Synthesis, characterization and 11C radiolabeling of aminophenyl benzothiazoles:structural effects on the alkylation of amino group

Several aminophenyl benzothiazoles were prepared with a view to using them as amyloid binding agents for imaging β-amyloid in Alzheimer's disease. These precursors were radiolabeled with 11C-positron-emitting radioisotope using an automated synthesizer and selected radiolabeled compounds were further purified by HPLC. Our results demonstrate that changes in structure have a major influence on the radioactive yield and the ease with which the radiolabel can be introduced. Aminophenyl benzothiazoles with an attached isopropyl group resisted dialkylation perhaps due to steric hindrance caused by this group. Straight chain attachment of methyl, ethyl, butyl, and crotyl groups in the structure decreased the radiochemical yield. Notably, the o-aminophenyl benzothiazole derivatives were difficult to alkylate despite stringent experimental conditions. This reactivity difference is attributed to the hydrogen bonding characteristics of the o-amino group with the nitrogen atom of the thiazole ring

Enhanced characterization of the zebrafish brain as revealed by super-resolution track-density imaging

In this study, we explored the use of super-resolution track-density imaging (TDI) for neuroanatomical characterization of the adult zebrafish brain. We compared the quality of image contrast and resolution obtained with T-2* magnetic resonance imaging (MRI), diffusion tensor-based imaging (DTI), TDI, and histology. The anatomical structures visualized in 5 mu m TDI maps corresponded with histology. Moreover, the super-resolution property and the local-directional information provided by directionally encoded color TDI facilitated delineation of a larger number of brain regions, commissures and small white matter tracks when compared to conventional MRI and DTI. In total, we were able to visualize 17 structures that were previously unidentifiable using MR microimaging, such as the four layers of the optic tectum. This study demonstrates the use of TDI for characterization of the adult zebrafish brain as a pivotal tool for future phenotypic examination of transgenic models of neurological diseases

Regional cerebral blood flow changes as a function of delta and spindle activity during slow wave sleep in humans

In the present study, we investigated changes in regional cerebral blood flow (rCBF) in humans during the progression from relaxed wakefulness through slow wave sleep (SWS). These changes were examined as a function of spindle (12-15 Hz) and delta (1.5-4.0 Hz) electroencephalographic (EEG) activity of SWS. rCBF was studied with positron emission tomography (PET) using the H215O bolus method. A maximum of six 60 sec scans were performed per subject during periods of wakefulness and stages 1-4 of SWS, as determined by on-line EEG monitoring. Spectral analysis was performed off-line on the EEG epochs corresponding to the scans for computation of activity in specific frequency bands. The relationship between EEG frequency band activity and normalized rCBF was determined by means of a voxel-by-voxel analysis of covariance. delta activity covaried negatively with rCBF most markedly in the thalamus and also in the brainstem reticular formation, cerebellum, anterior cingulate, and orbitofrontal cortex. After the effect of delta was removed, a significant negative covariation between spindle activity and the residual rCBF was evident in the medial thalamus. These negative covariations may reflect the disfacilitation and active inhibition of thalamocortical relay neurons in association with delta and spindles, as well as the neural substrates underlying the progressive attenuation of sensory awareness, motor responsiveness, and arousal that occur during SWS. delta activity covaried positively with rCBF in the visual and auditory cortex, possibly reflecting processes of dream-like mentation purported to occur during SW

The Neurocognitive Components of Pitch Processing: Insights from Absolute Pitch

The natural variability of pitch naming ability in the population (known as absolute pitch or AP) provides an ideal method for investigating individual differences in pitch processing and auditory knowledge formation and representation. We have demonstrated the involvement of different cognitive processes in AP ability that reflects varying skill expertise in the presence of similar early age of onset of music tuition. These processes were related to different regions of brain activity, including those involved in pitch working memory (right prefrontal cortex) and the long-term representation of pitch (superior temporal gyrus). They reflected expertise through the use of context dependent pitch cues and the level of automaticity of pitch naming. They impart functional significance to structural asymmetry differences in the planum temporale of musicians and establish a neurobiological basis for an AP template. More generally, they indicate variability of knowledge representation in the presence of environmental fostering of early cognitive development that translates to differences in cognitive ability

The Neurocognitive Components of Pitch Processing: Insights from Absolute Pitch

The natural variability of pitch naming ability in the population (known as absolute pitch or AP) provides an ideal method for investigating individual differences in pitch processing and auditory knowledge formation and representation. We have demonstrated the involvement of different cognitive processes in AP ability that reflects varying skill expertise in the presence of similar early age of onset of music tuition. These processes were related to different regions of brain activity, including those involved in pitch working memory (right prefrontal cortex) and the long-term representation of pitch (superior temporal gyrus). They reflected expertise through the use of context dependent pitch cues and the level of automaticity of pitch naming. They impart functional significance to structural asymmetry differences in the planum temporale of musicians and establish a neurobiological basis for an AP template. More generally, they indicate variability of knowledge representation in the presence of environmental fostering of early cognitive development that translates to differences in cognitive ability

Super-resolution track-density imaging studies of mouse brain: Comparison to histology

The recently proposed track-density imaging (TDI) technique was introduced as a means to achieve superresolution using diffusion MRI. This technique is able to increase the spatial resolution of the reconstructed images beyond the acquired MRI resolution by incorporating information from whole-brain fibre-tracking results. It not only achieves super-resolution, but also provides very high anatomical contrast with a new MRI contrast mechanism. However, the anatomical information-content of this novel contrast mechanism has not yet been assessed. In this work, we perform such a study using diffusion MRI of ex vivo mouse brains acquired at 16.4T, to compare the results of the super-resolution TDI technique with histological staining (myelin and Nissl stains) in the same brains. Furthermore, a modified version of the directionally-encoded colour TDI map using short-tracks is introduced, which reduces the TDI intensity dynamic range, and therefore enhances the directionality colour-contrast. Good agreement was observed between structures visualised in the superresolution TDI maps and in the histological sections, supporting the anatomical information-content of the images generated using the TDI technique. The results therefore show that the TDI methodology does provide meaningful and rich anatomical contrast, in addition to achieving super-resolution. Furthermore, this study is the first to show the application of TDI to mouse brain imaging: the high-resolution, high-quality images demonstrate the useful complementary information that can be achieved using super-resolution TDI

Segmentation of the C57BL/6J mouse cerebellum in magnetic resonance images

The C57BL mouse is the centerpiece of efforts to use gene-targeting technology to understand cerebellar pathology, thus creating a need for a detailed magnetic resonance imaging (MRI) atlas of the cerebellum of this strain. In this study we present a methodology for systematic delineation of the vermal and hemispheric lobules of the C57BL/6J mouse cerebellum in magnetic resonance images. We have successfully delineated 38 cerebellar and cerebellar-related structures. The higher signal-to-noise ratio achieved by group averaging facilitated the identification of anatomical structures. In addition, we have calculated average region volumes and created probabilistic maps for each structure. The segmentation method and the probabilistic maps we have created will provide a foundation for future studies of cerebellar disorders using transgenic mouse models

Elemental spatial and temporal association formation in left temporal lobe epilepsy

The mesial temporal lobe (MTL) is typically understood as a memory structure in clinical settings, with the sine qua non of MTL damage in epilepsy being memory impairment. Recent models, however, understand memory as one of a number of higher cognitive functions that recruit the MTL through their reliance on more fundamental processes, such as “self-projection” or “association formation”. We examined how damage to the left MTL influences these fundamental processes through the encoding of elemental spatial and temporal associations. We used a novel fMRI task to image the encoding of simple visual stimuli, either rich or impoverished, in spatial or spatial plus temporal information. Participants included 14 typical adults (36.4 years, sd. 10.5 years) and 14 patients with left mesial temporal lobe damage as evidenced by a clinical diagnosis of left temporal lobe epilepsy (TLE) and left MTL impairment on imaging (34.3 years, sd. 6.6 years). In-scanner behavioral performance was equivalent across groups. In the typical group whole-brain analysis revealed highly significant bilateral parahippocampal activation (right > left) during spatial associative processing and left hippocampal/parahippocampal deactivation in joint spatial-temporal associative processing. In the left TLE group identical analyses indicated patients used MTL structures contralateral to the seizure focus differently and relied on extra-MTL regions to a greater extent. These results are consistent with the notion that epileptogenic MTL damage is followed by reorganization of networks underlying elemental associative processes. In addition, they provide further evidence that task-related fMRI deactivation can meaningfully index brain function. The implications of these findings for clinical and cognitive neuropsychological models of MTL function in TLE are discussed

Visualization of mouse barrel cortex using ex-vivo track density imaging

We describe the visualization of the barrel cortex of the primary somatosensory area (S1) of ex vivo adult mouse brain with short-tracks track density imaging (stTDI). stTDI produced much higher definition of barrel structures than conventional fractional anisotropy (FA), directionally-encoded color FA maps, spin-echo and T2-weighted imaging and gradient echo Ti/T2*-weighted imaging. 3D high angular resolution diffusion imaging (HARDI) data were acquired at 48 micron isotropic resolution for a (3 mm)3 block of cortex containing the barrel field and reconstructed using stTDI at 10 micron isotropic resolution. HARDI data were also acquired at 100 micron isotropic resolution to image the whole brain and reconstructed using stTDI at 20 micron isotropic resolution. The 10 micron resolution stTDI maps showed exceptionally clear delineation of barrel structures. Individual barrels could also be distinguished in the 20 micron stTDI maps but the septa separating the individual barrels appeared thicker compared to the 10 micron maps, indicating that the ability of stTDI to produce high quality structural delineation is dependent upon acquisition resolution. Close homology was observed between the barrel structure delineated using stTDI and reconstructed histological data from the same samples. stTDI also detects barrel deletions in the posterior medial barrel sub-field in mice with infraorbital nerve cuts. The results demonstrate that stTDI is a novel imaging technique that enables three-dimensional characterization of complex structures such as the barrels in S1 and provides an important complementary non-invasive imaging tool for studying synaptic connectivity, development and plasticity of the sensory system. (C) 2013 Elsevier Inc. All rights reserved

Pathway-based expression profiling of benign prostatic hyperplasia and prostate cancer delineates an immunophilin molecule associated with cancer progression

Aberrant restoration of AR activity is linked with prostate tumor growth, therapeutic failures and development of castrate-resistant prostate cancer. Understanding the processes leading to ARreactivation should provide the foundation for novel avenues of drug discovery. A differential gene expression study was conducted using biopsies from CaP and BPH patients to identify the components putatively responsible for reinstating AR activity in CaP. From the set of genes upregulated in CaP, FKBP52, an AR co-chaperone, was selected for further analysis. Expression of FKBP52 was positively correlated with that of c-Myc. The functional cross-talk between c-Myc and FKBP52 was established using c-Myc specific-siRNA to LNCaP cells that resulted in reduction of FKBP52. A non-canonical E-box sequence housing a putative c-Myc binding site was detected on the FKBP4 promoter using in silico search. LNCaP cells transfected with the FKBP52 promoter cloned in pGL3 basic showed increased luciferase activity which declined considerably when the promoter-construct was co-transfected with c-Myc specific-siRNA. ChIP-PCR confirmed the binding of c-Myc with the conserved E-box located in the FKBP52 promoter. c-Myc downregulation concomitantly affected expression of FGF8. Since expression of FGF8 is controlled by AR, our study unveiled a novel functional axis between c-Myc, AR and FGF8 operating through FKBP52