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Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering.

Lacustrine sediments from the Northeast Plain of China are an ideal archive for recording the climatic history and variability of the East Asian monsoon during the Quaternary in mid-latitude East Asia. However, the lack of a high-resolution stratigraphy and high-precision geochronology of these sediments has limited our understanding of the mechanisms of Quaternary climatic and environmental changes in the region. In this study, we present a high-resolution magnetic susceptibility stratigraphy and precise paleomagnetic and optically stimulated luminescence (OSL) chronologies for core Qiananlingzi (QAL) from the Northeast Plain. Paleomagnetic data were obtained using alternating-field (AF) demagnetization with a peak AF of 80 mT and increments of 2.5−10 mT. In addition, OSL dating was conducted on coarse-grained quartz (90−150 µm) using the single aliquot regenerative dose (SAR) protocol. Correlation of the recognized polarity intervals of the QAL core to the geomagnetic polarity timescale was achieved by combining the magnetostratigraphic and OSL geochronologic data. The results indicate that the sedimentary sequence spans the interval from the Olduvai normal subchron to the end of the Brunhes normal chron. According to the lithology and the magnetic susceptibility record, the core can be divided into four intervals, from bottom to top: the Qian’an Formation (fluvial yellow-green, brown-red and grey-brown silty sand, interbedded with brown-black silty clay, with gravel layers in the lower part); the Lingzi Formation and Lindian Formation (lacustrine grey-green clay interbedded with grey-white silty sand, with fossil bivalves); and a loess-like soil (predominantly brown-yellow clayey silt, alternating with fluviolacustrine grey-white, brown and black clay). The magnetic susceptibilities (MS) of the sediments of the lower fluvial Qian’an Formation and upper loess-like soil strata are generally higher, indicating the neoformation of strongly magnetic minerals under predominantly oxidizing conditions. By contrast, lower MS values occur in the lacustrine sediments of the Lingzi Formation and Lindian Formation, which indicate a reducing environment. Overall, the MS record of the QAL core exhibits clear orbital-scale variations, with higher MS values in coarse-grained silt layers, and lower values in fine-grained clay layers. After the application of a 300 mT DC field, the isothermal remanence (IRM) is only 70%, and a hysteresis loop remained unclosed at 500 mT. These characteristics indicate the substantial presence of high-coercivity magnetic minerals in the intervals with low MS values. Thermomagnetic measurements ( χ - T ) curves show an abrupt decrease in the heating curve at 580°C, indicating that magnetite is the dominant magnetic mineral, and a further decrease above 580°C indicates the presence of hematite. After the application of an applied DC field of 300 mT, the IRM reached 90%, the hysteresis loop was closed, and the heating limb of the χ - T curve did not decrease significantly after 580°C, indicating that low-coercivity magnetic minerals contributed substantially to the magnetic properties within the intervals of higher MS. The lacustrine sediments of the core were dated to ~1180‒450 ka based on paleomagnetic and QSL dating, and interpolation of the age-depth relationship suggests that Songnen paleo-lake existed for ~730 ka. The grain-size record of the loess in the northeastern monsoon region shows no evidence of drought events at 450 ka, and records of MS and FeD/FeT from the deposits of the loess Plateau indicate a trend of increasing summer monsoon precipitation at this time. Therefore, the disappearance of the paleo-lake may be related to the multiple episodes of subsidence of the Yishu fault, which caused a diversion of the discharge of the Songhua River from the Songnen paleo-lake to the Sanjiang Plain. The high-resolution MS record and the precise chronology obtained in this study indicate that the lacustrine sedimentary sequence of QAL core can potentially resolve orbital-scale paleoclimate changes during the middle Pleistocene in mid-latitude East Asia. The Mid-Pleistocene Transition (MPT) is one of the most important climatic events in Quaternary paleoclimatology, and it is necessary to understand the response of different climatic systems to the MPT. Detailed environmental magnetic, sedimentological and geochemical studies of lacustrine sedimentary strata in the Northeast Plain in China should be carried out to explore the paleoclimatic record of the area, including the regional climatic response to the MPT.

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and the brains of HD mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in neurons and mouse brains that have undergone accelerated aging, including a selective increase in DNA damage. These findings suggest a role for aging in HD pathogenesis and an interaction between the biological age of HD neurons and sensitivity to exogenous stress.

Hypoxic/ischemic insult, a leading cause of functional brain defects, has been extensively studied in both clinical and experimental animal research, including its etiology, neuropathogenesis, and pharmacological interventions. Transient sublethal hypoxia (TSH) is a common clinical occurrence in the perinatal period. However, its effect on early developing brains remains poorly understood. The present study was designed to investigate the effect of TSH on the dendrite and dendritic spine formation, neuronal and synaptic activity, and cognitive behavior of early postnatal Day 1 rat pups. While TSH showed no obvious effect on gross brain morphology, neuron cell density, or glial activation in the hippocampus, we found transient hypoxia did cause significant changes in neuronal structure and function. In brains exposed to TSH, hippocampal neurons developed shorter and thinner dendrites, with decreased dendritic spine density, and reduced strength in excitatory synaptic transmission. Moreover, TSH-treated rats showed impaired cognitive performance in spatial learning and memory. Our findings demonstrate that TSH in newborn rats can cause significant impairments in synaptic formation and function, and long-lasting brain functional deficits. Therefore, this study provides a useful animal model for the study of TSH on early developing brains and to explore potential pharmaceutical interventions for patients subjected to TSH insult.

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in huntingtin (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in iPSC-derived neurons and mouse brains that have undergone accelerated aging. These findings suggest a role for aging in HD pathogenesis and interaction between biological age of HD neurons and sensitivity to exogenous stress.

Fluvial, lacustrine and aeolian sediments in the Hulun Buir Sandy Land (HBSL), northeast China are investigated for the first time to be a key supplementation of the Asian aeolian dust system. Fine-grained components (

Oxidative stress is a prominent feature of Huntington disease (HD), and we have shown previously that reduced levels of hace1 (HECT domain and Ankyrin repeat containing E3 ubiquitin protein ligase 1) in patient striatum may contribute to the pathogenesis of HD. Hace1 promotes the stability of Nrf2 and thus plays an important role in antioxidant response mechanisms, which are dysfunctional in HD. Moreover, hace1 overexpression mitigates mutant huntingtin (mHTT)-induced oxidative stress in vitro through promotion of the Nrf2 antioxidant response. Here, we show that the genetic ablation of hace1 in the YAC128 mouse model of HD accelerates motor deficits and exacerbates cognitive and psychiatric phenotypes in vivo. We find that both the expression of mHTT and the ablation of hace1 alone are sufficient to cause deficits in astrocytic mitochondrial respiration. We confirm the crucial role of hace1 in astrocytes in vivo, since its ablation is sufficient to cause dramatic astrogliosis in wild-type FVB/N mice. Astrogliosis is not observed in the presence of mHTT but a strong dysregulation in the expression of astrocytic markers in HACE1-/- x YAC128 striatum suggests an additive effect of mHTT expression and hace1 loss on this cell type. HACE1-/- x YAC128 mice and primary cells derived from these animals therefore provide model systems that will allow for the further dissection of Nrf2 pathways and astrocyte dysfunction in the context of HD.

The Harbin loess in Northeast China, located in the easternmost part of the Eurasian loess belt, has great potential to reconstruct the aridity history of the Songnen Plain and to reveal its dynamic process. However, the relationship between coupled tectonic-climate-drainage evolution and the aridification in the Songnen Plain is currently poorly understood. In this study, we present a high-resolution magnetic susceptibility, grain-size, trace element, Sr Nd isotope, total organic carbon (TOC), and organic carbon isotope composition (δ13C) record retrieved from the Harbin loess-paleosol sequences to reveal the aridification history in the Songnen Plain. These results reveal a long-term drying trend in the Songnen Plain since 0.46 Ma, indicating the birth of the Songnen Sandy Land at that time. Superimposed on the major aridification trend, two significant abrupt drying events were found at ~300 ka and ~ 380 ka. However, the climate in the Songnen Plain became wetter and warmer under the background of the long-term drought since 180 ka. The global ice/temperature changes, regional tectonics (i.e., uplift of the Songliao divide) and drainage change (i.e., river pattern shift in the Songnen Plain from endorheic to exorheic drainage, and termination of the Songnen paleolake) were collectively responsible for the aridification in the Songnen Plain. This study has further improved knowledge of the process of the aridification in Northeast China, which is of great significance to control land desertification and ecological imbalance.

The Harbin loess, typical of the loess in NE China, is located in the easternmost margin of the Eurasian loess belt, and was recently investigated from the perspective of an Asian aeolian dust system. Before this study, the geochemical composition and provenance of the Harbin loess remained poorly understood. More importantly, the study of the Harbin loess also provides a unique opportunity to understand the geomorphological evolution process of the large Songliao palaeolake in the Northeast Plain. This study presents the results on the geochemical characteristics (major elements, trace elements, rare earth elements and Sr–Nd isotope) of the Harbin loess. There are markedly consistent geochemical compositions in and between the loess and palaeosol sediments, revealing stable dust sources and identical sources for the loess and palaeosol. Various indicators illustrating weathering and recycling indicate that the Harbin loess–palaeosol sediments were derived from sources with a low degree of weathering and from material with first-cycle alluvial–lacustrine deposits. Combinations of various provenance tracing indicators indicate that the Harbin loess has a strong geochemical affinity with the Songnen Sandy Land and to a certain extent the Horqin Sandy Land but not with the Hulun Buir Sandy Land, which indicates that these loess deposits are derived from a mixed provenance, with the dominant source being the neighbouring Songnen Sandy Land and a second, distal source being the Horqin Sandy Land. Finally, we advocate that the Harbin loess accumulation could serve as the direct record of the Songliao palaeolake disappearance. Supplementary material: Data for the NE Sandy Lands of China, and full provenance discrimination diagrams are available at https://doi.org/10.6084/m9.figshare.c.3835009.

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) protein, resulting in acquisition of toxic functions. Previous studies have shown that lowering mutant HTT has the potential to be broadly beneficial. We previously identified HTT single-nucleotide polymorphisms (SNPs) tightly linked to the HD mutation and developed antisense oligonucleotides (ASOs) targeting HD-SNPs that selectively suppress mutant HTT. We tested allele-specific ASOs in a mouse model of HD. Both early and late treatment reduced cognitive and behavioral impairments in mice. To determine the translational potential of the treatment, we examined the effect of ASO administration on HTT brain expression in nonhuman primates. The treatment induced robust HTT suppression throughout the cortex and limbic system, areas implicated in cognition and psychiatric function. The results suggest that ASOs specifically targeting mutated HTT might have therapeutic effects on HD-mediated cognitive impairments.

The study of drainage evolution in the Songnen Plain, Northeast China, is essential for understanding the interactions between tectonics-topography-climate-drainage evolution in the region. Despite this, it remains unclear whether the paleo-Songhua River (upper-middle reaches of the Songhua River) once flowed westward into the Songnen Plain and what forcings influenced the drainage development of the Songnen Plain. In this contribution, we provide insight into drainage development on the Songnen Plain using an integrated approach of magnetic susceptibility, geochemical (elemental and Sr Nd isotopic) and heavy mineral composition recovered from a 102-m sediment core sediments extracted from the eastern edge of the Songnen Plain with sedimentological and topographic archives. Our results show that a dramatic provenance shift occurred at the depth of 62.2 m (~0.94 Ma) in the core sediments. It is proposed that the Songhua River was separated by the Jia-Yi (Jiamushi-Yilan) divide into two segments before ~0.94 Ma, the west-flowing proto-Songhua River and the east-flowing proto-Sanjiang River (lower reach of the Songhua River). However, the proto-Songhua River reversed direction at ~0.94 Ma when the Jia-Yi divide was cut through by headward erosion of the proto-Sanjiang River, marking the birth of the Songhua River as a single, eastward-flowing river system. Tectonics is suggested as the first-order control on the evolution of the Songhua River before 1.20 Ma, whereas climate changes may be responsible after 1.20 Ma.

White matter (WM) atrophy is a significant feature of Huntington disease (HD), although its aetiology and early pathological manifestations remain poorly defined. In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WM abnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus callosum indicated that myelin sheaths are thinner in YAC128 mice as early as 1.5 months of age, well before any neuronal loss can be detected. Transcript levels of myelin-related genes in striatal and cortical tissues were significantly lower in YAC128 mice from 2 weeks of age, and these findings were replicated in differentiated primary oligodendrocytes from YAC128 mice, suggesting a possible mechanistic explanation for the observed structural deficits. Concordant with these observations, we demonstrate reduced expression of myelin-related genes at 3 months of age and WM microstructural abnormalities using DT-MRI at 12 months of age in the BACHD rats. These findings indicate that WM deficits in HD are an early phenotype associated with cell-intrinsic effects of mutant huntingtin on myelin-related transcripts in oligodendrocytes, and raise the possibility that WM abnormalities may be an early contributing factor to the pathogenesis of HD.

The Sr-Nd isotopic study of the Northeast Sandy Land (NESL), China is of great significance for a thorough understanding of the dust system in this area. The 162 bulk (

The toxic functions of the mutant Huntingtin protein (mutHTT) were studied extensively and in addition to neuronal based symptoms, also peripheral changes upon mutHTT expression were described. An important finding in Huntington’s disease (HD) research from the last years is the discovery of extracellular mutHTT and evidence of cell to cell spreading of the mutant protein. This offers new opportunities for targeting mutHTT by antibodies or target-specific vaccines. Recent publications revealed that mutHTT protein was largely present in a free, non-encapsulated form in the extracellular compartment thereby making it accessible by antibodies. We previously demonstrated peripheral target engagement in actively and passively vaccinated YAC128 mice. In these experiments, mutHTT lowering was accompanied by motor improvement in rotarod assays. We sought to generate an in vitro model for testing the molecular mode of action of newly developed mutHTT targeting antibodies and vaccines. Lead antibody C6–17 was capable of depleting mutHTT and blocking intercellular mutHTT transmission, thereby interfering with a potentially disease amplifying mechanism. Our work sets the ground for the development of new antibody-based therapeutics targeting extracellular HD. It is expected that, besides mutHTT depletion, systemic antibody-based targeting will provide inhibition of mutHTT spreading and intercellular transmission. We understand our systemic approach as an addition to forthcoming tissue-specific mutHTT lowering approaches.

A strong dust-storm event occurred in Harbin, China on May 11, 2011. The dry and wet dust deposits from this dust-storm event were examined in terms of grain-size and Sr–Nd isotopic compositions, along with scanning electron microscope. The dry-deposited dusts are characterized by bimodal grain-size distributions with fine mode of 3.6 μm and coarse mode of 28 μm, while the wet-deposited dusts are indicative of unimodal grain-size modes with a fine mode of 6 μm. These dust-storm depositions are derived from distal sources, for instance >1000 km away from dust sink spot, regardless of the occurrence of relatively coarse component with coarse mode at 28 μm for dry-deposited dusts. The Sr–Nd isotopic compositions of the dust-storm depositions are suggestive of the derivation from Horqin Sandy Land and, to a certain extent, Hunsandake Sandy Land, for both dry-deposited dust and wet-deposited dust. The fine mode (

Huntington disease (HD) is an inherited, fatal neurodegenerative disease with no disease-modifying therapy currently available. In addition to characteristic motor deficits and atrophy of the caudate nucleus, signature hallmarks of HD include behavioral abnormalities, immune activation, and cortical and white matter loss. The identification and validation of novel therapeutic targets that contribute to these degenerative cellular processes may lead to new interventions that slow or even halt the course of this insidious disease. Semaphorin 4D (SEMA4D) is a transmembrane signaling molecule that modulates a variety of processes central to neuroinflammation and neurodegeneration including glial cell activation, neuronal growth cone collapse and apoptosis of neural precursors, as well as inhibition of oligodendrocyte migration, differentiation and process formation. Therefore, inhibition of SEMA4D signaling could reduce CNS inflammation, increase neuronal outgrowth and enhance oligodendrocyte maturation, which may be of therapeutic benefit in the treatment of several neurodegenerative diseases, including HD. To that end, we evaluated the preclinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody, which prevents the interaction between SEMA4D and its receptors, in the YAC128 transgenic HD mouse model. Anti-SEMA4D treatment ameliorated neuropathological signatures, including striatal atrophy, cortical atrophy, and corpus callosum atrophy and prevented testicular degeneration in YAC128 mice. In parallel, a subset of behavioral symptoms was improved in anti-SEMA4D treated YAC128 mice, including reduced anxiety-like behavior and rescue of cognitive deficits. There was, however, no discernible effect on motor deficits. The preservation of brain gray and white matter and improvement in behavioral measures in YAC128 mice treated with anti-SEMA4D suggest that this approach could represent a viable therapeutic strategy for the treatment of HD. Importantly, this work provides in vivo demonstration that inhibition of pathways initiated by SEMA4D constitutes a novel approach to moderation of neurodegeneration.

Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than nonselective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering. Here we evaluate ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs. We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 16 weeks or more after a single intracerebroventricular (ICV) injection. With further validation, these ASOs could provide a therapeutic option for individuals afflicted with HD.

There has long been disagreement about the provenance of sandy dust deposits in Harbin city, Heilongjiang province, China. The present paper contributes to a better understanding of the source of sandy dust deposits in Harbin by the application of REE geochemistry. The REE composition of samples from sand–dust deposit events in Harbin was compared with that of three different grain size fractions (

Silencing the mutant huntingtin gene (muHTT) is a direct and simple therapeutic strategy for the treatment of Huntington disease (HD) in principle. However, targeting the HD mutation presents challenges because it is an expansion of a common genetic element (a CAG tract) that is found throughout the genome. Moreover, the HTT protein is important for neuronal health throughout life, and silencing strategies that also reduce the wild-type HTT allele may not be well tolerated during the long-term treatment of HD. Several HTT silencing strategies are in development that target genetic sites in HTT that are outside of the CAG expansion, including HD mutation-linked single-nucleotide polymorphisms and the HTT promoter. Preclinical testing of these genetic therapies has required the development of a new mouse model of HD that carries these human-specific genetic targets. To generate a fully humanized mouse model of HD, we have cross-bred BACHD and YAC18 on the Hdh(-/-) background. The resulting line, Hu97/18, is the first murine model of HD that fully genetically recapitulates human HD having two human HTT genes, no mouse Hdh genes and heterozygosity of the HD mutation. We find that Hu97/18 mice display many of the behavioral changes associated with HD including motor, psychiatric and cognitive deficits, as well as canonical neuropathological abnormalities. This mouse line will be useful for gaining additional insights into the disease mechanisms of HD as well as for testing genetic therapies targeting human HTT.

Perturbations in neurogenesis in the adult brain have been implicated in impaired learning and memory. In the present study, we investigated which stages of the neurogenic process are affected in the transgenic YAC128 mouse model of Huntington disease (HD). Hippocampal neuronal proliferation was altered in the dentate gyrus (DG) of YAC128 mice as compared with wild-type (WT) littermate controls in early symptomatic to end-stage mice. In addition, we detected a significantly lower number of immature neurons in the DG of young, pre-symptomatic YAC128 mice. This decrease in neuronal differentiation persisted through the progression of the disease, and resulted in an overall reduction in the number of new mature neurons in the DG of YAC128 mice. There were no changes in cell proliferation and differentiation in the subventricular zone (SVZ). In this study, we demonstrate decreases in neurogenesis in the DG of YAC128 mice, and these deficits may contribute to the cognitive abnormalities observed in these animals.

Levels of full-length huntingtin (FL htt) influence organ and body weight, independent of polyglutamine length. The growth hormone-insulin like growth factor-1 (GH-IGF-1) axis is well established as a regulator of organ growth and body weight. In this study, we investigate the involvement of the IGF-1 pathway in mediating the effect of htt on body weight. IGF-1 expression was examined in transgenic mouse lines expressing different levels of FL wild-type (WT) htt (YAC18 mice), FL mutant htt (YAC128 and BACHD mice) and truncated mutant htt (shortstop mice). We demonstrate that htt influences body weight by modulating the IGF-1 pathway. Plasma IGF-1 levels correlate with body weight and htt levels in the transgenic YAC mice expressing human htt. The effect of htt on IGF-1 expression is independent of CAG size. No effect on body weight is observed in transgenic YAC mice expressing a truncated N-terminal htt fragment (shortstop), indicating that FL htt is required for the modulation of IGF-1 expression. Treatment with 17beta-estradiol (17beta-ED) lowers the levels of circulating IGF-1 in mammals. Treatment of YAC128 with 17beta-ED, but not placebo, reduces plasma IGF-1 levels and decreases the body weight of YAC128 animals to WT levels. Furthermore, given the ubiquitous expression of IGF-1 within the central nervous system, we also examined the impact of FL htt levels on IGF-1 expression in different regions of the brain, including the striatum, cerebellum of YAC18, YAC128 and littermate WT mice. We demonstrate that the levels of FL htt influence IGF-1 expression in striatal tissues. Our data identify a novel function for FL htt in influencing IGF-1 expression.

In the peripheral nervous system (PNS), root avulsion causes motoneuron degeneration, but the majority of motoneurons can survive axotomy. In order to study the mechanism of motoneuron degeneration, we compared the expression patterns of c-jun and neuronal nitric oxide synthase (nNOS), the well-known molecular players in PNS regeneration and degeneration, among adult rats having undergone axotomy (Ax), avulsion (Av), or pre-axotomy plus secondary avulsion (Ax + Av) of the brachial plexus. Our results showed that the highest and longest-lasting c-jun activation occurred in Ax, which was much stronger than those in Av and Ax + Av. The time course and intensity of c-jun expression in Ax + Av were similar to those in Av except on day 1, while the pre-axotomy condition resulted in a transient up-regulation of c-jun to a level comparable to that in Ax. Axotomy alone did not induce nNOS expression in motoneurons. Pre-axotomy left-shifted the time course of nNOS induction in Ax + Av compared to that in Av. Motoneuron loss was not evident in Ax, while it was 70% in Av and more than 85% in Ax + Av at 8 weeks postinjury. The survival of motoneurons was positively correlated with c-jun induction, but not with nNOS expression in motoneurons. Moreover, c-jun induction was negatively correlated with nNOS induction in injured motoneurons. Our results indicate that functional crosstalk between c-jun and nNOS might play an important role in avulsion-induced motoneuron degeneration, while c-jun might act as a prerequisite survival factor and nNOS might act as a predictor for the onset of motoneuron degeneration.

Transplantation of exogenous cells is one approach to spinal cord repair that could potentially enhance the growth and myelination of endogenous axons. Here, we asked whether skin-derived precursors (SKPs), a neural crest-like precursor that can be isolated and expanded from mammalian skin, could be used to repair the injured rat spinal cord. To ask this question, we isolated and expanded genetically tagged murine SKPs and either transplanted them directly into the contused rat spinal cord or differentiated them into Schwann cells (SCs), and performed similar transplantations with the isolated, expanded SKP-derived SCs. Neuroanatomical analysis of these transplants 12 weeks after transplantation revealed that both cell types survived well within the injured spinal cord, reduced the size of the contusion cavity, myelinated endogenous host axons, and recruited endogenous SCs into the injured cord. However, SKP-derived SCs also provided a bridge across the lesion site, increased the size of the spared tissue rim, myelinated spared axons within the tissue rim, reduced reactive gliosis, and provided an environment that was highly conducive to axonal growth. Importantly, SKP-derived SCs provided enhanced locomotor recovery relative to both SKPs and forebrain subventricular zone neurospheres, and had no impact on mechanical or heat sensitivity thresholds. Thus, SKP-derived SCs provide an accessible, potentially autologous source of cells for transplantation into and treatment of the injured spinal cord.

The first postmitotic neurons in the developing neocortex establish the preplate layer. These early-born neurons have a significant influence on the circuitry of the developing cortex. However, the exact timing and trajectory of their projections, between cortical hemispheres and intra- and extra-cortical regions, remain unresolved. Here, we describe the creation of a transgenic mouse using a 1.3 kb golli promoter element of the myelin basic protein gene to target expression of a tau-green fluorescent protein (GFP) fusion protein in the cell bodies and processes of pioneer cortical neurons. During embryonic and early neonatal development, the timing and patterning of process extension from these neurons was examined. Analysis of tau-GFP fluorescent fibers revealed that progression of early labeled projections was interrupted unexpectedly by transient pauses at the corticostriatal and telencephalic-diencephalic boundaries before invading the thalamus just prior to birth. After birth the pioneering projections differentially invaded the thalamus, excluding some nuclei, e.g. medial and lateral geniculate, until postnatal days 10-14. Early labeled projections were also found to cross to the contralateral hemisphere as well as to the superior colliculus. These results indicate that early corticothalamic projections appear to pause before invading specific subcortical regions during development, that there is developmental regulation of innervation of individual thalamic nuclei, and that these early-generated neurons also establish early projections to commissural and subcortical targets.

Background Nr2e1 (nuclear receptor subfamily 2, group e, member 1) encodes a transcription factor important in neocortex development. Previous work has shown that nuclear receptors can have hundreds of target genes, and bind more than 300 co-interacting proteins. However, recognition of the critical role of Nr2e1 in neural stem cells and neocortex development is relatively recent, thus the molecular mechanisms involved for this nuclear receptor are only beginning to be understood. Serial analysis of gene expression (SAGE), has given researchers both qualitative and quantitative information pertaining to biological processes. Thus, in this work, six LongSAGE mouse libraries were generated from laser microdissected tissue samples of dorsal VZ/SVZ (ventricular zone and subventricular zone) from the telencephalon of wild-type (Wt) and Nr2e1-null embryos at the critical development ages E13.5, E15.5, and E17.5. We then used a novel approach, implementing multiple computational methods followed by biological validation to further our understanding of Nr2e1 in neocortex development. Results In this work, we have generated a list of 1279 genes that are differentially expressed in response to altered Nr2e1 expression during in vivo neocortex development. We have refined this list to 64 candidate direct-targets of NR2E1. Our data suggested distinct roles for Nr2e1 during different neocortex developmental stages. Most importantly, our results suggest a possible novel pathway by which Nr2e1 regulates neurogenesis, which includes Lhx2 as one of the candidate direct-target genes, and SOX9 as a co-interactor. Conclusions In conclusion, we have provided new candidate interacting partners and numerous well-developed testable hypotheses for understanding the pathways by which Nr2e1 functions to regulate neocortex development. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1770-3) contains supplementary material, which is available to authorized users.

Quantitation of huntingtin protein in the brain is needed, both as a marker of Huntington disease (HD) progression and for use in clinical gene silencing trials. Measurement of huntingtin in cerebrospinal fluid could be a biomarker of brain huntingtin, but traditional protein quantitation methods have failed to detect huntingtin in cerebrospinal fluid. Using micro-bead based immunoprecipitation and flow cytometry (IP-FCM), we have developed a highly sensitive mutant huntingtin detection assay. The sensitivity of huntingtin IP-FCM enables accurate detection of mutant huntingtin protein in the cerebrospinal fluid of HD patients and model mice, demonstrating that mutant huntingtin levels in cerebrospinal fluid reflect brain levels, increasing with disease stage and decreasing following brain huntingtin suppression. This technique has potential applications as a research tool and as a clinical biomarker.

Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than non-selective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering. We have evaluated ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs. We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 36 weeks or more after a single intracerebroventricular injection.We next conducted a pre-clinical therapeutic efficacy trial of lead ASOs and evaluated them for effect on the HD-like phenotypes of Hu97/18 mice. Treated mice underwent longitudinal behavioral and biochemical assessment followed by terminal neuropathology. Thus far we have determined that pre-symptomatic allele-specific muHTT silencing prevents onset of behavioral HD-like phenotypes. Evaluation of neuropathology and post-symptomatic intervention is ongoing. Contingent on findings from these studies and using delivery and dosing information gained from ongoing CNS ASO clinical trials, a primary SNP-targeted ASO drug could be fairly rapidly translated for human applications.

From the sedimentologic view, this paper analyses the grain-size distribution and the chemical composition of the deposits from sand-dust storm, occurring in Harbin on March 20, 2002. The result indicates that there exist plentiful coarse matters in the sand-dust deposits in Harbin, and the sand-dust composition presents obvious three peak distribution characteristics, indicating that the sand-dust in Harbin is composed of multi-origin components. The grain-size composition consists of silt (4–8Φ), accounting for 71.18% of the total, sand (>4Φ), 21.70%, and clay (

Adult spinal motoneurons can regenerate their axons into a peripheral nerve (PN) graft following root avulsion injury if the graft is implanted immediately after the lesion is induced. The present study was designed to determine how avulsed motoneurons respond to a PN graft if implantation takes place a few days to a few weeks later. Survival, regeneration, and gene expression changes of injured motoneurons after delayed PN graft implantation were studied. The survival rates of spinal motoneurons were 78%, 65%, 57%, or 53% if a PN graft was implanted immediately, 1, 2, or 3 weeks after root avulsion, respectively. Interestingly, most of the surviving motoneurons were able to regenerate their axons into the graft regardless of the delay. All regenerating motoneurons expressed p75, but not nNOS, while all motoneurons that failed to regenerate expressed nNOS, but not p75. p75 and nNOS may, therefore, be used as markers for success or failure to regenerate axons. In the group with immediate graft implantation, 85% of the surviving motoneurons extended axons into the PN graft, while in the groups in which implantation was delayed 1, 2, or 3 weeks, 84%, 82%, and 83% of the surviving motoneurons, respectively, were found to have regenerated into the grafts. These findings indicate that avulsed spinal motoneurons retain the ability to regenerate for at least 3 weeks, and perhaps for as long as they survive. Therefore, the delayed implantation of a PN graft after root avulsion may provide a continued conducive environment to support regeneration.

In the present study, we examined the effects of glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and insulin growth factor (IGF-1) on adult motoneuron survival following spinal root avulsion. The expression of neuronal nitric oxide synthase (nNOS), c-Jun, and the low-affinity neurotrophin receptor (P75) following treatment with these neurotrophic factors was also examined. In control animals, approximately 80% of spinal motoneurons were nNOS positive at 3 weeks following the lesion, whereas in GDNF or BDNF treated animals no nNOS positive motoneurons were found at the same time point. Following injury and treatment with GDNF and BDNF increased numbers of motoneurons were c-Jun and P75 positive. By 6 weeks following the lesion, only approximately 28% of motoneurons persisted in control animals whereas about 90% of motoneurons survived injury following treatment with either GDNF or BDNF. In contrast, CNTF and IGF-1 were ineffective in either inhibiting nNOS expression or preventing motoneuron death. Our results provide in vivo evidence that the survival of injured adult mammalian motoneurons can be promoted by specific neurotrophic factors, and that this effect is associated with inhibition of nNOS expression and up-regulation of c-Jun and P75 expression.

Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent.

The present study investigated expression of beta-amyloid protein (AP) and Amyloid precursor protein (APP) in spinal motor neurons of young adult (3 month old) and aged (26-30 month old) rats. The total number of spinal motor neurons in the seventh cervical (C7) spinal segment was also examined in both young adult and aged rats. There was an approximately 21% (p