High intensity neutrino oscillation facilities in Europe

The EUROnu project has studied three possible options for future, high intensity neutrino oscillation facilities in Europe. The first is a Super Beam, in which the neutrinos come from the decay of pions created by bombarding targets with a 4 MW proton beam from the CERN High Power Superconducting Proton Linac. The far detector for this facility is the 500 kt MEMPHYS water Cherenkov, located in the Fréjus tunnel. The second facility is the Neutrino Factory, in which the neutrinos come from the decay of μ+ and μ− beams in a storage ring. The far detector in this case is a 100 kt magnetized iron neutrino detector at a baseline of 2000 km. The third option is a Beta Beam, in which the neutrinos come from the decay of beta emitting isotopes, in particular He6 and Ne18, also stored in a ring. The far detector is also the MEMPHYS detector in the Fréjus tunnel. EUROnu has undertaken conceptual designs of these facilities and studied the performance of the detectors. Based on this, it has determined the physics reach of each facility, in particular for the measurement of CP violation in the lepton sector, and estimated the cost of construction. These have demonstrated that the best facility to build is the Neutrino Factory. However, if a powerful proton driver is constructed for another purpose or if the MEMPHYS detector is built for astroparticle physics, the Super Beam also becomes very attractive

Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety

Knock-in mice were generated that harbored a leucine-to-serine mutation in the alpha4 nicotinic receptor near the gate in the channel pore. Mice with intact expression of this hypersensitive receptor display dominant neonatal lethality. These mice have a severe deficit of dopaminergic neurons in the substantia nigra, possibly because the hypersensitive receptors are continuously activated by normal extracellular choline concentrations. A strain that retains the neo selection cassette in an intron has reduced expression of the hypersensitive receptor and is viable and fertile. The viable mice display increased anxiety, poor motor learning, excessive ambulation that is eliminated by very low levels of nicotine, and a reduction of nigrostriatal dopaminergic function upon aging. These knock-in mice provide useful insights into the pathophysiology of sustained nicotinic receptor activation and may provide a model for Parkinson's disease

High-Resolution Mapping of Quantitative Trait Loci for Emotionality in Selected Strains of Mice

r confirmation and further finemapping of QTLs. We have previously shown, using an F 2 genome scan, that three QTL (on Chrs 1, 12, and 15) contribute to the genetic variance of a psychological trait in mice termed emotionality. In that experiment, we used two measures of emotionality: total distance the animal traverses in 5 minutes in an open-field arena (open-field activity, OFA) and the number of fecal boli produced in the open field during the 5-min test period (open-field defecation, OFD; Flint et al. 1995). Calvin Hall devised the open-field arena in the 1930s (Hall 1934) as a way of assessing emotionality in rats primarily because strong emotion, especially fear, is known to result in defecation and urination in humans (Stouffer et al. 1949). The open-field arena is a white box or circular arena that is brightly lit and considered to be unpleasant for rats and mice. Animals that are relatively inactive (low OFA scores) and have high defecation scores are regard

Gene Expression in Brain: A Window on Ethanol Dependence, Neuroadaptation, and Preference

This article represents the proceedings of a symposium at the 2002 joint RSA/ISBRA Conference in San Francisco, California. The organizer was Paula L. Hoffman and the co-chairs were Paula L. Hoffman and Michael Miles. The presentations were (1) Introduction and overview of the use of DNA microarrays, by Michael Miles; (2) DNA microarray analysis of gene expression in brains of P and NP rats, by Howard J. Edenberg; (3) Gene expression patterns in brain regions of AA and ANA rats, by Wolfgang Sommer; (4) Patterns of gene expression in brains of selected lines of mice that differ in ethanol tolerance, by Boris Tabakoff; (5) Gene expression profiling related to initial sensitivity and tolerance in gamma-protein kinase C mutants, by Jeanne Wehner; and (6) Gene expression patterns in human alcoholic brain: from microarrays to protein profiles, by Joanne Lewohl

Acetylcholine-Stimulated [3H]GABA Release from Mouse Brain Synaptosomes is Modulated by α4β2 and α4α5β2 Nicotinic Receptor Subtypes

Nicotinic acetylcholine receptor (nAChR) agonists stimulate the release of GABA from GABAergic nerve terminals, but the nAChR subtypes that mediate this effect have not been elucidated. The studies reported here used synaptosomes derived from the cortex, hippocampus, striatum, and thalamus of wild-type and α4-, α5-, α7-, β2-, and β4-null mutant mice to identify nAChR subtypes involved in acetylcholine (ACh)-evoked GABA release. Null mutation of genes encoding the α4 or β2 subunits resulted in complete loss of ACh-stimulated [3H]GABA release in all four brain regions. In contrast, α5 gene deletion exerted a small but significant decrease in maximal ACh-evoked [3H]GABA release in hippocampus and striatum, with a more profound effect in cortex. Acetylcholine-stimulated [3H]GABA release from thalamic synaptosomes was not significantly affected by α5 gene deletion. No effect was detected in the four brain regions examined in α7- or β4-null mutant mice. Further analysis of ACh-evoked [3H]GABA release revealed biphasic concentration-response relationships in the four brain regions examined from all wild-type animals and in α5 null mutant mice. Moreover, a selective reduction in the maximum response of the high-affinity component was apparent in α5-null mutant mice. The results demonstrate that α4β2-type nAChRs are critical for ACh-stimulated [3H]GABA release from all four brain regions examined. In addition, the results suggest that α5-containing receptors on GABAergic nerve terminals comprise a fraction of the high ACh-sensitivity component of the concentration-response curve and contribute directly to the ability of nicotinic agonists to evoke GABA release in these regions

α4β2* Nicotinic Acetylcholine Receptors Modulate the Effects of Ethanol and Nicotine on the Acoustic Startle Response

Background: Ethanol modulates the functional activity of α4β2 neuronal nicotinic cholinergic receptors (nAChR) when measured in vitro, but the potential role of α4β2 nAChRs in regulating behavioral effects of ethanol is unknown. Recently, Tritto et al. (Tritto T, Stitzel JA, Marks MJ, Romm E, Collins AC (2002) Variability in response to nicotine in the LS×SS RI strains: potential role of polymorphisms in alpha4 and alpha6 nicotinic receptor genes. Pharmacogenetics 12:197–208) reported that a polymorphism (A529T) in the α4 nAChR subunit gene is associated with variability in nicotine's effects on startle in the LS×SS recombinant inbred (RI) strains. Ethanol also alters the acoustic startle response. Thus, we evaluated the potential role of α4β2 nAChRs in modulating ethanol's effects on acoustic startle. Methods: The effects of ethanol on acoustic startle were determined in the LS×SS RI strains. In addition, the effects of ethanol and nicotine were also measured in α4 gain of function and β2 null mutant mice. The β2 mutants do not express the major variant of α4 nAChRs, α4β2. Results: An association between the α4 A529T polymorphism and ethanol's effects on startle was found in the LS×SS RI strains; those strains that express the A529 variant of α4 were more sensitive to ethanol‐induced depression of startle. The α4 gain of function mutants were more sensitive to the effects of both nicotine and ethanol and the β2 null mutants were less sensitive to both drugs. Conclusions: α4β2‐containing nAChRs may play important roles in modulating the effects of both ethanol and nicotine on the acoustic startle response. We suggest that nAChR subunit genes should be evaluated as potential contributors to both alcoholism and tobacco abuse