Habenular expression of rare missense variants of the β4 nicotinic receptor subunit alters nicotine consumption

The CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the {alpha}5, {alpha}3, and {beta}4 nicotinic acetylcholine receptor (nAChR) subunits, has been linked to nicotine dependence. The habenulo-interpeduncular (Hb-IPN) tract is particularly enriched in {alpha}3{beta}4 nAChRs. We recently showed that modulation of these receptors in the medial habenula (MHb) in mice altered nicotine consumption. Given that {beta}4 is rate-limiting for receptor activity and that single nucleotide polymorphisms (SNPs) in CHRNB4 have been linked to altered risk of nicotine dependence in humans, we were interested in determining the contribution of allelic variants of {beta}4 to nicotine receptor activity in the MHb. We screened for missense SNPs that had allele frequencies >0.0005 and introduced the corresponding substitutions in Chrnb4. Fourteen variants were analyzed by co-expression with {alpha}3. We found that {beta}4A90I and {beta}4T374I variants, previously shown to associate with reduced risk of smoking, and an additional variant {beta}4D447Y, significantly increased nicotine-evoked current amplitudes, while {beta}4R348C, the mutation most frequently encountered in sporadic amyotrophic lateral sclerosis (sALS), showed reduced nicotine currents. We employed lentiviruses to express {beta}4 or {beta}4 variants in the MHb. Immunoprecipitation studies confirmed that {beta}4 lentiviral-mediated expression leads to specific upregulation of {alpha}3{beta}4 but not {beta}2 nAChRs in the Mhb. Mice injected with the {beta}4-containing virus showed pronounced aversion to nicotine as previously observed in transgenic Tabac mice overexpressing Chrnb4 at endogenous sites including the MHb. Habenular expression of the {beta}4 gain-of-function allele T374I also resulted in strong aversion, while transduction with the {beta}4 loss-of function allele R348C failed to induce nicotine aversion. Altogether, these data confirm the critical role of habenular {beta}4 in nicotine consumption, and identify specific SNPs in CHRNB4 that modify nicotine-elicited currents and alter nicotine consumption in mice

Arecibo HI Absorption Measurements of Pulsars and the Electron Density at Intermediate Longitudes in the First Galactic Quadrant

We have used the Arecibo telescope to measure the HI absorption spectra of eight pulsars. We show how kinematic distance measurements depend upon the values of the galactic constants R_o and Theta_o, and we select our preferred current values from the literature. We then derive kinematic distances for the low-latitude pulsars in our sample and electron densities along their lines of sight. We combine these measurements with all others in the inner galactic plane visible from Arecibo to study the electron density in this region. The electron density in the interarm range 48 degrees < l < 70 degrees is [0.017 (-0.007,+0.012) (68% c.l.)] cm^(-3). This is 0.75 (-0.22,+0.49) (68% c.l.) of the value calculated by the Cordes & Lazio (2002) galactic electron density model. The model agrees more closely with electron density measurements toward Arecibo pulsars lying closer to the galactic center, at 30 degrees<l<48 degrees. Our analysis leads to the best current estimate of the distance of the relativistic binary pulsar B1913+16: d=(9.0 +/- 3) kpc. We use the high-latitude pulsars to search for small-scale structure in the interstellar hydrogen observed in absorption over multiple epochs. PSR B0301+19 exhibited significant changes in its absorption spectrum over 22 yr, indicating HI structure on a ~500 AU scale.Comment: Accepted by Astrophysical Journal September 200

Multi-Frequency Synthesis of VLBI Images Using a Generalized Maximum Entropy Method

A new multi-frequency synthesis algorithm for reconstructing images from multi-frequency VLBI data is proposed. The algorithm is based on a generalized maximum-entropy method, and makes it possible to derive an effective spectral correction for images over a broad frequency bandwidth, while simultaneously reconstructing the spectral-index distribution over the source. The results of numerical simulations demonstrating the capabilities of the algorithm are presented.Comment: 17 pages, 8 figure

Sco X-1: The Evolution and Nature of the Twin Compact Radio Lobes

The radio components associated with the LMXB Sco X-1 have been monitored with extensive VLBI imaging at 1.7 and 5.0 GHz over four years, including a 56-hour continuous VLBI observation in 1999 June. We often detected one strong and one weak compact radio component, moving in opposite directions from the radio core. We suggest that the moving components are radio lobes generated by the disruption of energy flow in a twin-beam from the binary system. The average lifetime of a lobe-pair, the space motion of the lobes and the measured energy flow in the beam are discussed in arXiv:astro-ph/0104325. The lobe has a flux density that is variable over a time-scale of one hour, a measured minimum size of 1 mas (2.8 au), and is extended perpendicular to its motion. This short electron radiative lifetime may be caused by synchrotron losses if the lobe magnetic field is 300 G, or by adiabatic expansion of the electrons as soon as they are produced at the working surface. The lobes also show periods of slow expansion and a steepening radio spectrum, perhaps related to the characteristics of the beam energy flow. The radio morphology for Sco X-1 is more simple than for most other Galactic jet sources. The lobes of Sco X-1 are similar to hot-spots found in many extragalactic double sources. Scaling the phenomena observed in Sco X-1 to extragalactic sources implies hot-spot variability time-scales of 10^4 yr and hot-spot lifetimes of 10^5 yr. The recurrent formation of lobes in Sco X-1 probably does not occur for extragalactic radio sources.Comment: 22 pages of text + 16 figures. ApJ, in pres

Optimal Image Reconstruction in Radio Interferometry

We introduce a method for analyzing radio interferometry data which produces maps which are optimal in the Bayesian sense of maximum posterior probability density, given certain prior assumptions. It is similar to maximum entropy techniques, but with an exact accounting of the multiplicity instead of the usual approximation involving Stirling's formula. It also incorporates an Occam factor, automatically limiting the effective amount of detail in the map to that justified by the data. We use Gibbs sampling to determine, to any desired degree of accuracy, the multi-dimensional posterior density distribution. From this we can construct a mean posterior map and other measures of the posterior density, including confidence limits on any well-defined function of the posterior map.Comment: 41 pages, 11 figures. High resolution figures 8 and 9 available at http://www.astro.uiuc.edu/~bwandelt/SuttonWandelt200

Instruments of RT-2 Experiment onboard CORONAS-PHOTON and their test and evaluation III: Coded Aperture Mask and Fresnel Zone Plates in RT-2/CZT Payload

Imaging in hard X-rays of any astrophysical source with high angular resolution is a challenging job. Shadow-casting technique is one of the most viable options for imaging in hard X-rays. We have used two different types of shadow-casters, namely, Coded Aperture Mask (CAM) and Fresnel Zone Plate (FZP) pair and two types of pixellated solid-state detectors, namely, CZT and CMOS in RT-2/CZT payload, the hard X-ray imaging instrument onboard the CORONAS-PHOTON satellite. In this paper, we present the results of simulations with different combinations of coders (CAM & FZP) and detectors that are employed in the RT-2/CZT payload. We discuss the possibility of detecting transient Solar flares with good angular resolution for various combinations. Simulated results are compared with laboratory experiments to verify the consistency of the designed configuration.Comment: 27 pages, 16 figures, Accepted for publication in Experimental Astronomy (in press

Ascl1 (Mash1) Defines Cells with Long-Term Neurogenic Potential in Subgranular and Subventricular Zones in Adult Mouse Brain

Ascl1 (Mash1) is a bHLH transcription factor essential for neural differentiation during embryogenesis but its role in adult neurogenesis is less clear. Here we show that in the adult brain Ascl1 is dynamically expressed during neurogenesis in the dentate gyrus subgranular zone (SGZ) and more rostral subventricular zone (SVZ). Specifically, we find Ascl1 levels low in SGZ Type-1 cells and SVZ B cells but increasing as the cells transition to intermediate progenitor stages. In vivo genetic lineage tracing with a tamoxifen (TAM) inducible Ascl1CreERT2 knock-in mouse strain shows that Ascl1 lineage cells continuously generate new neurons over extended periods of time. There is a regionally-specific difference in neuron generation, with mice given TAM at postnatal day 50 showing new dentate gyrus neurons through 30 days post-TAM, but showing new olfactory bulb neurons even 180 days post-TAM. These results show that Ascl1 is not restricted to transit amplifying populations but is also found in a subset of neural stem cells with long-term neurogenic potential in the adult brain