JIP1-Mediated JNK Activation Negatively Regulates Synaptic Plasticity and Spatial Memory

The c-Jun N-terminal kinase (JNK) signal transduction pathway is implicated in learning and memory. Here, we examined the role of JNK activation mediated by the JIP1 scaffold protein. We compared male wild-type mice with a mouse model harboring a point mutation in the Jip1 gene that selectively blocks JIP1-mediated JNK activation. These male mutant mice exhibited increased NMDA receptor currents, increased NMDA receptor-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation. The JIP1 mutant mice also displayed improved hippocampus-dependent spatial memory and enhanced associative fear conditioning. These results were confirmed using a second JIP1 mutant mouse model that suppresses JNK activity. Together, these observations establish that JIP1-mediated JNK activation contributes to the regulation of hippocampus-dependent, NMDA receptor-mediated synaptic plasticity and learning. SIGNIFICANCE STATEMENT: The results of this study demonstrate that JNK activation induced by the JIP1 scaffold protein negatively regulates the threshold for induction of long-term synaptic plasticity through the NMDA-type glutamate receptor. This change in plasticity threshold influences learning. Indeed, mice with defects in JIP1-mediated JNK activation display enhanced memory in hippocampus-dependent tasks, such as contextual fear conditioning and Morris water maze, indicating that JIP1-JNK constrains spatial memory. This study reports the identification of JIP1-mediated JNK activation as a novel molecular pathway that negatively regulates NMDA receptor-dependent synaptic plasticity and memory

Optical Intensity Interferometry with the Cherenkov Telescope Array

With its unprecedented light-collecting area for night-sky observations, the Cherenkov Telescope Array (CTA) holds great potential for also optical stellar astronomy, in particular as a multi-element intensity interferometer for realizing imaging with sub-milliarcsecond angular resolution. Such an order-of-magnitude increase of the spatial resolution achieved in optical astronomy will reveal the surfaces of rotationally flattened stars with structures in their circumstellar disks and winds, or the gas flows between close binaries. Image reconstruction is feasible from the second-order coherence of light, measured as the temporal correlations of arrival times between photons recorded in different telescopes. This technique (once pioneered by Hanbury Brown and Twiss) connects telescopes only with electronic signals and is practically insensitive to atmospheric turbulence and to imperfections in telescope optics. Detector and telescope requirements are very similar to those for imaging air Cherenkov observatories, the main difference being the signal processing (calculating cross correlations between single camera pixels in pairs of telescopes). Observations of brighter stars are not limited by sky brightness, permitting efficient CTA use during also bright-Moon periods. While other concepts have been proposed to realize kilometer-scale optical interferometers of conventional amplitude (phase-) type, both in space and on the ground, their complexity places them much further into the future than CTA, which thus could become the first kilometer-scale optical imager in astronomy.Comment: Astroparticle Physics, in press; 47 pages, 10 figures, 124 reference

Stellar Intensity Interferometry: Prospects for sub-milliarcsecond optical imaging

Using kilometric arrays of air Cherenkov telescopes, intensity interferometry may increase the spatial resolution in optical astronomy by an order of magnitude, enabling images of rapidly rotating stars with structures in their circumstellar disks and winds, or mapping out patterns of nonradial pulsations across stellar surfaces. Intensity interferometry (pioneered by Hanbury Brown and Twiss) connects telescopes only electronically, and is practically insensitive to atmospheric turbulence and optical imperfections, permitting observations over long baselines and through large airmasses, also at short optical wavelengths. The required large telescopes with very fast detectors are becoming available as arrays of air Cherenkov telescopes, distributed over a few square km. Digital signal handling enables very many baselines to be synthesized, while stars are tracked with electronic time delays, thus synthesizing an optical interferometer in software. Simulated observations indicate limiting magnitudes around m(v)=8, reaching resolutions ~30 microarcsec in the violet. The signal-to-noise ratio favors high-temperature sources and emission-line structures, and is independent of the optical passband, be it a single spectral line or the broad spectral continuum. Intensity interferometry provides the modulus (but not phase) of any spatial frequency component of the source image; for this reason image reconstruction requires phase retrieval techniques, feasible if sufficient coverage of the interferometric (u,v)-plane is available. Experiments are in progress; test telescopes have been erected, and trials in connecting large Cherenkov telescopes have been carried out. This paper reviews this interferometric method in view of the new possibilities offered by arrays of air Cherenkov telescopes, and outlines observational programs that should become realistic already in the rather near future.Comment: New Astronomy Reviews, in press; 101 pages, 11 figures, 185 reference

Spectrophotometric Distances to Galactic H\,{\sc{ii}} Regions

We present a near infrared study of the stellar content of 35 H\,{\sc{ii}} regions in the Galactic plane. In this work, we have used the near infrared domain $J-$, $H-$ and $K_{s}-$ band color images to visually inspect the sample. Also, color-color and color-magnitude diagrams were used to indicate ionizing star candidates, as well as, the presence of young stellar objects such as classical TTauri Stars (CTTS) and massive young stellar objects (MYSOs). We have obtained {\it Spitzer} IRAC images for each region to help further characterize them. {\it Spitzer} and near infrared morphology to place each cluster in an evolutionary phase of development. {\it Spitzer} photometry was also used to classify the MYSOs. Comparison of the main sequence in color-magnitude diagrams to each observed cluster was used to infer whether or not the cluster kinematic distance is consistent with brightnesses of the stellar sources. We find qualitative agreement for a dozen of the regions, but about half the regions have near infrared photometry that suggests they may be closer than the kinematic distance. A significant fraction of these already have spectrophotometric parallaxes which support smaller distances. These discrepancies between kinematic and spectrophotometric distances are not due to the spectrophotometric methodologies, since independent non-kinematic measurements are in agreement with the spectrophotometric results. For instance, trigonometric parallaxes of star-forming regions were collected from the literature and show the same effect of smaller distances when compared to the kinematic results. In our sample of H\,{\sc{ii}} regions, most of the clusters are evident in the near infrared images. Finally, it is possible to distinguish among qualitative evolutionary stages for these objects.Comment: 59 pages, 146 figures and 4 tables. MNRAS accepte

Adenylyl Cyclases 1 and 8 Initiate a Presynaptic Homeostatic Response to Ethanol Treatment

BACKGROUND:Although ethanol exerts widespread action in the brain, only recently has progress been made in understanding the specific events occurring at the synapse during ethanol exposure. Mice deficient in the calcium-stimulated adenylyl cyclases, AC1 and AC8 (DKO), demonstrate increased sedation duration and impaired phosphorylation by protein kinase A (PKA) following acute ethanol treatment. While not direct targets for ethanol, we hypothesize that these cyclases initiate a homeostatic presynaptic response by PKA to reactivate neurons from ethanol-mediated inhibition. METHODOLOGY/PRINCIPAL FINDINGS:Here, we have used phosphoproteomic techniques and identified several presynaptic proteins that are phosphorylated in the brains of wild type mice (WT) after ethanol exposure, including synapsin, a known PKA target. Phosphorylation of synapsins I and II, as well as phosphorylation of non-PKA targets, such as, eukaryotic elongation factor-2 (eEF-2) and dynamin is significantly impaired in the brains of DKO mice. This deficit is primarily driven by AC1, as AC1-deficient, but not AC8-deficient mice also demonstrate significant reductions in phosphorylation of synapsin and eEF-2 in cortical and hippocampal tissues. DKO mice have a reduced pool of functional recycling vesicles and fewer active terminals as measured by FM1-43 uptake compared to WT controls, which may be a contributing factor to the impaired presynaptic response to ethanol treatment. CONCLUSIONS/SIGNIFICANCE:These data demonstrate that calcium-stimulated AC-dependent PKA activation in the presynaptic terminal, primarily driven by AC1, is a critical event in the reactivation of neurons following ethanol-induced activity blockade

Chronic Alcohol Exposure Alters Behavioral and Synaptic Plasticity of the Rodent Prefrontal Cortex

In the present study, we used a mouse model of chronic intermittent ethanol (CIE) exposure to examine how CIE alters the plasticity of the medial prefrontal cortex (mPFC). In acute slices obtained either immediately or 1-week after the last episode of alcohol exposure, voltage-clamp recording of excitatory post-synaptic currents (EPSCs) in mPFC layer V pyramidal neurons revealed that CIE exposure resulted in an increase in the NMDA/AMPA current ratio. This increase appeared to result from a selective increase in the NMDA component of the EPSC. Consistent with this, Western blot analysis of the postsynaptic density fraction showed that while there was no change in expression of the AMPA GluR1 subunit, NMDA NR1 and NRB subunits were significantly increased in CIE exposed mice when examined immediately after the last episode of alcohol exposure. Unexpectedly, this increase in NR1 and NR2B was no longer observed after 1-week of withdrawal in spite of a persistent increase in synaptic NMDA currents. Analysis of spines on the basal dendrites of layer V neurons revealed that while the total density of spines was not altered, there was a selective increase in the density of mushroom-type spines following CIE exposure. Examination of NMDA-receptor mediated spike-timing-dependent plasticity (STDP) showed that CIE exposure was associated with altered expression of long-term potentiation (LTP). Lastly, behavioral studies using an attentional set-shifting task that depends upon the mPFC for optimal performance revealed deficits in cognitive flexibility in CIE exposed mice when tested up to 1-week after the last episode of alcohol exposure. Taken together, these observations are consistent with those in human alcoholics showing protracted deficits in executive function, and suggest these deficits may be associated with alterations in synaptic plasticity in the mPFC

Systematic review of the epidemiological evidence comparing lung cancer risk in smokers of mentholated and unmentholated cigarettes

<p>Abstract</p> <p>Background</p> <p>US mentholated cigarette sales have increased considerably over 50 years. Preference for mentholated cigarettes is markedly higher in Black people. While menthol itself is not genotoxic or carcinogenic, its acute respiratory effects might affect inhalation of cigarette smoke. This possibility seems consistent with the higher lung cancer risk in Black men, despite Black people smoking less and starting smoking later than White people. Despite experimental data suggesting similar carcinogenicity of mentholated and non-mentholated cigarettes, the lack of convincing evidence that mentholation increases puffing, inhalation or smoke uptake, and the similarity of lung cancer rates in Black and White females, a review of cigarette mentholation and lung cancer is timely given current regulatory interest in the topic.</p> <p>Methods</p> <p>Epidemiological studies comparing lung cancer risk in mentholated and non-mentholated cigarette smokers were identified from MedLine and other sources. Study details were extracted and strengths and weaknesses assessed. Relative risk estimates were extracted, or derived, for ever mentholated use and for long-term use, overall and by gender, race, and current/ever smoking, and meta-analyses conducted.</p> <p>Results</p> <p>Eight generally good quality studies were identified, with valid cases and controls, and appropriate adjustment for age, gender, race and smoking. The studies afforded good power to detect possible effects. However, only one study presented results by histological type, none adjusted for occupation or diet, and some provided no results by length of mentholated cigarette use.</p> <p>The data do not suggest any effect of mentholation on lung cancer risk. Adjusted relative risk estimates for ever use vary from 0.81 to 1.12, giving a combined estimate of 0.93 (95% confidence interval 0.84-1.02, n = 8), with no increase in males (1.01, 0.84-1.22, n = 5), females (0.80, 0.67-0.95, n = 5), White people (0.87, 0.75-1.03, n = 4) or Black people (0.90, 0.73-1.10, n = 4). Estimates for current and ever smokers are similar. The combined estimate for long-term use (0.95, 0.80-1.13, n = 4) again suggests no effect of mentholation.</p> <p>Conclusion</p> <p>Higher lung cancer rates in Black males cannot be due to their greater preference for mentholated cigarettes. While some study weaknesses exist, the epidemiological evidence is consistent with mentholation having no effect on the lung carcinogenicity of cigarettes.</p