Deep brain stimulation of hypothalamus for narcolepsy-cataplexy in mice

Abstract

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) doseresponsively 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.

Chemogenetic modulation of histaminergic neurons in the tuberomamillary nucleus alters territorial aggression and wakefulness

“…Three weeks after microinjection, open field and resident–intruder tests were performed as described (“ Behavioural experiments ”). After the resident–intruder test, all mice were implanted with a head mount and electrodes (E363/76//NS/SPC, P1 Technologies, Manhattan Beach, CA) for EEG and electromyogram (EMG) recordings 55 . The EEG electrodes were inserted by threading through stainless steel screws while EMG electrodes were inserted directly into the neck extensor muscles.…”

Hypothalamic deep brain stimulation as a strategy to manage anxiety disorders

“…In the past century the deep brain stimulation (DBS) method was shown to be an important modality of treatment in various neuropsychiatric disorders such as depression, obsessive-compulsive disorders, movement disorders, obesity, and narcolepsy ( 9 – 13 ). Clinical DBS involves programmable electrical stimulation through an electrode implanted at a specific target in the brain ( 14 ).…”

Chemogenetic modulation of histaminergic neurons in the tuberomammillary nucleus alters territorial aggression and wakefulness

“…2.5). After the resident-intruder test, all mice were implanted with a head mount and electrodes (E363/76//NS/SPC, P1 Technologies, Manhattan Beach, CA) for EEG and electromyogram (EMG) recordings 53 . The EEG electrodes were inserted by threading through stainless steel screws while EMG electrodes were inserted directly into the neck extensor muscles.…”