1,721,290 research outputs found
Targeting synapse dysfunction in Parkinson's disease
No full textParkinson's disease (PD) affects 1.2 million people in Europe[1]. Ten% of PD cases are due to genetic mutations and 90%
are idiopathic[2]. No neuroprotective therapy exists. Since synaptic dysfunction is a major contributor to the death of
dopamine (DA) neurons in PD[3,4], synapses can provide druggable targets for neuroprotection. The kainate receptor (KAR)
is a glutamate receptor expressed in many synapses including the glutamatergic synapse to nigral DA neurons[5,6].
Evidence suggests that KAR antagonism rescues disease features in a genetic model of juvenile PD[7] (see preliminary
data), raising the possibility that drugs acting on KAR may exert neuroprotective activity also in other PD forms. This project
will test whether KAR antagonism rescues DA neuron synaptopathy and viability in genetic and/or idiopathic PD. Since
ageing and PD share detrimental mechanisms[8,9], this project will also compare synaptopathy occurring in human DA
neurons during aging and PD
Truncated step response models for model predictive control
No full textA method for deriving truncated step response models for model predictive control (MPC) is derived and demonstrated. Truncated step response models can result in a dramatic reduction in the number of step response coefficients needed, and can therefore significantly reduce the computational load on the control system. The truncated models are derived in a way which attempts to minimize the robustness degradation caused by the modelling error introduced by truncation. The truncation of the step response model only affects the state estimation part of the MPC. The algorithm for finding the control move is not affected as long as the prediction horizon is kept smaller than the truncation time. © 1993
Striatal and nigral muscarinic type 1 and type 4 receptors modulate levodopa-induced dyskinesia and striato-nigral pathway activation in 6-hydroxydopamine hemilesioned rats
Full text linkAcetylcholine muscarinic receptors (mAChRs) contribute to both the facilitation and inhibition of levodopa-induced dyskinesia operated by striatal cholinergic interneurons, although the receptor subtypes involved remain elusive. Cholinergic afferents from the midbrain also innervate the substantia nigra reticulata, although the role of nigral mAChRs in levodopa-induced dyskinesia is unknown. Here, we investigate whether striatal and nigral M1 and/or M4 mAChRs modulate dyskinesia and the underlying striato-nigral GABAergic pathway activation in 6-hydroxydopamine hemilesioned rats. Reverse microdialysis allowed to deliver the mAChR antagonists telenzepine (M1 subtype preferring), PD-102807 and tropicamide (M4 subtype preferring), as well as the selective M4 mAChR positive allosteric modulator VU0152100 in striatum or substantia nigra, while levodopa was administered systemically. Dyskinetic movements were monitored along with nigral GABA (and glutamate) and striatal glutamate dialysate levels, taken as neurochemical correlates of striato-nigral pathway and cortico-basal ganglia-thalamo-cortical loop activation. We observed that intrastriatal telenzepine, PD-102807 and tropicamide alleviated dyskinesia and inhibited nigral GABA and striatal glutamate release. This was partially replicated by intrastriatal VU0152100. The M2 subtype preferring antagonist AFDX-116, used to elevate striatal acetylcholine levels, blocked the behavioral and neurochemical effects of PD-102807. Intranigral VU0152100 prevented levodopa-induced dyskinesia and its neurochemical correlates whereas PD-102807 was ineffective. These results suggest that striatal, likely postsynaptic, M1 mAChRs facilitate dyskinesia and striato-nigral pathway activation in vivo. Conversely, striatal M4 mAChRs can both facilitate and inhibit dyskinesia, possibly depending on their localization. Potentiation of striatal and nigral M4 mAChR transmission leads to powerful multilevel inhibition of striato-nigral pathway and attenuation of dyskinesia
COMPARISON OF INTERNAL MODEL CONTROL AND LINEAR QUADRATIC OPTIMAL-CONTROL FOR SISO SYSTEMS
No full textIn this paper internal model control (IMC) is formulated for general inputs and compared with linear quadratic (H-2) optimal control (LQOC) with a general (dynamic) input penalty weight. Analogies and differences between the two methods for robustness study are clearly pointed out. Both controllers can be expressed in terms of the same nominal controller and a robustness filter. The difference is that the LQOC filter depends also on process and disturbance parameters. As a consequence, performance may be different in general, even if in many cases quite similar results are obtained. The design for robustness is much more straightforward in IMC
Robust inferential control of multi-rate sampled-data systems
No full textA framework called generalized inferential control (GIC) is established for designing robust, linear inferential control systems for multi-rate sampled-data systems. Practical issues such as model/plant mismatch, constraints, and actuator/measurement failure tolerance are addressed rigorously in the GIC framework. Various H2-optimal design techniques such as linear quadratic Gaussian (LQG), model-predictive control (MPC), and internal model control (IMC) are discussed and extended in the context of GIC. In addition, a connection between MPC and IMC is established and a method for replacing th
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