TY - JOUR
T1 - Deep brain stimulation of hypothalamus for narcolepsy-cataplexy in mice
AU - Rogers, Anna A.
AU - Aiani, Lauren M.
AU - Blanpain, Lou T.
AU - Yuxian, Sun
AU - Moore, Renee
AU - Willie, Jon T.
N1 - Publisher Copyright:
© 2020
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Background: Narcolepsy type 1 (NT1, narcolepsy with cataplexy) is a disabling neurological disorder caused by loss of excitatory orexin neurons from the hypothalamus and is characterized by decreased motivation, sleep-wake fragmentation, intrusion of rapid-eye-movement sleep (REMS) during wake, and abrupt loss of muscle tone, called cataplexy, in response to sudden emotions. Objective: We investigated whether subcortical stimulation, analogous to clinical deep brain stimulation (DBS), would ameliorate NT1 using a validated transgenic mouse model with postnatal orexin neuron degeneration. Methods: Using implanted electrodes in freely behaving mice, the immediate and prolonged effects of DBS were determined upon behavior using continuous video-electroencephalogram-electromyogram (video/EEG/EMG) and locomotor activity, and neural activation in brain sections, using immunohistochemical labeling of the immediate early gene product c-Fos. Results: Brief 10-s stimulation to the region of the lateral hypothalamus and zona incerta (LH/ZI) dose-responsively reversed established sleep and cataplexy episodes without negative sequelae. Continuous 3-h stimulation increased ambulation, improved sleep-wake consolidation, and ameliorated cataplexy. Brain c-Fos from mice sacrificed after 90 min of DBS revealed dose-responsive neural activation within wake-active nuclei of the basal forebrain, hypothalamus, thalamus, and ventral midbrain. Conclusion: Acute and continuous LH/ZI DBS enhanced behavioral state control in a mouse model of NT1, supporting the feasibility of clinical DBS for NT1 and other sleep-wake disorders.
AB - Background: Narcolepsy type 1 (NT1, narcolepsy with cataplexy) is a disabling neurological disorder caused by loss of excitatory orexin neurons from the hypothalamus and is characterized by decreased motivation, sleep-wake fragmentation, intrusion of rapid-eye-movement sleep (REMS) during wake, and abrupt loss of muscle tone, called cataplexy, in response to sudden emotions. Objective: We investigated whether subcortical stimulation, analogous to clinical deep brain stimulation (DBS), would ameliorate NT1 using a validated transgenic mouse model with postnatal orexin neuron degeneration. Methods: Using implanted electrodes in freely behaving mice, the immediate and prolonged effects of DBS were determined upon behavior using continuous video-electroencephalogram-electromyogram (video/EEG/EMG) and locomotor activity, and neural activation in brain sections, using immunohistochemical labeling of the immediate early gene product c-Fos. Results: Brief 10-s stimulation to the region of the lateral hypothalamus and zona incerta (LH/ZI) dose-responsively reversed established sleep and cataplexy episodes without negative sequelae. Continuous 3-h stimulation increased ambulation, improved sleep-wake consolidation, and ameliorated cataplexy. Brain c-Fos from mice sacrificed after 90 min of DBS revealed dose-responsive neural activation within wake-active nuclei of the basal forebrain, hypothalamus, thalamus, and ventral midbrain. Conclusion: Acute and continuous LH/ZI DBS enhanced behavioral state control in a mouse model of NT1, supporting the feasibility of clinical DBS for NT1 and other sleep-wake disorders.
KW - Arousal
KW - Cataplexy
KW - Deep brain stimulation
KW - Hypocretin
KW - Lateral hypothalamus
KW - Narcolepsy
KW - Orexin
KW - Sleep disorder
KW - Subcortical stimulation
KW - Zona incerta
UR - https://www.scopus.com/pages/publications/85087031049
U2 - 10.1016/j.brs.2020.04.006
DO - 10.1016/j.brs.2020.04.006
M3 - Article
C2 - 32320748
AN - SCOPUS:85087031049
SN - 1935-861X
VL - 13
SP - 1305
EP - 1316
JO - Brain Stimulation
JF - Brain Stimulation
IS - 5
ER -