Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L‐DOPA in a mouse model of Parkinson's disease

Background and Purpose: L-DOPA-induced dyskinesia (LID) remains a major complication of L-DOPA therapy in Parkinson's disease. LID is believed to result from inhibition of substantia nigra reticulata (SNr) neurons by GABAergic striatal projection neurons that become supersensitive to dopamine receptor stimulation after severe nigrostriatal degeneration. Here, we asked if stimulation of direct medium spiny neuron (dMSN) GABAergic terminals at the SNr can produce a full dyskinetic state similar to that induced by L-DOPA. Experimental Approach: Adult C57BL6 mice were lesioned with 6-hydroxydopamine in the medial forebrain bundle. Channel rhodopsin was expressed in striatonigral terminals by ipsilateral striatal injection of adeno-associated viral particles under the CaMKII promoter. Optic fibres were implanted on the ipsilateral SNr. Optical stimulation was performed before and 24 hr after three daily doses of L-DOPA at subthreshold and suprathreshold dyskinetic doses. We also examined the combined effect of light stimulation and an acute L-DOPA challenge. Key Results: Optostimulation of striatonigral terminals inhibited SNr neurons and induced all dyskinesia subtypes (optostimulation-induced dyskinesia [OID]) in 6-hydroxydopamine animals, but not in sham-lesioned animals. Additionally, chronic L-DOPA administration sensitised dyskinetic responses to striatonigral terminal optostimulation, as OIDs were more severe 24 hr after L-DOPA administration. Furthermore, L-DOPA combined with light stimulation did not result in higher dyskinesia scores than OID alone, suggesting that optostimulation has a masking effect on LID. Conclusion and Implications: This work suggests that striatonigral inhibition of basal ganglia output (SNr) is a decisive mechanism mediating LID and identifies the SNr as a target for managing LID.Fil: Keifman, Ettel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Consejo Superior de Investigaciones Científicas; EspañaFil: Ruiz De Diego, Irene. Consejo Superior de Investigaciones Científicas; EspañaFil: Pafundo, Diego Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Paz, Rodrigo Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Solís, Oscar. Consejo Superior de Investigaciones Científicas; EspañaFil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Moratalla, Rosario. Consejo Superior de Investigaciones Científicas; Españ

Modelling of electrical power demand characteristics for composite machine shopps

none2Stochastic models of both the active and reactive electrical power demand of composite industrial plants are obtained from a detailed analysis of the use of individual pieces of equipment. Since the reactive load patterns differ significantly from the active ones, two distinct models should be identified. The load-duration curves are then determined and, in particular, the probability distributions of maximum 15 min average demands are derived. In this way, energy consumption, peak power demand and the optimal power factor correction may be found. The methodology has been successfully applied to the study of a machine-shop comprising more than 200 machines.noneR. Caldon;U. ViaroCaldon, Roberto; U., Viar

Simulazione del carico elettrico di utenze industriali

Viene illustrato un metodo probabilistico per la stima delle ca\uacratteristiche delle richieste di potenza elettrica di utenze industriali con carico ripartito su pi\uf9 macchine. Si mostra come il metodo possa essere im\uacpiegato per valutare i costi dell'energia elettrica corrispondenti a regimi alternativi di utilizzo delle apparecchiature ed in particolare ottenere le indicazioni necessarie al contenimento dei picchi di potenza nelle fasce orarie di punta ed alla migliore correzione del fattore di potenza. Vengono indicati i risultati ottenuti dall'applicazione del metodo ad un impianto in esercizio

Previsione delle curve di massimo carico del sistema elettrico italiano in rapporto ai grandi settori di utenza

La carretta programmazione di nuovi impianti di generazione e di accumula e la determinazione della riserva su cui fare assegnamento rendano di par ticolare importanza l'analisi e la previsione delle curve di carico nei giorni di punta massima annuale, che presentano generalmente anche la maggia re escursione fra i valori massimo e minimo della domanda di potenza. Per individuare possibili effetti di variazioni della struttura tariffaria è inaltre opportuno che tale previsione consideri pure i contributi delle principali categorie di utenza (industria e settori domestico e terziario) alla formazione della pò tenza totale richiesta

SHORT-TERM FORELIMB MOTOR CORTEX (FM1) PLASTICITY AFTER INACTIVATION OF THE CORRESPONDING CORTEX IN THE OPPOSITE HEMISPHERE

Aim: In the primary motor cortex (M1) of adult mammals, electrophysiological changes which are behind the interhemispheric diaschisis remain unclear. In the present study we aimed to demonstrate rapid changes in the M1 forelimb movement representation as the effect of inactivation of the homotopic cortical region. Methods: Five adult rats underwent three injections of Lidocaine (L-group) within the FM1 of one hemisphere (10μL delivered through a Hamilton syringe at a depth of 1mm from the pial surface). After injections, rats underwent intracortical microstimulation (ICMS) for M1 mapping in both hemispheres. Under ketamine anaesthesia (50mg\Kg i.p.), ICMS (30ms trains of 0.2ms cathodal pulses at 300Hz, stimulation current ≤ 60μA ) was delivered at a depth of 1.5mm from the pial surface using glass-insulated tungsten microelettrodes (impedance:0.6-1.2 ΩM). Other 5 rats were used as Sham-group and 5 rats were used as Control-group. Results: The cortical area that elicits forelimb movement was analyzed in the hemisphere contralateral to lidocaine injections. We observed significant increase in the forelimb area in the L-group as compared to Sham and Control- group (P<0.005, ANOVA). The forelimb area in L-group expanded in the medial direction overlapping the lateral portion of the vibrissa representation. In this part of M1, the ICMS evoked forelimb and vibrissa movement at the same current threshold. These dual movement sites increase significantly in L-group rats relative to Control and Sham- group of rats (P<0.001, ANOVA). Conclusions: Our results suggest that FM1 inactivation leads to shaping and size changes of forelimb movement representation in the contralateral hemisphere. We conclude that the loss of the inhibitory interhemispheric input induces the loss of the sharp border between vibrissa and forelimb representation

Suppression of activity in the forelimb motor cortex temporarily enlarges forelimb representation in the homotopic cortex in adult rats.

After forelimb motor cortex (FMC) damage, the unaffected homotopic motor cortex showed plastic changes. The present experiments were designed to clarify the electrophysiological nature of these interhemispheric effects. To this end the output reorganization of the forelimb motor cortex (FMC) was investigated after homotopic area activity was suppressed in adult rats. FMC output was compared after Lidocaine-induced inactivation (L group) or Quinolinic acid-induced lesion (Q-group) of the contralateral homotopic cortex. In the Q-group of animals, FMC mapping was performed, respectively, three days (Q3D group) and two weeks (Q2W group) after cortical lesion. In each animal, FMC output was assessed by mapping movements induced by intracortical microstimulation (ICMS) in both hemispheres (hemisphere Ipsilateral and Contralateral to injections). Findings demonstrated that in the L-group, the size of forelimb representation was 42.2% higher than in the Control group (P<0.0001). The percentage of dual forelimb-vibrissa movement sites significantly increased over the Controls (P<0.0005). The dual-movement sites occupied a strip of the map along the rostro-caudal border between the forelimb and vibrissa representation. This form of interhemispheric diaschisis had completely reversed, with the recovery of the baseline map, 3 days after the lesion in the contalatreral FMC. This restored forelimb map showed no ICMS-induced changes 2 weeks after the lesion in the contralateral FMC. The present results suggest that the FMCs in the two hemispheres interact continuously through predominantly inhibitory influences that preserve the forelimb representation and the border vs. vibrissa representation

Progressive motor cortex functional reorganization following 6-hydroxydopamine lesioning in rats

Many studies have attempted to correlate changes of motor cortex activity with progression of Parkinson’s disease, although results have been controversial. In the present study we haves used intracortical microstimulation (ICMS) combined with behavioral testing in 6-hydroxydopamine hemilesioned rats to evaluate the impact of dopamine depletion on movement representations in primary motor cortex (M1) and motor behavior. ICMS allows for motor-effective stimulation of corticofugal neurons in motor areas, so to obtain topographic movements representations based on movement type, area size and threshold currents. Rats received unilateral 6-hydroxydopamine in the nigrostriatal bundle causing motor impairment. Changes in M1 were time-dependent and bilateral, although stronger in the lesioned than intact hemisphere. Representation size and threshold current were maximally impaired at 15 days, although inhibition was still detectable at 60-120 days after lesion. Proximal forelimb movements emerged at the expense of the distal ones. Movement lateralization was lost mainly at 30 days after lesion. Systemic L-dopa partially attenuated motor impairment and cortical changes, particularly in the caudal forelimb area, and completely rescued distal forelimb movements. Local application of the GABAA antagonist bicuculline partially restored cortical changes, particularly in the rostral forelimb area. The local anaesthetic lidocaine injected in the M1 of the intact hemisphere restored movement lateralization in the lesioned hemisphere. This study provides evidence for motor cortex remodelling after unilateral dopamine denervation, suggesting that cortical changes were associated with dopamine denervation, pathogenic intracortical GABA inhibition and altered interhemispheric activity