Neonatal 5,7-DHT Lesions Cause Sex-Specific Changes in Mouse Cortical Morphogenesis

Both monoaminergic and cholinergic afferent projections to the neocortex putatively modulate cortical morphogenesis and plasticity. Previously we showed that neonatal,electrolytic lesions: the cholinergic nucleus basalis magnocel!ularis (nBM) projections to the neocortex result in significant decreases-of cortical layer width that correlate with cognitive alterations. Such electrolytic lesions, performed for lack of a selective neurotoxin in mice, may affect mono- aminergic fibers of passage. Here, we investigate the effects of neonatal 5,7 dihydroxytryptamine (5,7-DHT) focal injections into the nBM region on cortical laminar morphology in adult male and female mice. 5,7-DHT lesions on the first postnatal day resulted in significant cortical depletion of both serotonin and norepinephrine that attenuated with age. Generally, cortical layer widths increased in response to the lesion; the effects were layer, region, and sex specific. Previous reports from our laboratories described longterm behavioral alterations after comparable focal, neonatal 5,7-DHT lesions. The studies described here provide an anatomical basis for such behavioral alterations. Our data suggest that monoaminergic and cholinergic projections to the cortex may have opposite effects on the developing cortical neuropil. Jointly, our morphological and behavioral findings may have important implications for a variety of developmental disorders in humans and provide some insights into sex differences in the penetrance of these disorders

Displaying the Heterogeneity of the SN 2002cx-like Subclass of Type Ia Supernovae with Observations of the Pan-STARRS-1 Discovered SN2009ku

SN2009ku, discovered by Pan-STARRS-1, is a Type Ia supernova (SNIa), and a member of the distinct SN2002cx-like class of SNeIa. Its light curves are similar to the prototypical SN2002cx, but are slightly broader and have a later rise to maximum in g. SN2009ku is brighter (~0.6 mag) than other SN2002cx-like objects, peaking at M_V = -18.4 mag - which is still significantly fainter than typical SNeIa. SN2009ku, which had an ejecta velocity of ~2000 kms^-1 at 18 days after maximum brightness is spectroscopically most similar to SN2008ha, which also had extremely low-velocity ejecta. However, SN2008ha had an exceedingly low luminosity, peaking at M_V = -14.2 mag, ~4 mag fainter than SN2009ku. The contrast of high luminosity and low ejecta velocity for SN2009ku is contrary to an emerging trend seen for the SN2002cx class. SN2009ku is a counter-example of a previously held belief that the class was more homogeneous than typical SNeIa, indicating that the class has a diverse progenitor population and/or complicated explosion physics. As the first example of a member of this class of objects from the new generation of transient surveys, SN2009ku is an indication of the potential for these surveys to find rare and interesting objects.Comment: 7 pages, 3 figure

Rapid β-amyloid deposition and cognitive impairment after cholinergic denervation in APP/PS1 mice

Although extensive evidence supports the role of amyloid-β (Aβ) in Alzheimer disease (AD), the neurotoxic mechanisms underlying AD pathogenesis are not understood. On the other hand, neuronal loss is the pathological feature that best correlates with cognitive impairment. We hypothesized that cholinergic neurodegeneration may lead to Aβ deposition and tested this by inducing selective cholinergic lesions in APPswe/PS1dE9 mice with murine p75(NTR) saporin (mu p75-SAP). Intracerebroventricular lesions that removed ~50% of cholinergic innervation to the cortex and hippocampus were induced in animals with incipient (~3 months) and marked (~7 months of age) Aβ deposition. Cranial windows were implanted and Aβ deposition was monitored in vivo using multiphoton microscopy. Aβ deposition was increased as soon as 7 days after the lesion and this effect was maintained up to 3 months later. Postmortem studies using immunohistochemistry with an anti-Aβ antibody corroborated these findings in both cerebral cortex and hippocampus. Tau phosphorylation was also significantly increased after the lesions. Cholinergic denervation resulted in early memory impairment at 3 months of age that worsened with age (~7 months); there was a synergistic effect between cholinergic denervation and the presence of APP/PS1 transgenes. Altogether, our data suggest that cholinergic denervation may trigger Aβ deposition and synergistically contribute to cognitive impairment in AD patients

Cosmological Constraints from Measurements of Type Ia Supernovae discovered during the first 1.5 years of the Pan-STARRS1 Survey

We present griz light curves of 146 spectroscopically confirmed Type Ia Supernovae ($0.03 < z <0.65$) discovered during the first 1.5 years of the Pan-STARRS1 Medium Deep Survey. The Pan-STARRS1 natural photometric system is determined by a combination of on-site measurements of the instrument response function and observations of spectrophotometric standard stars. We find that the systematic uncertainties in the photometric system are currently 1.2\% without accounting for the uncertainty in the HST Calspec definition of the AB system. A Hubble diagram is constructed with a subset of 113 out of 146 SNe Ia that pass our light curve quality cuts. The cosmological fit to 310 SNe Ia (113 PS1 SNe Ia + 222 light curves from 197 low-z SNe Ia), using only SNe and assuming a constant dark energy equation of state and flatness, yields $w=-1.120^{+0.360}_{-0.206}\textrm{(Stat)} ^{+0.269}_{-0.291}\textrm{(Sys)}$. When combined with BAO+CMB(Planck)+$H_0$, the analysis yields $\Omega_{\rm M}=0.280^{+0.013}_{-0.012}$ and $w=-1.166^{+0.072}_{-0.069}$ including all identified systematics (see also Scolnic et al. 2014). The value of $w$ is inconsistent with the cosmological constant value of $-1$ at the 2.3$\sigma$ level. Tension endures after removing either the BAO or the $H_0$ constraint, though it is strongest when including the $H_0$ constraint. If we include WMAP9 CMB constraints instead of those from Planck, we find $w=-1.124^{+0.083}_{-0.065}$, which diminishes the discord to $<2\sigma$. We cannot conclude whether the tension with flat $\Lambda$CDM is a feature of dark energy, new physics, or a combination of chance and systematic errors. The full Pan-STARRS1 supernova sample with $\sim\!\!$3 times as many SNe should provide more conclusive results.Comment: 38 pages, 16 figures, 14 tables, ApJ in pres

Systematic Uncertainties Associated with the Cosmological Analysis of the First Pan-STARRS1 Type Ia Supernova Sample

We probe the systematic uncertainties from 113 Type Ia supernovae (SNIa) in the Pan-STARRS1 (PS1) sample along with 197 SN Ia from a combination of low-redshift surveys. The companion paper by Rest et al. (2013) describes the photometric measurements and cosmological inferences from the PS1 sample. The largest systematic uncertainty stems from the photometric calibration of the PS1 and low-z samples. We increase the sample of observed Calspec standards from 7 to 10 used to define the PS1 calibration system. The PS1 and SDSS-II calibration systems are compared and discrepancies up to ~0.02 mag are recovered. We find uncertainties in the proper way to treat intrinsic colors and reddening produce differences in the recovered value of w up to 3%. We estimate masses of host galaxies of PS1 supernovae and detect an insignificant difference in distance residuals of the full sample of 0.037\pm0.031 mag for host galaxies with high and low masses. Assuming flatness in our analysis of only SNe measurements, we find $w = {-1.120^{+0.360}_{-0.206}\textrm{(Stat)} ^{+0.269}_{-0.291}\textrm{(Sys)}}$. With additional constraints from BAO, CMB(Planck) and H0 measurements, we find $w = -1.166^{+0.072}_{-0.069}$ and $\Omega_M=0.280^{+0.013}_{-0.012}$ (statistical and systematic errors added in quadrature). Significance of the inconsistency with $w=-1$ depends on whether we use Planck or WMAP measurements of the CMB: $w_{\textrm{BAO+H0+SN+WMAP}}=-1.124^{+0.083}_{-0.065}$.Comment: 24 pages, 20 figures. Accepted by Ap

Long-term potentiation-like cortical plasticity is disrupted in Alzheimer's disease patients independently from age of onset

OBJECTIVE Alzheimer's disease (AD) is considered an age-related disorder. However, it is unclear whether AD induces the same pathological and neurophysiological modifications in synaptic functions independently from age of disease onset. We used transcranial magnetic stimulation tools to investigate the mechanisms of cortical plasticity and sensory-motor integration in AD patients with a wide range of disease onset. METHODS We evaluated newly diagnosed sporadic AD (n = 54) in comparison with healthy age-matched controls (HS; n = 24). Cortical plasticity mechanisms of long-term potentiation (LTP) or of long-term depression (LTD) were assessed using respectively intermittent (iTBS) or continuous theta burst stimulation (cTBS) protocols. Sensory-motor integration was evaluated by means of short afferent inhibition (SAI) protocol. RESULTS AD patients show after iTBS an impairment of LTP-like cortical plasticity forming a paradoxical LTD in comparison to HS. LTD-like cortical plasticity is similar between AD and HS. LTP-like cortical plasticity is not associated with age, but AD patients presenting with more altered LTP-like cortical plasticity have more-severe cognitive decline at 18 months. SAI is impaired in AD and shows a strong association with the individual age of subjects rather than with disease age of onset. INTERPRETATION Cortical LTP disruption is a central mechanism of AD that is independent from age of onset. AD can be described primarily as a disorder of LTP-like cortical plasticity not influenced by physiological aging and associated with a more-severe cognitive decline. Ann Neurol 2016;80:202-210

A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

Discovery of Very High Energy Gamma Rays from 1ES 1440+122

The BL Lacertae object 1ES 1440+122 was observed in the energy range from 85 GeV to 30 TeV by the VERITAS array of imaging atmospheric Cherenkov telescopes. The observations, taken between 2008 May and 2010 June and totalling 53 hours, resulted in the discovery of $\gamma$-ray emission from the blazar, which has a redshift $z$=0.163. 1ES 1440+122 is detected at a statistical significance of 5.5 standard deviations above the background with an integral flux of (2.8$\pm0.7_{\mathrm{stat}}\pm0.8_{\mathrm{sys}}$) $\times$ 10$^{-12}$ cm$^{-2}$ s$^{-1}$ (1.2\% of the Crab Nebula's flux) above 200 GeV. The measured spectrum is described well by a power law from 0.2 TeV to 1.3 TeV with a photon index of 3.1 $\pm$ 0.4$_{\mathrm{stat}}$ $\pm$ 0.2$_{\mathrm{sys}}$. Quasi-simultaneous multi-wavelength data from the Fermi Large Area Telescope (0.3--300 GeV) and the Swift X-ray Telescope (0.2--10 keV) are additionally used to model the properties of the emission region. A synchrotron self-Compton model produces a good representation of the multi-wavelength data. Adding an external-Compton or a hadronic component also adequately describes the data.Comment: 8 pages, 4 figures. Accepted for publication in MNRA