Postsynaptic nigrostriatal dopamine receptors and their role in movement regulation

The article presents the hypothesis that nigrostriatal dopamine may regulate movement by modulation of tone and contraction in skeletal muscles through a concentration-dependent influence on the postsynaptic D1 and D2 receptors on the follow manner: nigrostriatal axons innervate both receptor types within the striatal locus somatotopically responsible for motor control in agonist/antagonist muscle pair around a given joint. D1 receptors interact with lower and D2 receptors with higher dopamine concentrations. Synaptic dopamine concentration increases immediately before movement starts. We hypothesize that increasing dopamine concentrations stimulate first the D1 receptors and reduce muscle tone in the antagonist muscle and than stimulate D2 receptors and induce contraction in the agonist muscle. The preceded muscle tone reduction in the antagonist muscle eases the efficient contraction of the agonist. Our hypothesis is applicable for an explanation of physiological movement regulation, different forms of movement pathology and therapeutic drug effects. Further, this hypothesis provides a theoretical basis for experimental investigation of dopaminergic motor control and development of new strategies for treatment of movement disorders

Arbetsmiljöarbete och effekter en kunskapsöversikt

Work environment improvements and effects a literature review This report addresses the question 'Do work-environment improvements have any effects?' The aim was to produce a summary of knowledge that includes the methodological problems of measuring and evaluating effects, as well as literature reviews of effects from work environment improvement efforts on musculoskeletal health, health promotion, and economy. Results show that published literature reviews do not give unambiguous support for health benefits of interventions against musculoskeletal problems, when only studies using natural science criteria with experimental or quasi-experimental design are included. There are, on the other hand, many case studies in the so called 'grey' literature that report positive effects. Further, results show that health promotion interventions, and especially physical activity, have a positive effect on low back pain. Workplace interventions to increase physical activity are effective and lead to increased physical activity amongst employees. More studies are needed, however, at the organisational level. There is some support for the profitability of work-environment investments at the organisational level; even though there are few studies and methodological problems. The review also indicates that the financial benefits come mostly from quality and productivity improvements and, to a lesser extent from reductions in costs related to sickness absenteeism. While more recent literature reviews of the effects of health promotion interventions seem to show a stronger effect than older studies, comparisons of older versus more recent studies of interventions against musculoskeletal problems give a more ambiguous picture. Often, the focus of these reviews is on study design with less priority on the quality of the interventions themselves. Multifactorial interventions are particularly difficult to evaluate. At the same time, many studies and research reviews emphasise the need for multifactorial approaches as necessary for successful intervention. Inclusion criteria in literature reviews that only consider experimental designs in organisational interventions exclude studies with good interventions that can't be evaluated with traditional experimental methods. Difficulties in proving the effectiveness of interventions depends on views of what constitutes good scientific quality in the studies. This shows a need for a critical examination of the assumptions used for knowledge generation in this area. Conclusions are that work-environment improvement efforts have effects that are clear in some cases but are difficult to show in others. Effect evaluation poses large methodological challenges. These difficulties are considered to be an important cause of the lack of clear evidence, especially in the area of interventions against musculoskeletal problems. There is a need for new non-experimental research strategies that are suited to today's complex systems and an increased focus on practical, well conducted multifactorial interventions. Key words: Intervention, health promotion, ergonomics, economy, methodology, researchDetta arbete har inriktats mot frågeställningen om arbetsmiljöarbete har några effekter. Syftet har varit att göra en kunskapssammanställning som omfattar en beskrivning och problematisering av metodiken att mäta eller utvärdera effekter, samt litteraturöversikter om vad arbetsmiljöarbete har för belastningsergonomiska, hälsofrämjande och ekonomiska effekter. Resultaten visar att publicerade litteraturöversikter inte ger säkra belägg för att belastningsergonomiska interventioner har effekter på besvärsförekomst, i de fall enbart studier inkluderats utifrån naturvetenskapliga kriterier med krav på experimentell eller kvasi-experimentell metodik. Däremot finns ett flertal fallstudier och så kallad grå litteratur som i högre grad rapporterar positiva effekter. Vidare framgår det att hälsofrämjande interventioner, och speciellt fysisk aktivitet har en positiv effekt på ländryggsbesvär. Interventioner på arbetsplatser för att öka den fysiska aktiviteten är effektiva och ger en ökad fysisk aktivitet hos arbetstagarna. Fler studier behövs emellertid på organisationsnivå. Det finns visst belägg för att arbetsmiljösatsningar ofta är lönsamma på organisationsnivå, även om studierna är få och uppvisar metodbrister. Det finns flera indikationer på att lönsamheten i huvudsak härrör från produktivitets- och kvalitetsförbättringar, och i mindre grad från minskade frånvarokostnader. Nya litteraturöversikter om hälsofrämjande interventioner tycks uppvisa starkare effekter än gamla, medan jämförelser mellan äldre och nyare studier om belastningsergonomiska interventioner ger en mer mångtydig bild. Ofta ligger fokus på utvärderingsdesign, samtidigt som kvaliteten hos interventionens genomförande och utformning i sig inte ges samma prioritet. Interventioner med multifaktoriella insatser blir synnerligen svåra och komplexa att utvärdera, samtidigt som det i många studier och forskningsöversikter betonas att en förutsättning för framgång i förändringsarbetet är att man arbetar med en mångfald av insatser. Inklusionskriterier i litteraturöversikter som förutsätter experimentella upplägg i organisationsinterventioner selekterar bort studier med goda interventioner som inte kan utvärderas med traditionella metoder. Svårigheten att identifiera effekter av interventioner bedöms bero på synen om vad som utmärker god vetenskaplig kvalitet hos studier. Detta visar på behovet att närmare kritiskt granska förutsättningarna för kunskapsbildning inom området. Slutsatsen är att arbetsmiljöarbete i vissa fall har effekter men att det i andra fall är svårt att påvisa effekter. Effektutvärdering innebär stora metodologiska svårigheter. Dessa svårigheter bedöms vara en viktig orsak till bristen på underlag, speciellt inom det belastningsergonomiska området. Det finns ett stort behov av nya icke experimentella undersökningsstrategier som är anpassade till dagens komplexa system, såväl som ett behov av starkare fokus på praktiskt väl genomförda multifaktoriella interventioner

Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of huntington's disease

Predictive genetic testing for Huntington's disease (HD) has revealed early cognitive deficits in asymptomatic gene carriers, such as altered working memory, executive function and impaired recognition memory. The perirhinal cortex processes aspects of recognition memory and the underlying mechanism is believed to be long-term depression (LTD) of excitatory neurotransmission, the converse of long-term potentiation (LTP). We have used the R6/1 mouse model of HD to assess synaptic plasticity in the perirhinal cortex. We report here a progressive derailment of both LTD and short-term plasticity at perirhinal synapses. Layer II/III neurones gradually lose their ability to support LTD, show early nuclear localization of mutant huntingtin and display a progressive loss of membrane integrity (depolarization and loss of cell capacitance) accompanied by a reduction in the expression of D-1 and D-2 dopamine receptors visualized in layer I of the perirhinal cortex. Importantly, abnormalities in both short-term and long-term plasticity can be reversed by the introduction of a D-2 dopamine receptor agonist (Quinpirole), suggesting that alterations in dopaminergic signalling may underlie early cognitive dysfunction in HD