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The subthalamic nucleus (STN) is an effective therapeutic target for deep brain stimulation (DBS) for Parkinson's disease (PD) and histamine level is elevated in the basal ganglia in PD patients. However, the endogenous histaminergic modulation on STN neuronal activities and the neuronal mechanism underlying STN-DBS are unknown. Here we report that STN neuronal firing patterns are more crucial than firing rates for motor control. Histamine excited STN neurons, but paradoxically ameliorated parkinsonian motor deficits, which we attributed to regularizing firing patterns of STN neurons via HCN2 channel coupled to H2 receptor. Intriguingly, DBS increased histamine release in the STN and regularized STN neuronal firing patterns under parkinsonian conditions. HCN2 contributed to the DBS-induced regularization of neuronal firing patterns, suppression of excessive beta oscillations, and alleviation of motor deficits in PD. The results reveal an indispensable role for regularizing STN neuronal firing patterns in amelioration of parkinsonian motor dysfunction and a functional compensation for histamine in parkinsonian basal ganglia circuitry. The findings provide insights into mechanisms of STN-DBS as well as potential therapeutic targets and STN-DBS strategies for PD.
This article was published in the following journal.
Name: The Journal of clinical investigation
The subthalamic nucleus (STN) possesses microcircuits distinguished by subtypes of nicotinic acetylcholine receptors (nAChRs). Although dysfunction of the STN is well-known in Parkinson's disease, the...
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Networks of nerve cells that control the firing patterns of MOTOR NEURONS to produce rhythmic movements such as MASTICATION; WALKING; SWIMMING; RESPIRATION; and PERISTALSIS.
Lens-shaped structure on the inner aspect of the internal capsule. The subthalamic nucleus and pathways traversing this region are concerned with the integration of somatic motor function. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p52)
Motor neurons which activate the contractile regions of intrafusal SKELETAL MUSCLE FIBERS, thus adjusting the sensitivity of the MUSCLE SPINDLES to stretch. Gamma motor neurons may be "static" or "dynamic" according to which aspect of responsiveness (or which fiber types) they regulate. The alpha and gamma motor neurons are often activated together (alpha gamma coactivation) which allows the spindles to contribute to the control of movement trajectories despite changes in muscle length.
A group of disorders which feature impaired motor control characterized by bradykinesia, MUSCLE RIGIDITY; TREMOR; and postural instability. Parkinsonian diseases are generally divided into primary parkinsonism (see PARKINSON DISEASE), secondary parkinsonism (see PARKINSON DISEASE, SECONDARY) and inherited forms. These conditions are associated with dysfunction of dopaminergic or closely related motor integration neuronal pathways in the BASAL GANGLIA.
A disorder characterized by recurrent localized paroxysmal discharges of cerebral neurons that give rise to seizures that have motor manifestations. The majority of partial motor seizures originate in the FRONTAL LOBE (see also EPILEPSY, FRONTAL LOBE). Motor seizures may manifest as tonic or clonic movements involving the face, one limb or one side of the body. A variety of more complex patterns of movement, including abnormal posturing of extremities, may also occur.
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