RGS9 modulates dopamine signaling in the basal ganglia

Regulators of G protein signaling (RGS) modulate heterotrimeric G proteins in part by serving as GTPase-activating proteins for Galpha subunits. We examined a role for RGS9-2, an RGS subtype highly enriched in striatum, in modulating dopamine D2 receptor function. Viral-mediated overexpression of RGS9-2 in rat nucleus accumbens (ventral striatum) reduced locomotor responses to cocaine (an indirect dopamine agonist) and to D2 but not to D1 receptor agonists. Conversely, RGS9 knockout mice showed heightened locomotor and rewarding responses to cocaine and related psychostimulants. In vitro expression of RGS9-2 in Xenopus oocytes accelerated the off-kinetics of D2 receptor-induced GIRK currents, consistent with the in vivo data. Finally, chronic cocaine exposure increased RGS9-2 levels in nucleus accumbens. Together, these data demonstrate a functional interaction between RGS9-2 and D2 receptor signaling and the behavioral actions of psychostimulants and suggest that psychostimulant induction of RGS9-2 represents a compensatory adaptation that diminishes drug responsiveness.     

The presynaptic active zone protein RIM1alpha is critical for normal learning and memory

The active zone protein RIM1alpha is required both for maintaining normal probability of neurotransmitter release and for long-term presynaptic potentiation at brain synapses. We now demonstrate that RIM1alpha(-/-) mice exhibit normal coordination and anxiety-related behaviors but display severely impaired learning and memory. Mice with a synaptotagmin 1 mutation, which selectively lowers release probability, and mice with Rab3A deletion, which selectively abolishes presynaptic long-term potentiation, do not exhibit this abnormality. Our data suggest that a decrease in release probability or a loss of presynaptic LTP alone is not sufficient to cause major behavioral alterations, but the combination of presynaptic abnormalities in RIM1alpha(-/-) mice severely alters learning and memory.     

Chronic Administration of Lithium or Other Antidepressants Increases Levels of DARPP-32 in Rat Frontal Cortex

Abstract: We studied the chronic actions of lithium on rat brain by investigating its effects on cyclic AMP-dependent protein phos-phorylation by use of a back-phosphorylation procedure. We identified one heavily regulated phosphoprotein in frontal cortex as the 32-kDa dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32). Immunoblot experiments demonstrated that chronic lithium regulation of DARPP-32 back-phosphorylation is associated with equivalent increases in levels of DARPP-32 immunoreactivity. Lithium regulation of DARPP-32 immunoreactivity required chronic drug administration and was not observed in several other brain regions examined. Moreover, chronic administration of the antidepressant imipramine or tranylcypromine produced a similar increase in levels of DARPP-32 in frontal cortex, whereas other types of psychotropic drugs, including haloperidol. morphine, and cocaine, did not influence DARPP-32 levels. Increased levels of DARPP-32 could reflect a common functional effect on frontal cortex of long-term exposure to lithium and some other antidepressant medications, an effect possibly related to the clinical actions of these drugs.     

Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons

While the abuse of opiate drugs continues to rise, the neuroadaptations that occur with long-term drug exposure remain poorly understood. We describe here a series of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons, which are mediated via downregulation of AKT-mTORC2 (mammalian target of rapamycin complex-2). Chronic opiates decrease the size of VTA dopamine neurons in rodents, an effect seen in humans as well, and concomitantly increase the excitability of the cells but decrease dopamine output to target regions. Chronic morphine decreases mTORC2 activity, and overexpression of Rictor,?a component of mTORC2, prevents morphine-induced changes in cell morphology and activity. Further, local knockout of Rictor in VTA decreases DA soma size and reduces rewarding responses to morphine, consistent with the hypothesis that these adaptations represent a mechanism of reward tolerance. Together, these findings demonstrate a novel role for AKT-mTORC2 signaling in mediating neuroadaptations to opiate drugs of abuse.     

Geographic and topographic determinants of local FMD transmission applied to the 2001 UK FMD epidemic

Background

Models of Foot and Mouth Disease (FMD) transmission have assumed a homogeneous landscape across which Euclidean distance is a suitable measure of the spatial dependency of transmission. This paper investigated features of the landscape and their impact on transmission during the period of predominantly local spread which followed the implementation of the national movement ban during the 2001 UK FMD epidemic. In this study 113 farms diagnosed with FMD which had a known source of infection within 3 km (cases) were matched to 188 control farms which were either uninfected or infected at a later timepoint. Cases were matched to controls by Euclidean distance to the source of infection and farm size. Intervening geographical features and connectivity between the source of infection and case and controls were compared.

Results

Road distance between holdings, access to holdings, presence of forest, elevation change between holdings and the presence of intervening roads had no impact on the risk of local FMD transmission (p > 0.2). However the presence of linear features in the form of rivers and railways acted as barriers to FMD transmission (odds ratio = 0.507, 95% CIs = 0.297,0.887, p = 0.018).

Conclusion

This paper demonstrated that although FMD spread can generally be modelled using Euclidean distance and numbers of animals on susceptible holdings, the presence of rivers and railways has an additional protective effect reducing the probability of transmission between holdings.

     

Above‐ and belowground linkages in Sphagnum peatland: climate warming affects plant‐microbial interactions

Peatlands contain approximately one third of all soil organic carbon (SOC). Warming can alter above‐ and belowground linkages that regulate soil organic carbon dynamics and C‐balance in peatlands. Here we examine the multiyear impact of in situ experimental warming on the microbial food web, vegetation, and their feedbacks with soil chemistry. We provide evidence of both positive and negative impacts of warming on specific microbial functional groups, leading to destabilization of the microbial food web. We observed a strong reduction (70%) in the biomass of top‐predators (testate amoebae) in warmed plots. Such a loss caused a shortening of microbial food chains, which in turn stimulated microbial activity, leading to slight increases in levels of nutrients and labile C in water. We further show that warming altered the regulatory role of Sphagnum‐polyphenols on microbial community structure with a potential inhibition of top predators. In addition, warming caused a decrease in Sphagnum cover and an increase in vascular plant cover. Using structural equation modelling, we show that changes in the microbial food web affected the relationships between plants, soil water chemistry, and microbial communities. These results suggest that warming will destabilize C and nutrient recycling of peatlands via changes in above‐ and belowground linkages, and therefore, the microbial food web associated with mosses will feedback positively to global warming by destabilizing the carbon cycle. This study confirms that microbial food webs thus constitute a key element in the functioning of peatland ecosystems. Their study can help understand how mosses, as ecosystem engineers, tightly regulate biogeochemical cycling and climate feedback in peatlands