Measurement of the 2νßß Decay Rate and Spectral Shape of

Neutrinoless double beta decay (0νßß) is a yet unobserved nuclear process that would demonstrate Lepton number violation, a clear evidence of beyond standard model physics. The process two neutrino double beta decay (2νßß) is allowed by the standard model and has been measured in numerous experiments. In this Letter, we report a measurement of 2νßß decay half-life of ^{100}Mo to the ground state of ^{100}Ru of [7.07±0.02(stat)±0.11(syst)]×10^{18} yr by the CUPID-Mo experiment. With a relative precision of ±1.6% this is the most precise measurement to date of a 2νßß decay rate in ^{100}Mo. In addition, we constrain higher-order corrections to the spectral shape, which provides complementary nuclear structure information. We report a novel measurement of the shape factor ξ_{3,1}=0.45±0.03(stat)±0.05(syst) based on a constraint on the ratio of higher-order terms from theory, which can be reliably calculated. This is compared to theoretical predictions for different nuclear models. We also extract the first value for the effective axial vector coupling constant obtained from a spectral shape study of 2νßß decay.

Evaluation of Memantine in AAV-AD Rat: A Model of Late-Onset Alzheimer's Disease Predementia.

BACKGROUND: Though our understanding of Alzheimer's disease (AD) remains elusive, it is well known that the disease starts long before the first signs of dementia. This is supported by the large number of symptomatic drug failures in clinical trials and the increased trend to enroll patients at predementia stages with either mild or no cognitive symptoms. However, the design of pre-clinical studies does not follow this attitude, in particular regarding the choice of animal models, often irrelevant to mimic predementia Late Onset Alzheimer's Disease (LOAD). OBJECTIVES: We aimed to pharmacologically validate the AAV-AD rat model to evaluate preventive treatment of AD. METHODS: We evaluated an N-methyl-D-aspartate receptor antagonist, named memantine, in AAV-AD rats, an age-dependent amyloid rat model which closely mimics Alzheimer's pathology including asymptomatic and prodromal stages. Memantine was used at a clinically relevant dose (20 mg daily oral administration) from 4 (asymptomatic phase) to 10 (mild cognitive impairment phase) months of age. RESULTS: A 6-month treatment with memantine promoted a non-amyloidogenic cleavage of APP followed by a decrease in soluble Aß42. Consequently, both long-term potentiation and cognitive impairments were prevented. By contrast, the levels of hyperphosphorylated endogenous tau remained unchanged, indicating that a long-term memantine treatment is ineffective to restrain the APP processing-induced tauopathy. CONCLUSIONS: Together, our data confirm that relevant models to LOAD, such as the AAV-AD rat, can provide a framework for a better understanding of the disease and accurate assessment of preventive treatments.

New Limit for Neutrinoless Double-Beta Decay of

The CUPID-Mo experiment at the Laboratoire Souterrain de Modane (France) is a demonstrator for CUPID, the next-generation ton-scale bolometric 0νßß experiment. It consists of a 4.2 kg array of 20 enriched Li_{2}^{100}MoO_{4} scintillating bolometers to search for the lepton-number-violating process of 0νßß decay in ^{100}Mo. With more than one year of operation (^{100}Mo exposure of 1.17 kg×yr for physics data), no event in the region of interest and, hence, no evidence for 0νßß is observed. We report a new limit on the half-life of 0νßß decay in ^{100}Mo of T_{1/2}>1.5×10^{24} yr at 90% C.I. The limit corresponds to an effective Majorana neutrino mass ⟨m_{ßß}⟩<(0.31-0.54) eV, dependent on the nuclear matrix element in the light Majorana neutrino exchange interpretation.

d-serine in physiological and pathological brain aging.

Among aging-induced impairments, those affecting cognitive functions certainly represent one the most major challenge to face to improve elderly quality of life. In last decades, our knowledge on changes in the morphology and function of neuronal networks associated with normal and pathological brain aging has rapidly progressed, initiating the development of different pharmacological and behavioural strategies to alleviate cognitive aging. In particular, experimental evidences have accumulated indicating that the communication between neurons and its plasticity gradually weakens with aging. Because of its pivotal role for brain functional plasticity, the N-Methyl­d-Aspartate receptor subtype of glutamate receptors (NMDAr) has gathered much of the experimental interest. NMDAr activation is regulated by many mechanisms. Among is the mandatory binding of a co-agonist, such as the amino acid d-serine, in order to activate NMDAr. This mini-review presents the most recent information indicating how d-serine could contribute to mechanisms of physiological cognitive aging and also considers the divergent views relative of the role of the NMDAr co-agonist in Alzheimer's disease.

First Germanium-Based Constraints on Sub-MeV Dark Matter with the EDELWEISS Experiment.

We present the first Ge-based constraints on sub-MeV/c^{2} dark matter (DM) particles interacting with electrons using a 33.4 g Ge cryogenic detector with a 0.53 electron-hole pair (rms) resolution, operated underground at the Laboratoire Souterrain de Modane. Competitive constraints are set on the DM-electron scattering cross section, as well as on the kinetic mixing parameter of dark photons down to 1 eV/c^{2}. In particular, the most stringent limits are set for dark photon DM in the 6 to 9 eV/c^{2} range. These results demonstrate the high relevance of Ge cryogenic detectors for the search of DM-induced eV-scale electron signals.

Development of 100 Mo -containing scintillating bolometers for a high-sensitivity neutrinoless double-beta decay search.

This paper reports on the development of a technology involving 100 Mo -enriched scintillating bolometers, compatible with the goals of CUPID, a proposed next-generation bolometric experiment to search for neutrinoless double-beta decay. Large mass ( ∼ 1 kg ), high optical quality, radiopure 100 Mo -containing zinc and lithium molybdate crystals have been produced and used to develop high performance single detector modules based on 0.2-0.4 kg scintillating bolometers. In particular, the energy resolution of the lithium molybdate detectors near the Q-value of the double-beta transition of 100 Mo (3034 keV) is 4-6 keV FWHM. The rejection of the α -induced dominant background above 2.6 MeV is better than 8 σ . Less than 10 µ Bq/kg activity of 232 Th ( 228 Th ) and 226 Ra in the crystals is ensured by boule recrystallization. The potential of 100 Mo -enriched scintillating bolometers to perform high sensitivity double-beta decay searches has been demonstrated with only 10 kg × d exposure: the two neutrino double-beta decay half-life of 100 Mo has been measured with the up-to-date highest accuracy as T 1 / 2 = [6.90 ± 0.15(stat.) ± 0.37(syst.)] × 10 18 years . Both crystallization and detector technologies favor lithium molybdate, which has been selected for the ongoing construction of the CUPID-0/Mo demonstrator, containing several kg of 100 Mo .

New Results from the Search for Low-Mass Weakly Interacting Massive Particles with the CDMS Low Ionization Threshold Experiment.

The CDMS low ionization threshold experiment (CDMSlite) uses cryogenic germanium detectors operated at a relatively high bias voltage to amplify the phonon signal in the search for weakly interacting massive particles (WIMPs). Results are presented from the second CDMSlite run with an exposure of 70 kg day, which reached an energy threshold for electron recoils as low as 56 eV. A fiducialization cut reduces backgrounds below those previously reported by CDMSlite. New parameter space for the WIMP-nucleon spin-independent cross section is excluded for WIMP masses between 1.6 and 5.5 GeV/c^{2}.

First direct limits on lightly ionizing particles with electric charge less than e/6.

While the standard model of particle physics does not include free particles with fractional charge, experimental searches have not ruled out their existence. We report results from the Cryogenic Dark Matter Search (CDMS II) experiment that give the first direct-detection limits for cosmogenically produced relativistic particles with electric charge lower than e/6. A search for tracks in the six stacked detectors of each of two of the CDMS II towers finds no candidates, thereby excluding new parameter space for particles with electric charges between e/6 and e/200.

Circuit-specific changes in D-serine-dependent activation of the N-methyl-D-aspartate receptor in the aging hippocampus.

Age-related memory deficits have recently been associated with the impaired expression of D-serine-dependent synaptic plasticity in neuronal networks of the hippocampal CA1 area. However, whether such functional alterations are common to the entire hippocampus during aging remains unknown. Here, we found that D-serine was also required for the induction of N-methyl-D-aspartate receptor (NMDA-R)-dependent long-term potentiation (LTP) at perforant path-granule cell synapses of the dentate gyrus. LTP as well as isolated NMDA-R synaptic potentials were impaired in slices from aged rats, but in contrast to the CA1, this defect was not reversed by exogenous D-serine. The lower activation of the glycine-binding site by the endogenous co-agonist does not therefore appear to be a critical mechanism underlying age-related deficits in NMDA-R activation in the dentate gyrus. Instead, our data highlight the role of changes in presynaptic inputs as illustrated by the weaker responsiveness of afferent glutamatergic fibers, as well as changes in postsynaptic NMDA-R density. Thus, our study indicates that although NMDA-R-dependent mechanisms driving synaptic plasticity are quite similar between hippocampal circuits, they show regional differences in their susceptibility to aging, which could hamper the development of effective therapeutic strategies aimed at reducing cognitive aging.

Search for low-mass weakly interacting massive particles with SuperCDMS.

We report a first search for weakly interacting massive particles (WIMPs) using the background rejection capabilities of SuperCDMS. An exposure of 577 kg days was analyzed for WIMPs with mass <30 GeV/c(2), with the signal region blinded. Eleven events were observed after unblinding. We set an upper limit on the spin-independent WIMP-nucleon cross section of 1.2×10(-42) cm(2) at 8 GeV/c(2). This result is in tension with WIMP interpretations of recent experiments and probes new parameter space for WIMP-nucleon scattering for WIMP masses <6 GeV/c(2).

Development of a µ-TPC detector as a standard instrument for low-energy neutron field characterisation.

In order to measure the energy and fluence of neutron fields, in the energy range of 8 to 1 MeV, a new primary standard is being developed at the Institute for Radioprotection and Nuclear Safety (IRSN). This project, Micro Time Projection Chamber (µ-TPC), carried out in collaboration with the Laboratoire de Physqique Subatomique et de Cosmologie (LPSC), is based on the nucleus recoil detector principle. The measurement strategy requires track reconstruction of recoiling nuclei down to a few kiloelectronvolts, which can be achieved using a micro-pattern gaseous detector. A gas mixture, mainly isobutane, is used as an n-p converter to detect neutrons within the detection volume. Then electrons, coming from the ionisation of the gas by the proton recoil, are collected by the pixelised anode (2D projection). A self-triggered electronics system is able to perform the anode readout at a 50-MHz frequency in order to give the third dimension of the track. Then, the scattering angle is deduced from this track using algorithms. The charge collection leads to the proton energy, taking into account the ionisation quenching factor. This article emphasises the neutron energy measurements of a monoenergetic neutron field produced at 127 keV. The fluence measurement is not shown in this article. The measurements are compared with Monte Carlo simulations using realistic neutron fields and simulations of the detector response. The discrepancy between experiments and simulations is 5 keV mainly due to the calibration uncertainties of 10 %.

Search for low-mass weakly interacting massive particles using voltage-assisted calorimetric ionization detection in the SuperCDMS experiment.

SuperCDMS is an experiment designed to directly detect weakly interacting massive particles (WIMPs), a favored candidate for dark matter ubiquitous in the Universe. In this Letter, we present WIMP-search results using a calorimetric technique we call CDMSlite, which relies on voltage-assisted Luke-Neganov amplification of the ionization energy deposited by particle interactions. The data were collected with a single 0.6 kg germanium detector running for ten live days at the Soudan Underground Laboratory. A low energy threshold of 170 eVee (electron equivalent) was obtained, which allows us to constrain new WIMP-nucleon spin-independent parameter space for WIMP masses below 6 GeV/c2.

Serine racemase as a prime target for age-related memory deficits.

The learning and memory deficits associated with non-pathological ageing mainly result from alterations to the plasticity of neuronal network dynamics within the hippocampus. In addition to the broad spectrum of changes that affect the morphology and function of hippocampal excitatory circuits in the ageing brain, the impaired activation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDA-R) is a typical feature, altering the induction and maintenance of long-term potentiation, a major form of synaptic plasticity. In addition to glutamate, the binding of a co-agonist at the strychnine-insensitive glycine-binding site is required for NMDA-R activation. This review presents recent evidence that: (i) the amino acid D-serine is an endogenous co-agonist of synaptic NMDA-R and necessary for long-term potentiation expression, (ii) reduced d-serine levels in the hippocampus contribute to synaptic plasticity and memory deficits in normal ageing, and (iii) age-related oxidative stress selectively targets hippocampal serine racemase to impact D-serine availability in neuronal networks. These results emphasize the critical role of the hippocampal d-serine-dependent pathway in changes affecting neuronal network dynamics in physiological ageing that underlie memory deficits. In addition, the central role of serine racemase in these changes opens new perspectives in the search for relevant therapeutic strategies aimed at reducing age-related memory defects.

Silicon detector dark matter results from the final exposure of CDMS II.

We report results of a search for weakly interacting massive particles (WIMPS) with the silicon detectors of the CDMS II experiment. This blind analysis of 140.2 kg day of data taken between July 2007 and September 2008 revealed three WIMP-candidate events with a surface-event background estimate of 0.41(-0.08)(+0.20)(stat)(-0.24)(+0.28)(syst). Other known backgrounds from neutrons and 206Pb are limited to <0.13 and <0.08 events at the 90% confidence level, respectively. The exposure of this analysis is equivalent to 23.4 kg day for a recoil energy range of 7-100 keV for a WIMP of mass 10 GeV/c2. The probability that the known backgrounds would produce three or more events in the signal region is 5.4%. A profile likelihood ratio test of the three events that includes the measured recoil energies gives a 0.19% probability for the known-background-only hypothesis when tested against the alternative WIMP+background hypothesis. The highest likelihood occurs for a WIMP mass of 8.6 GeV/c2 and WIMP-nucleon cross section of 1.9×10(-41) cm2.

Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity.

Unlike other serine proteases that are zymogens, the single-chain form of tissue plasminogen activator (sc-tPA) exhibits an intrinsic activity similar to that of its cleaved two-chain form (tc-tPA), especially in the presence of fibrin. In the central nervous system tPA controls brain functions and dysfunctions through its proteolytic activity. We demonstrated here, both in vitro and in vivo, that the intrinsic activity of sc-tPA selectively modulates N-methyl-D-aspartate receptor (NMDAR) signaling as compared with tc-tPA. Thus, sc-tPA enhances NMDAR-mediated calcium influx, Erk(½) activation and neurotoxicity in cultured cortical neurons, excitotoxicity in the striatum and NMDAR-dependent long-term potentiation in the hippocampal CA-1 network. As the first demonstration of a differential function for sc-tPA and tc-tPA, this finding opens a new area of investigations on tPA functions in the absence of its allosteric regulator, fibrin.

Rescue of cognitive aging by long-lasting environmental enrichment exposure initiated before median lifespan.

The rescue of cognitive function through environmental enrichment (EE) during aging has been extensively documented. However, the age at onset, the duration of EE, and the cerebral mechanisms required to obtain the greatest benefits still remain to be determined. We have recently shown that EE applied for 3 mo after the median lifespan, i.e., the age at which 50% of the population is still alive (from 17 to 20 mo in NMRI mice), failed to prevent cognitive deficits in senescent animals. In the present study, mice were exposed to EE prior to the median lifespan, and for a longer total duration (from 14 to 20 mo), before the assessment of memory performance and the electrophysiological properties of hippocampal neuronal networks. The EE prevented memory deficits and reduced anxiety as the animal aged. Moreover, EE attenuated the age-related impairment of basal glutamatergic neurotransmission in CA1 hippocampal slices, and reversed the decrease in isolated N-methyl-D-Aspartate receptor (NMDA-R)-dependent synaptic potentials. Surprisingly, EE did not prevent the age-related alteration of theta-burst-induced long-term potentiation (LTP). This study therefore suggests that EE needs to be initiated before the age corresponding to the median lifespan and/or required long duration (> 3 mo) to have an effect on cognitive aging. In addition, we show that EE probably acts through theta-burst-independent mechanisms of synaptic plasticity.

Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function.

To gain insight into the contribution of d-serine to impaired cognitive aging, we compared the metabolic pathway and content of the amino acid as well as d-serine-dependent synaptic transmission and plasticity in the hippocampus of young and old rats of the Wistar and Lou/C/Jall strains. Wistar rats display cognitive impairments with aging that are not found in the latter strain, which is therefore considered a model of healthy aging. Both mRNA and protein levels of serine racemase, the d-serine synthesizing enzyme, were decreased in the hippocampus but not in the cerebral cortex or cerebellum of aged Wistar rats, whereas the expression of d-amino acid oxidase, which degrades the amino acid, was not affected. Consequently, hippocampal levels of endogenous d-serine were significantly lower. In contrast, serine racemase expression and d-serine levels were not altered in the hippocampus of aged Lou/C/Jall rats. Ex vivo electrophysiological recordings in hippocampal slices showed a marked reduction in N-methyl-d-aspartate-receptor (NMDA-R)-mediated synaptic potentials and theta-burst-induced long-term potentiation (LTP) in the CA1 area of aged Wistar rats, which were restored by exogenous d-serine. In contrast, NMDA-R activation, LTP induction and responses to d-serine were not altered in aged Lou/C/Jall rats. These results further strengthen the notion that the serine racemase-dependent pathway is a prime target of hippocampus-dependent cognitive deficits with aging. Understanding the processes that specifically affect serine racemase during aging could thus provide key insights into the treatment of memory deficits in the elderly.

Contribution of the d-Serine-Dependent Pathway to the Cellular Mechanisms Underlying Cognitive Aging.

An association between age-related memory impairments and changes in functional plasticity in the aging brain has been under intense study within the last decade. In this article, we show that an impaired activation of the strychnine-insensitive glycine site of N-methyl-d-aspartate receptors (NMDA-R) by its agonist d-serine contributes to deficits of synaptic plasticity in the hippocampus of memory-impaired aged rats. Supplementation with exogenous d-serine prevents the age-related deficits of isolated NMDA-R-dependent synaptic potentials as well as those of theta-burst-induced long-term potentiation and synaptic depotentiation. Endogenous levels of d-serine are reduced in the hippocampus with aging, that correlates with a weaker expression of serine racemase synthesizing the amino acid. On the contrary, the affinity of d-serine binding to NMDA-R is not affected by aging. These results point to a critical role for the d-serine-dependent pathway in the functional alterations of the brain underlying memory impairment and provide key information in the search for new therapeutic strategies for the treatment of memory deficits in the elderly.

Preserved memory capacities in aged Lou/C/Jall rats.

Although memory impairments are a hallmark of aging, the degree of deficit varies across animal models, and is likely to reflect different states of deterioration in metabolic and endocrinological properties. This study investigated memory-related processes in young (3-4 months) and old (24 months) Sprague-Dawley rats (SD), which develop age-linked pathologies such as obesity or insulin-resistance and Lou/C/Jall rats, which do not develop such impairments. In short- and long-term memory recognition tasks, old Lou/C/Jall rats were never impaired whereas old SD rats were deficient at 1 and 24h latencies. The expression of N-methyl-d-aspartate receptors (NMDAR)-mediated synaptic plasticity in CA1 hippocampal networks shifted towards lower activity values in old Lou/C/Jall rats whereas long-term potentiation was impaired in age-matched SD rats. Age-related decrease in NR2A subunits occurred in both strains, extended to NR2B, NR1 and GluR1 subunits in older animals (28 months) but only in SD rats. Therefore, the Lou/C/Jall rats can be considered as a model of healthy aging, not only in terms of its preserved metabolism, but also in terms of cognition and synaptic plasticity.

D-serine signalling as a prominent determinant of neuronal-glial dialogue in the healthy and diseased brain.

Rather different from their initial image as passive supportive cells of the CNS, the astrocytes are now considered as active partners at synapses, able to release a set of gliotransmitter-like substances to modulate synaptic communication within neuronal networks. Whereas glutamate and ATP were first regarded as main determinants of gliotransmission, growing evidence indicates now that the amino acid D-serine is another important player in the neuronal-glial dialogue. Through the regulation of glutamatergic neurotransmission through both N-methyl-D-aspartate (NMDA-R) and non-NMDA-R, D-serine is helping in modelling the appropriate connections in the developing brain and influencing the functional plasticity within neuronal networks throughout lifespan. The understanding of D-serine signalling, which has increased linearly in the last few years, gives new insights into the critical role of impaired neuronal-glial communication in the diseased brain, and offers new opportunities for developing relevant strategies to treat cognitive deficits associated to brain disorders.