Project Details
Abstract
Parkinson’s disease (PD) is one of the most prevalent movement disorder caused by
degeneration of the midbrain dopaminergic neurons. The dopaminergic input to the striatum
and the subthalamic nucleus (STN) is therefore decreased, apparently resulting in significant
derangements in the relevant motor-planning networks. STN neurons could discharge in the
singe-spike or the burst modes. A significant increase in STN burst discharges has been
unequivocally observed in dopamine-deprived conditions such as PD. Recently, we
demonstrated that the increase in burst discharges of subthalamic neurons has a direct causal
relation with parkinsonian symptoms, and that alterations of membrane potential could switch
the discharge pattern of subthalamic neurons between the singe spikes and the pathogenic
bursts. In theory, the membrane potential and the firing pattern of a neuron would be
influenced by the intrinsic membrane properties of the cell and the sum of excitatory and
inhibitory synaptic inputs. Dopamine and other neuromodulators have been reported to
affect the intrinsic membrane properties of STN by modulation of different kinds of ion
channels. However, the synaptic influences on the subthalamic pathogenic discharges
remain largely unclear. Subthalamic neurons receive direct excitatory and inhibitory
synaptic inputs from the cortex and the external segment of the globus pallidus (GPe),
respectively. We hypothesize that the GABAergic inputs from GPe probably constitute the
major external hyperpolarizing drive for the subthalamic neurons and may therefore shift the
firing mode from tonic firings to (rhythmic or semirhythmic) bursts. On the other hand, the
cortico-subthalamic glutamatergic projection presumably may provide either a phasic
depolarizing force to start a discharge (in single-spike or burst mode) or a tonic depolarizing
force to make the neuron favor single-spike discharges upon subsequent phasic stimulation.
We would therefore propose to test these hypotheses and study the contributions of
cortico-subthalamic and pallido-subthalamic synaptic inputs to subthalamic discharges in
detail. We will characterize the basic properties, such as the strength and short-term
plasticity, of cortico-subthalamic and pallido-subthalamic synaptic transmission in acute
mouse brain slices. The computation of the excitatory and inhibitory synaptic inputs over
multiple temporal and spatial scales will be investigated. Their consequences in the coding
of electrical signals such as discharge patterns and timing will be documented, and possible
effects on the physiological and pathophysiological information processing in the relevant
networks will be discussed. We will also explore the neuromodulatory effects of dopamine,
norepinephrine, serotonin, and acetylcholine (all of which are known to have innervations
onto the STN neurons) on the synaptic transmission and plasticity in the cortico-subthalamic
and pallido-subthalamic pathways. Moreover, the influences of
cortico-subthalamic and
pallido-subthalamic synaptic information on the subthalamic pathogenic discharges will be
verified with experimentally mimicked parkinsonian state both in vivo and in vitro. With
the execution of this proposal, we shall have more in-depth understandings of the critical
cortical and pallidal synaptic drives that determine subthalamic discharge outputs, and thus
would be able to elucidate more fundamental physiological as well as pathophysiological
rationales underlying the operation of the motor-planning networks in the normal and
parkinsonian mammalian brain.
Project IDs
Project ID:PA10501-1098
External Project ID:MOST103-2311-B182-001-MY3
External Project ID:MOST103-2311-B182-001-MY3
Status | Finished |
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Effective start/end date | 01/08/16 → 31/07/17 |
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