Impaired hippocampal plasticity in mice lacking the Cbeta1 catalytic subunit of cAMP-dependent protein kinase.

Neural pathways within the hippocampus undergo use-dependent changes in synaptic efficacy, and these changes are mediated by a number of signaling mechanisms, including cAMP-dependent protein kinase (PKA). The PKA holoenzyme is composed of regulatory and catalytic (C) subunits, both of which exist as multiple isoforms. There are two C subunit genes in mice, Calpha and Cbeta, and the Cbeta gene gives rise to several splice variants that are specifically expressed in discrete regions of the brain. We have used homologous recombination in embryonic stem cells to introduce an inactivating mutation into the mouse Cbeta gene, specifically targeting the Cbeta1-subunit isoform. Homozygous mutants showed normal viability and no obvious pathological defects, despite a complete lack of Cbeta1. The mice were analyzed in electrophysiological paradigms to test the role of this isoform in long-term modulation of synaptic transmission in the Schaffer collateral-CA1 pathway of the hippocampus. A high-frequency stimulus produced potentiation in both wild-type and Cbeta1-/- mice, but the mutants were unable to maintain the potentiated response, resulting in a late phase of long-term potentiation that was only 30% of controls. Paired pulse facilitation was unaffected in the mutant mice. Low-frequency stimulation produced long-term depression and depotentiation in wild-type mice but failed to produce lasting synaptic depression in the Cbeta1 -/- mutants. These data provide direct genetic evidence that PKA, and more specifically the Cbeta1 isoform, is required for long-term depression and depotentiation, as well as the late phase of long-term potentiation in the Schaffer collateral-CA1 pathway.

Early Alzheimer disease-like histopathology increases in frequency with age in mice transgenic for beta-APP751.

beta-Amyloid deposition and neurofibrillary tangle formation are two histopathological features of Alzheimer disease. We have previously reported that beta-amyloid immunoreactive deposits form in the brains of transgenic mice programmed for neuronal expression of the 751-amino acid isoform of human beta-amyloid precursor protein (beta-APP751) and now describe that these animals also display Alz50 intraneuronal immunoreactivity similar to that seen in early Alzheimer disease. This suggests that abnormal beta-APP expression and/or beta-amyloid deposition promotes pathogenic alterations in tau protein. The frequency of both beta-amyloid deposition and Alz50-positive neurons was twice as prevalent in brains from old (22 months) as compared to young (2-3 months) beta-APP751 transgenic mice. This increase in histopathology with age in beta-APP751 transgenic mice parallels the time-dependent progression seen in the human disease.

The role of drinking restraint in alcohol dependence: validation of the temptation and restraint inventory in an alcohol dependent sample

Objective: The Temptation and Restraint Inventory (TRI) is commonly used to measure drinking restraint in relation to problem drinking behavior. However, as yet the TRI has not been validated in a clinical group with alcohol dependence. Method: Male (n = 111) and female (n = 57) inpatients with DSM-IV diagnosed alcohol dependence completed the TRI and measures of problem drinking severity, including the Alcohol Dependence Scale and the quantity, frequency and week total of alcohol consumed. Results: The factor structure of the TRI was replicated in the alcohol dependent sample. Cognitive Emotional Preoccupation (CEP), one of the two higher order factors of the TRI, demonstrated sound predictive power toward all dependence severity indices. The other higher order factor, Cognitive Behavioral Control (CBC), was related to frequency of drinking. There was limited support for the CEP/CBC interactional model of drinking restraint. Conclusions: Although the construct validity of the TRI was sound, the measure appears more useful in understanding the development, maintenance and severity of alcohol-related problems in nondependent drinkers. The TRI may show promise in detecting either continuous drinking or heavy episodic type dependent drinkers.

The relationship between personality and drinking restraint in an alcohol dependent sample

Consistent relationships have been demonstrated between problem drinking and certain personality characteristics. A contemporary cognitive model of alcohol misuse, drinking restraint, has recently shown promise in furthering our understanding of problematic drinking. This study examined the potential association between drinking restraint and personality characteristics in 168 alcohol dependent inpatients. Subjects completed the short-scale Revised Eysenck Personality Scales (EPS-R; Eysenck, Eysenck, & Barrett, 1985), Temptation and Restraint Inventory (TRI; Collins & Lapp, 1992), Alcohol Dependence Scale (ADS; Skinner & Allen, 1982) and drinking measures including quantity, frequency and weekly drinking total. Results indicated that although there was some conceptual overlap between drinking restraint and personality factors, the TRI had a unique relationship with indices of problem drinking once personality factors were taken into account. This indicates that restrained drinking and personality, although related, are discrete constructs. While restrained drinking may aid in the understanding of current drinking behavior, personality characteristics appear to contribute to the etiology and maintenance of drinking problems. (c) 2005 Elsevier Ltd. All rights reserved.

Transient temperature rise in a mouse due to low-frequency regional hyperthermia

A refined nonlinear heat transfer model of a mouse has been developed to simulate the transient temperature rise in a neoplastic tumour and neighbouring tissue during regional hyperthermia using a 150 kHz inductive coil. In this study, we incorporate various bio-energetic enhancements to the heat transfer equation and numerical validations based on experimental findings for the mouse, in terms of nonlinear metabolic heat production, homeothermy, blood perfusion parameters, thermoregulation, psychological and physiological effects. The discretized bio-heat transfer equation has been validated with the commercial software FEMLAB on a canonical multi-sphere object before applying the scheme to the inhomogeneous mouse voxel phantom. The time-dependent numerical results of regional hyperthermia of mouse thigh have been compared with the available experimental temperature results with only a few small disparities. During the first 20 min of local unfocused heating, the temperature in the tumour and the surrounding tissue increased by around 7.5 degrees C. The objective of this preliminary study was to develop a validated electrothermal numerical scheme for inductive hyperthermia of a small mammal with the intention of expanding the model into a complete numerical solution involving ferromagnetic nanoparticles for targeted heating of tumours at low frequencies. In addition, the numerical scheme herein could assist in optimizing and tailoring of focused electromagnetic fields for hyperthermia.

Quantification of the relationship between, magnetoencephalographic (MEG) and blood oxygenation dependent (BOLD) images of brain function

Magnetoencephalography (MEG) is the measurement of the magnetic fields generated outside the head by the brain’s electrical activity. The technique offers the promise of high temporal and spatial resolution. There is however an ambiguity in the inversion process of estimating what goes on inside the head from what is measured outside. Other techniques, such as functional Magnetic Resonance Imaging (fMRI) have no such inversion problems yet suffer from poorer temporal resolution. In this study we examined metrics of mutual information and linear correlation between volumetric images from the two modalities. Measures of mutual information reveal a significant, non-linear, relationship between MEG and fMRI datasets across a number of frequency bands.

Surface acoustic wave devices with low loss and high frequency operation

This thesis describes an industrial research project carried out in collaboration with STC Components, Harlow, Essex. Technical and market trends in the use of surface acoustic wave (SAW) devices are reviewed. As a result, three areas not previously addressed by STC were identified: lower insertion loss designs, higher operating frequencies and improved temperature dependent stability. A review of the temperature performance of alternative lower insertion loss designs,shows that greater use could be made of the on-site quartz growing plant. Data is presented for quartz cuts in the ST-AT range. This data is used to modify the temperature performance of a SAW filter. Several recently identified quartz orientations have been tested. These are SST, LST and X33. Problems associated with each cut are described and devices demonstrated. LST quartz, although sensitive to accuracy of cut, is shown to have an improved temperature coefficient over the normal ST orientation. Results show that its use is restricted due to insertion loss variations with temperature. Effects associated with split-finger transducers on LST-quartz are described. Two low-loss options are studied, coupled resonator filters for very narrow bandwidth applications and single phase unidirectional transducers (SPUDT) for fractional bandwidths up to about 1%. Both designs can be implemented with one quarter wavelength transducer geometries at operating frequencies up to 1GHz. The SPUDT design utilised an existing impulse response model to provide analysis of ladder or rung transducers. A coupled resonator filter at 400MHz is demonstrated with a matched insertion loss of less than 3.5dB and bandwidth of 0.05%. A SPUDT device is designed as a re-timing filter for timing extraction in a long haul PCM transmission system. Filters operating at 565MHz are demonstrated with insertion losses of less than 6dB. This basic SPUDT design is extended to a maximally distributed version and demonstrated at 450MHz with 9.8dB insertion loss.

Frequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus

In Parkinson's disease, subthalamic nucleus (STN) neurons burst fire with increased periodicity and synchrony. This may entail abnormal release of glutamate, the major source of which in STN is cortical afferents. Indeed, the cortico-subthalamic pathway is implicated in the emergence of excessive oscillations, which are reduced, as are symptoms, by dopamine-replacement therapy or deep brain stimulation (DBS) targeted to STN. Here we hypothesize that glutamatergic synapses in the STN may be differentially modulated by low-frequency stimulation (LFS) and high-frequency stimulation (HFS), the latter mimicking deep brain stimulation. Recordings of evoked and spontaneous excitatory post synaptic currents (EPSCs) were made from STN neurons in brain slices obtained from dopamine-intact and chronically dopamine-depleted adult rats. HFS had no significant effect on evoked (e) EPSC amplitude in dopamine-intact slices (104.4±8.0%) but depressed eEPSCs in dopamine-depleted slices (67.8±6.2%). Conversely, LFS potentiated eEPSCs in dopamine-intact slices (126.4±8.1%) but not in dopamine-depleted slices (106.7±10.0%). Analyses of paired-pulse ratio, coefficient of variation, and spontaneous EPSCs suggest that the depression and potentiation have a presynaptic locus of expression. These results indicate that the synaptic efficacy in dopamine-intact tissue is enhanced by LFS. Furthermore, the synaptic efficacy in dopamine-depleted tissue is depressed by HFS. Therefore the therapeutic effects of DBS in Parkinson's disease appear mediated, in part, by glutamatergic cortico-subthalamic synaptic depression and implicate dopamine-dependent increases in the weight of glutamate synapses, which would facilitate the transfer of pathological oscillations from the cortex.

Cross-orientation masking is speed invariant between ocular pathways but speed dependent within them

In human (D. H. Baker, T. S. Meese, & R. J. Summers, 2007b) and in cat (B. Li, M. R. Peterson, J. K. Thompson, T. Duong, & R. D. Freeman, 2005; F. Sengpiel & V. Vorobyov, 2005) there are at least two routes to cross-orientation suppression (XOS): a broadband, non-adaptable, monocular (within-eye) pathway and a more narrowband, adaptable interocular (between the eyes) pathway. We further characterized these two routes psychophysically by measuring the weight of suppression across spatio-temporal frequency for cross-oriented pairs of superimposed flickering Gabor patches. Masking functions were normalized to unmasked detection thresholds and fitted by a two-stage model of contrast gain control (T. S. Meese, M. A. Georgeson, & D. H. Baker, 2006) that was developed to accommodate XOS. The weight of monocular suppression was a power function of the scalar quantity ‘speed’ (temporal-frequency/spatial-frequency). This weight can be expressed as the ratio of non-oriented magno- and parvo-like mechanisms, permitting a fast-acting, early locus, as befits the urgency for action associated with high retinal speeds. In contrast, dichoptic-masking functions superimposed. Overall, this (i) provides further evidence for dissociation between the two forms of XOS in humans, and (ii) indicates that the monocular and interocular varieties of XOS are space/time scale-dependent and scale-invariant, respectively. This suggests an image-processing role for interocular XOS that is tailored to natural image statistics—very different from that of the scale-dependent (speed-dependent) monocular variety.

The effect of frequency and microstructure on corrosion fatigue crack propagation in high strength aluminium alloys

Fatigue crack growth in high strength aluminium alloy 7150 commercial plate material has been studied in both laboratory air and acidified aqueous salt solution. The aggressive aqueous environment enhanced fatigue crack growth rates by up to an order in magnitude compared to laboratory air. The enhancement in fatigue crack growth rate was accompanied by evidence of embrittlement in the crack path, involving both brittle intergranular and transgranular failure modes. Both the enhancement of fatigue crack growth rates and the extent of intergranular growth modes are dependent on cyclic frequency which, along with the absence of a similar frequency effect in a spray-formed version of the material with a significantly different grain structure, supports a mechanism of grain boundary hydrogen diffusion for intergranular corrosion fatigue crack growth. The convergence of corrosion fatigue crack growth rates at high ΔK in both spray-formed and conventional plate materials coincides with the operation of identical transgranular corrosion fatigue modes dependent on strain-controlled hydrogen diffusion ahead of the crack tip. © 1997 Acta Metallurgica Inc.

Spin dependent photoconductivity in silicon-on-sapphire

Resonant and non resonant spin dependent photoconductivity is observed in(100) silicon films grown on sapphire by CVD and MBE techniques. The CVD films are either in their as-grown state or have undergone single or double solid phase epitaxial regrowth. For all samples, a resonant decrease in photoconductivity is observed at a field of about 0.34 T for a microwave frequency of about 9.7 GHz and at about 3.3 mT when the frequency is about 92 MHz. For all samples the maximum fractional change in photoconductivity is approximately 10-4 independent of magnetic field strength.

Noise in gallium nitride-based quantum well structures used for nanometer devices in the frequency range 1 Hz--3 Mhz and temperature range 77K--324K

Electronic noise has been investigated in AlxGa1−x N/GaN Modulation-Doped Field Effect Transistors (MODFETs) of submicron dimensions, grown for us by MBE (Molecular Beam Epitaxy) techniques at Virginia Commonwealth University by Dr. H. Morkoç and coworkers. Some 20 devices were grown on a GaN substrate, four of which have leads bonded to source (S), drain (D), and gate (G) pads, respectively. Conduction takes place in the quasi-2D layer of the junction (xy plane) which is perpendicular to the quantum well (z-direction) of average triangular width ∼3 nm. A non-doped intrinsic buffer layer of ∼5 nm separates the Si-doped donors in the AlxGa1−xN layer from the 2D-transistor plane, which affords a very high electron mobility, thus enabling high-speed devices. Since all contacts (S, D, and G) must reach through the AlxGa1−xN layer to connect internally to the 2D plane, parallel conduction through this layer is a feature of all modulation-doped devices. While the shunting effect may account for no more than a few percent of the current IDS, it is responsible for most excess noise, over and above thermal noise of the device. ^ The excess noise has been analyzed as a sum of Lorentzian spectra and 1/f noise. The Lorentzian noise has been ascribed to trapping of the carriers in the AlxGa1−xN layer. A detailed, multitrapping generation-recombination noise theory is presented, which shows that an exponential relationship exists for the time constants obtained from the spectral components as a function of 1/kT. The trap depths have been obtained from Arrhenius plots of log (τT2) vs. 1000/T. Comparison with previous noise results for GaAs devices shows that: (a) many more trapping levels are present in these nitride-based devices; (b) the traps are deeper (farther below the conduction band) than for GaAs. Furthermore, the magnitude of the noise is strongly dependent on the level of depletion of the AlxGa1−xN donor layer, which can be altered by a negative or positive gate bias VGS. ^ Altogether, these frontier nitride-based devices are promising for bluish light optoelectronic devices and lasers; however, the noise, though well understood, indicates that the purity of the constituent layers should be greatly improved for future technological applications. ^

Calcium/Calmodulin-Dependent Protein Kinase II Serves as a Biochemical Integrator of Calcium Signals for the Induction of Synaptic Plasticity

Repetitive Ca2+ transients in dendritic spines induce various forms of synaptic plasticity by transmitting information encoded in their frequency and amplitude. CaMKII plays a critical role in decoding these Ca2+ signals to initiate long-lasting synaptic plasticity. However, the properties of CaMKII that mediate Ca2+ decoding in spines remain elusive. Here, I measured CaMKII activity in spines using fast-framing two-photon fluorescence lifetime imaging. Following each repetitive Ca2+ elevations, CaMKII activity increased in a stepwise manner. This signal integration, at the time scale of seconds, critically depended on Thr286 phosphorylation. In the absence of Thr286 phosphorylation, only by increasing the frequency of repetitive Ca2+ elevations could high peak CaMKII activity or plasticity be induced. In addition, I measured the association between CaMKII and Ca2+/CaM during spine plasticity induction. Unlike CaMKII activity, association of Ca2+/CaM to CaMKII plateaued at the first Ca2+ elevation event. This result indicated that integration of Ca2+ signals was initiated by the binding of Ca2+/CaM and amplified by the subsequent increases in Thr286-phosphorylated form of CaMKII. Together, these findings demonstrate that CaMKII functions as a leaky integrator of repetitive Ca2+ signals during the induction of synaptic plasticity, and that Thr286 phosphorylation is critical for defining the frequencies of such integration.

Growth and shrinkage in Antarctic krill Euphausia superba is sex-dependent

ABSTRACT: The ability of Antarctic krill Euphausia superba Dana to withstand the overwintering period is critical to their success. Laboratory evidence suggests that krill may shrink in body length during this time in response to the low availability of food. Nevertheless, verification that krill can shrink in the natural environment is lacking because winter data are difficult to obtain. One of the few sources of winter krill population data is from commercial vessels. We examined length-frequency data of adult krill (>35 mm total body length) obtained from commercial vessels in the Scotia-Weddell region and compared our results with those obtained from a combination of science and commercial sampling operations carried out in this region at other times of the year. Our analyses revealed body-length shrinkage in adult females but not males during overwinter, based on both the tracking of modal size classes over seasons and sex-ratio patterns. Other explanatory factors, such as differential mortality, immigration and emigration, could not explain the observed differences. The same pattern was also observed at South Georgia and in the Western Antarctic Peninsula. Fitted seasonally modulated von Bertalanffy growth functions predicted a pattern of overwintering shrinkage in all body-length classes of females, but only stagnation in growth in males. This shrinkage most likely reflects morphometric changes resulting from the contraction of the ovaries and is not necessarily an outcome of winter hardship. The sex-dependent changes that we observed need to be incorporated into life cycle and population dynamic models of this species, particularly those used in managing the fishery. KEY WORDS: Southern Ocean · Population dynamics · Production · Life cycle · Fishery

Growth and shrinkage in Antarctic krill Euphausia superba is sex-dependent

ABSTRACT: The ability of Antarctic krill Euphausia superba Dana to withstand the overwintering period is critical to their success. Laboratory evidence suggests that krill may shrink in body length during this time in response to the low availability of food. Nevertheless, verification that krill can shrink in the natural environment is lacking because winter data are difficult to obtain. One of the few sources of winter krill population data is from commercial vessels. We examined length-frequency data of adult krill (>35 mm total body length) obtained from commercial vessels in the Scotia-Weddell region and compared our results with those obtained from a combination of science and commercial sampling operations carried out in this region at other times of the year. Our analyses revealed body-length shrinkage in adult females but not males during overwinter, based on both the tracking of modal size classes over seasons and sex-ratio patterns. Other explanatory factors, such as differential mortality, immigration and emigration, could not explain the observed differences. The same pattern was also observed at South Georgia and in the Western Antarctic Peninsula. Fitted seasonally modulated von Bertalanffy growth functions predicted a pattern of overwintering shrinkage in all body-length classes of females, but only stagnation in growth in males. This shrinkage most likely reflects morphometric changes resulting from the contraction of the ovaries and is not necessarily an outcome of winter hardship. The sex-dependent changes that we observed need to be incorporated into life cycle and population dynamic models of this species, particularly those used in managing the fishery. KEY WORDS: Southern Ocean · Population dynamics · Production · Life cycle · Fishery