We showed that aging in A53T mice was accompanied by reductions in fat mass and increases in exploratory locomotion, spontaneous physical activity, and energy expenditure. We detected the presence of alpha-synuclein accumulations in orexin neurons, increased astrogliosis, and microglial activation. Moreover, loss of inhibitory pre-synaptic terminals and a reduced number of orexin cells were observed in A53T mice. As hypothesized, this chemogenetic intervention mitigated the behavioral disturbances induced by Parkinson’s disease pathology. This study implicates the involvement of orexin in early Parkinson’s-disease-associated impairment of hypothalamic-regulated physiological functions and highlights the importance of orexin neurons in Parkinson’s disease symptomology.
first_indexed 2024-03-09T04:46:31Z
format Article
id doaj.art-0b70479a6044444ea9d4280085a4a72e
institution Directory Open Access Journal
issn 1661-6596
1422-0067
language English
last_indexed 2024-03-09T04:46:31Z
publishDate 2021-01-01
publisher MDPI AG
record_format Article
series International Journal of Molecular Sciences
spelling doaj.art-0b70479a6044444ea9d4280085a4a72e2023-12-03T13:14:57ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-0122279510.3390/ijms22020795Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s DiseaseMilos Stanojlovic0Jean Pierre Pallais1Catherine M. Kotz2Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Bünteweg 17, 30559 Hannover, GermanyIntegrative Biology and Physiology, University of Minnesota, Minneapolis, 321 Church St SE, Minneapolis, MN 55455, USAIntegrative Biology and Physiology, University of Minnesota, Minneapolis, 321 Church St SE, Minneapolis, MN 55455, USAAside from the classical motor symptoms, Parkinson’s disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson’s. In this study, we hypothesized that Parkinson’s-disease-associated pathology affects orexin neurons and therefore impairs functions they regulate. To test this, we used a transgenic animal model of Parkinson’s, the A53T mouse. We measured body composition, exploratory locomotion, spontaneous physical activity, and energy expenditure. Further, we assessed alpha-synuclein accumulation, inflammation, and astrogliosis. Finally, we hypothesized that chemogenetic inhibition of orexin neurons would ameliorate observed impairments in the A53T mice. We showed that aging in A53T mice was accompanied by reductions in fat mass and increases in exploratory locomotion, spontaneous physical activity, and energy expenditure. We detected the presence of alpha-synuclein accumulations in orexin neurons, increased astrogliosis, and microglial activation. Moreover, loss of inhibitory pre-synaptic terminals and a reduced number of orexin cells were observed in A53T mice. As hypothesized, this chemogenetic intervention mitigated the behavioral disturbances induced by Parkinson’s disease pathology. This study implicates the involvement of orexin in early Parkinson’s-disease-associated impairment of hypothalamic-regulated physiological functions and highlights the importance of orexin neurons in Parkinson’s disease symptomology.https://www.mdpi.com/1422-0067/22/2/795Parkinson’s diseaseorexinneuromodulation
spellingShingle Milos Stanojlovic
Jean Pierre Pallais
Catherine M. Kotz
Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease
International Journal of Molecular Sciences
Parkinson’s disease
orexin
neuromodulation
title Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease
title_full Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease
title_fullStr Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease
title_full_unstemmed Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease
title_short Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease
title_sort inhibition of orexin hypocretin neurons ameliorates elevated physical activity and energy expenditure in the a53t mouse model of parkinson s disease
topic Parkinson’s disease
orexin
neuromodulation
url https://www.mdpi.com/1422-0067/22/2/795
work_keys_str_mv AT milosstanojlovic inhibitionoforexinhypocretinneuronsameliorateselevatedphysicalactivityandenergyexpenditureinthea53tmousemodelofparkinsonsdisease
AT jeanpierrepallais inhibitionoforexinhypocretinneuronsameliorateselevatedphysicalactivityandenergyexpenditureinthea53tmousemodelofparkinsonsdisease
AT catherinemkotz inhibitionoforexinhypocretinneuronsameliorateselevatedphysicalactivityandenergyexpenditureinthea53tmousemodelofparkinsonsdisease