Normal Aging Modulates the Neurotoxicity of Mutant Huntingtin

Aging likely plays a role in neurodegenerative disorders. In Huntington's disease (HD), a disorder caused by an abnormal expansion of a polyglutamine tract in the protein huntingtin (Htt), the role of aging is unclear. For a given tract length, the probability of disease onset increases with age. There are mainly two hypotheses that could explain adult onset in HD: Either mutant Htt progressively produces cumulative defects over time or “normal” aging renders neurons more vulnerable to mutant Htt toxicity. In the present study, we directly explored whether aging affected the toxicity of mutant Htt in vivo. We studied the impact of aging on the effects produced by overexpression of an N-terminal fragment of mutant Htt, of wild-type Htt or of a β-Galactosidase (β-Gal) reporter gene in the rat striatum. Stereotaxic injections of lentiviral vectors were performed simultaneously in young (3 week) and old (15 month) rats. Histological evaluation at different time points after infection demonstrated that the expression of mutant Htt led to pathological changes that were more severe in old rats, including an increase in the number of small Htt-containing aggregates in the neuropil, a greater loss of DARPP-32 immunoreactivity and striatal neurons as assessed by unbiased stereological counts

MOL-based In-Memory Computing of Binary Neural Networks

International audienceConvolutional neural networks (CNN) have proven very effective in a variety of practical applications involving Artificial Intelligence (AI). However, the layer depth of CNN deepens as user applications become more sophisticated, resulting in a huge number of operations and increased memory size. The massive amount of the produced intermediate data leads to intensive data movement between memory and computing cores causing a real bottleneck. In-Memory Computing (IMC) aims to address this bottleneck by directly computing inside memory, eliminating energy-intensive and time-consuming data movement. On the other hand, the emerging Binary Neural Networks (BNN), which is a special case of CNN, shows a number of hardware-friendly properties including memory saving. In BNN, the costly floating-point multiply-and-accumulate is replaced with lightweight bit-wise XNOR and popcount operations. In this paper, we propose an IMC programmable architecture targeting efficient implementation of BNN. Computational memories based on the recently introduced Memristor Overwrite Logic (MOL) design style are employed. The architecture, which is presented in semi-parallel and parallel models, efficiently executes the advanced quantization algorithm of XNOR-Net BNN. Performance evaluation based on CIFAR-10 dataset demonstrates between 1.24× to 3× speedup, and 49% to 99% energy saving compared to state-of-the-art implementations, and up to 273 image/sec/Watt throughput efficiency

Human ESC-Derived Dopamine Neurons Show Similar Preclinical Efficacy and Potency to Fetal Neurons when Grafted in a Rat Model of Parkinson's Disease.

Considerable progress has been made in generating fully functional and transplantable dopamine neurons from human embryonic stem cells (hESCs). Before these cells can be used for cell replacement therapy in Parkinson's disease (PD), it is important to verify their functional properties and efficacy in animal models. Here we provide a comprehensive preclinical assessment of hESC-derived midbrain dopamine neurons in a rat model of PD. We show long-term survival and functionality using clinically relevant MRI and PET imaging techniques and demonstrate efficacy in restoration of motor function with a potency comparable to that seen with human fetal dopamine neurons. Furthermore, we show that hESC-derived dopamine neurons can project sufficiently long distances for use in humans, fully regenerate midbrain-to-forebrain projections, and innervate correct target structures. This provides strong preclinical support for clinical translation of hESC-derived dopamine neurons using approaches similar to those established with fetal cells for the treatment of Parkinson's disease

Quantitative gene expression profiling of mouse brain regions reveals differential transcripts conserved in human and affected in disease models.

Using serial analysis of gene expression, we collected quantitative transcriptome data in 11 regions of the adult wild-type mouse brain: the orbital, prelimbic, cingulate, motor, somatosensory, and entorhinal cortices, the caudate-putamen, the nucleus accumbens, the thalamus, the substantia nigra, and the ventral tegmental area. With >1.2 million cDNA tags sequenced, this database is a powerful resource to explore brain functions and disorders. As an illustration, we performed interregional comparisons and found 315 differential transcripts. Most of them are poorly characterized and 20% lack functional annotation. For 78 differential transcripts, we provide independent expression level measurements in mouse brain regions by real-time quantitative RT-PCR. We also show examples where we used in situ hybridization to achieve infrastructural resolution. For 30 transcripts, we next demonstrated that regional enrichment is conserved in the human brain. We then quantified the expression levels of region-enriched transcripts in the R6/2 mouse model of Huntington disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease and observed significant alterations in the striatum, cerebral cortex, thalamus and substantia nigra of R6/2 mice and in the striatum of MPTP-treated mice. These results show that the gene expression data provided here for the mouse brain can be used to explore pathophysiological models and disclose transcripts differentially expressed in human brain regions

Absence of an effect of age on PGK promoter function.

<p>Young (3 week) and old (15 month) rats received stereotaxic injections of lentiviral vectors encoding β-Gal under the PGK promoter into the striatum. Histological evaluation was carried out 12 weeks after infection to determine the levels of expression of β-Gal using immunohistochemistry (<i>A, B, E, F</i>), β-Gal activity (<i>C, G</i>) and immunofluorescence (D, H). Typical photomicrographs showing the striatum after infection with lentiviral vectors encoding β-Gal in young (<i>A–D</i>) and old (<i>E–H</i>) rats. No major qualitative difference could be detected between young and old rats. <i>I</i>, quantification of the volume of the striatum expressing β-Gal. <i>J</i>, Quantification of β-Gal activity. <i>K</i>, Quantification of immunoreactivity using fluorescence detection. Note the absence of an effect of age. Scale bar = 500 µm for <i>A, C</i> and 50 µm for <i>B–D</i> and <i>F–H</i>. Results are expressed as mean+/−SEM. These are no significant differences as assessed by Student <i>t</i> test.</p

Experimental design to study age-dependent vulnerability of the striatum to mutant huntingtin (Htt).

<p>Young (3 week old) and old (15 month old) rats were injected with a lentiviral vector encoding the 171 N-terminal amino acids of mutant huntingtin with 82 polyglutamine repeats (Htt171-82Q), the corresponding wild-type fragment with 18 polyglutamine repeats (Htt171-18Q) or the reporter protein β-Galactosidase (β-Gal). In the first experiment (<i>A</i>), young and old rats received a stereotaxic injection of lentiviral vectors (2 µl, 200 ng/µl of p24) encoding β-Gal (left striatum) or Htt-171-82Q (right striatum). Histological evaluation was carried out 4 weeks after infection to determine the effects of aging on the expression of β-Gal and Htt171-82Q. In a second experiment (<i>B</i>), the actual degeneration produced by Htt171-82Q was characterized at a later time point after infection. Animals were injected with lentiviral vectors (4 µl, 200 ng/µl of p24) encoding β-Gal mixed with lentiviral vectors encoding either Htt171-82Q or Htt171-18Q. Histological characterization of the striatum consisting of an assessment of DARPP-32, EM48, and β-Gal immunoreactivity and activity was carried out 12 weeks post-infection. Unbiased stereological count of β-Gal-positive neurons were used to compare Htt-171-82Q toxicity with that of Htt171-18Q. Analysis of β-Gal levels in neurons in the Htt171-18Q-expressing striatum permitted the verification of the effect of age on transgene promoter (PGK) efficiency.</p

Loss of DARPP-32 induced by Htt171-82Q is more severe in old rats.

<p>Young (3 week) and old (15 month) rats received a stereotaxic injection of a mixture of lentiviral vectors (4 µl, 200 ng/µl of p24) encoding either Htt171-82Q and β-Gal or Htt171-18Q and β-Gal. Histological evaluation was carried out 12 weeks after infection using DARPP-32 immunohistochemistry. <i>A</i>, representative photomicrograph showing the loss of DARPP-32 in the striatum of a young rat. <i>B</i>, loss of DARPP-32 in the striatum of an old rat. Black arrowheads indicate the area with loss of staining. <i>C</i>, quantification of the volume of DARPP-32-depleted striatum. The loss measured after infection with lenti-Htt171-18Q corresponds to the mechanical damage caused by the injection needle. Note that lesions produced by Htt171-82Q are (+40%) larger in old rats. Results are expressed as mean+/−SEM. *p<0.05, Htt171-82Q vs. Htt171-18Q; #, p<0.01, young vs. old, ANOVA and Bonferroni's <i>post hoc</i> test.</p