Exponential Distribution of Locomotion Activity in Cell Cultures

In vitro velocities of several cell types have been measured using computer controlled video microscopy, which allowed to record the cells' trajectories over several days. On the basis of our large data sets we show that the locomotion activity displays a universal exponential distribution. Thus, motion resulting from complex cellular processes can be well described by an unexpected, but very simple distribution function. A simple phenomenological model based on the interaction of various cellular processes and finite ATP production rate is proposed to explain these experimental results.Comment: 4 pages, 3 figure

New insights into the classification and nomenclature of cortical GABAergic interneurons.

A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts' assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

Live Imaging at the Onset of Cortical Neurogenesis Reveals Differential Appearance of the Neuronal Phenotype in Apical versus Basal Progenitor Progeny

The neurons of the mammalian brain are generated by progenitors dividing either at the apical surface of the ventricular zone (neuroepithelial and radial glial cells, collectively referred to as apical progenitors) or at its basal side (basal progenitors, also called intermediate progenitors). For apical progenitors, the orientation of the cleavage plane relative to their apical-basal axis is thought to be of critical importance for the fate of the daughter cells. For basal progenitors, the relationship between cell polarity, cleavage plane orientation and the fate of daughter cells is unknown. Here, we have investigated these issues at the very onset of cortical neurogenesis. To directly observe the generation of neurons from apical and basal progenitors, we established a novel transgenic mouse line in which membrane GFP is expressed from the beta-III-tubulin promoter, an early pan-neuronal marker, and crossed this line with a previously described knock-in line in which nuclear GFP is expressed from the Tis21 promoter, a pan-neurogenic progenitor marker. Mitotic Tis21-positive basal progenitors nearly always divided symmetrically, generating two neurons, but, in contrast to symmetrically dividing apical progenitors, lacked apical-basal polarity and showed a nearly randomized cleavage plane orientation. Moreover, the appearance of beta-III-tubulin–driven GFP fluorescence in basal progenitor-derived neurons, in contrast to that in apical progenitor-derived neurons, was so rapid that it suggested the initiation of the neuronal phenotype already in the progenitor. Our observations imply that (i) the loss of apical-basal polarity restricts neuronal progenitors to the symmetric mode of cell division, and that (ii) basal progenitors initiate the expression of neuronal phenotype already before mitosis, in contrast to apical progenitors

Monitoring phagocytic uptake of amyloid beta into glial cell lysosomes in real time

Phagocytosis by glial cells is essential to regulate brain function during health and disease. Therapies for Alzheimer's disease (AD) have primarily focused on targeting antibodies to amyloid β (Aβ) or inhibitng enzymes that make it, and while removal of Aβ by phagocytosis is protective early in AD it remains poorly understood. Impaired phagocytic function of glial cells during later stages of AD likely contributes to worsened disease outcome, but the underlying mechanisms of how this occurs remain unknown. We have developed a human Aβ_{1-42} analogue (Aβ^{pH}) that exhibits green fluorescence upon internalization into the acidic organelles of cells but is non-fluorescent at physiological pH. This allowed us to image, for the first time, glial uptake of Aβ^{pH} in real time in live animals. We find that microglia phagocytose more AβpH than astrocytes in culture, in brain slices and in vivo. Aβ^{pH} can be used to investigate the phagocytic mechanisms responsible for removing Aβ from the extracellular space, and thus could become a useful tool to study Aβ clearance at different stages of AD

Sonic hedgehog expressing and responding cells generate neuronal diversity in the medial amygdala

<p>Abstract</p> <p>Background</p> <p>The mammalian amygdala is composed of two primary functional subdivisions, classified according to whether the major output projection of each nucleus is excitatory or inhibitory. The posterior dorsal and ventral subdivisions of the medial amygdala, which primarily contain inhibitory output neurons, modulate specific aspects of innate socio-sexual and aggressive behaviors. However, the development of the neuronal diversity of this complex and important structure remains to be fully elucidated.</p> <p>Results</p> <p>Using a combination of genetic fate-mapping and loss-of-function analyses, we examined the contribution and function of <it>Sonic hedgehog </it>(<it>Shh</it>)-expressing and <it>Shh</it>-responsive (<it>Nkx2-1</it>⁺and <it>Gli1</it>⁺) neurons in the medial amygdala. Specifically, we found that <it>Shh- </it>and <it>Nkx2-1-</it>lineage cells contribute differentially to the dorsal and ventral subdivisions of the postnatal medial amygdala. These <it>Shh</it>- and <it>Nkx2-1</it>-lineage neurons express overlapping and non-overlapping inhibitory neuronal markers, such as Calbindin, FoxP2, nNOS and Somatostatin, revealing diverse fate contributions in discrete medial amygdala nuclear subdivisions. Electrophysiological analysis of the <it>Shh</it>-derived neurons additionally reveals an important functional diversity within this lineage in the medial amygdala. Moreover, inducible <it>Gli1^CreER(T2)</it>temporal fate mapping shows that early-generated progenitors that respond to <it>Shh </it>signaling also contribute to medial amygdala neuronal diversity. Lastly, analysis of <it>Nkx2-1 </it>mutant mice demonstrates a genetic requirement for <it>Nkx2-1 </it>in inhibitory neuronal specification in the medial amygdala distinct from the requirement for <it>Nkx2-1 </it>in cerebral cortical development.</p> <p>Conclusions</p> <p>Taken together, these data reveal a differential contribution of <it>Shh-</it>expressing and <it>Shh</it>-responding cells to medial amygdala neuronal diversity as well as the function of <it>Nkx2-1 </it>in the development of this important limbic system structure.</p

The effect of walnut intake on factors related to prostate and vascular health in older men

<p>Abstract</p> <p>Background</p> <p>Tocopherols may protect against prostate cancer and cardiovascular disease (CVD).</p> <p>Methods</p> <p>We assessed the effect of walnuts, which are rich in tocopherols, on markers of prostate and vascular health in men at risk for prostate cancer. We conducted an 8-week walnut supplement study to examine effects of walnuts on serum tocopherols and prostate specific antigen (PSA). Subjects (<it>n </it>= 21) consumed (in random order) their usual diet +/- a walnut supplement (75 g/d) that was isocalorically incorporated in their habitual diets. Prior to the supplement study, 5 fasted subjects participated in an acute timecourse experiment and had blood taken at baseline and 1, 2, 4, and 8 h after consuming walnuts (75 g).</p> <p>Results</p> <p>During the timecourse experiment, triglycerides peaked at 4 h, and gamma-tocopherol (γ-T) increased from 4 to 8 h. Triglyceride – normalized γ-T was two-fold higher (<it>P </it>= 0.01) after 8 versus 4 h. In the supplement study, change from baseline was +0.83 ± 0.52 μmol/L for γ-T, -2.65 ± 1.30 μmol/L for alpha-tocopherol (α-T) and -3.49 ± 1.99 for the tocopherol ratio (α-T: γ-T). A linear mixed model showed that, although PSA did not change, the ratio of free PSA:total PSA increased and approached significance (P = 0.07). The α-T: γ-T ratio decreased significantly (<it>P </it>= 0.01), partly reflecting an increase in serum γ-T, which approached significance (<it>P </it>= 0.08).</p> <p>Conclusion</p> <p>The significant decrease in the α-T: γ-T ratio with an increase in serum γ-T and a trend towards an increase in the ratio of free PSA:total PSA following the 8-week supplement study suggest that walnuts may improve biomarkers of prostate and vascular status.</p