Enhancement of visual cortex plasticity by dark exposure

Dark rearing is known to delay the time course of the critical period for ocular dominance plasticity in the visual cortex. Recent evidence suggests that a period of dark exposure (DE) may enhance or reinstate plasticity even after closure of the critical period, mediated through modification of the excitatory–inhibitory balance and/or removal of structural brakes on plasticity. Here, we investigated the effects of a week of DE on the recovery from a month of monocular deprivation (MD) in the primary visual cortex (V1) of juvenile mice. Optical imaging of intrinsic signals revealed that ocular dominance in V1 of mice that had received DE recovered slightly more quickly than of mice that had not, but the level of recovery after three weeks was similar in both groups. Two-photon calcium imaging showed no significant difference in the recovery of orientation selectivity of excitatory neurons between the two groups. Parvalbumin-positive (PV+) interneurons exhibited a smaller ocular dominance shift during MD but again no differences in subsequent recovery. The percentage of PV+ cells surrounded by perineuronal nets, a structural brake on plasticity, was lower in mice with than those without DE. Overall, DE causes a modest enhancement of mouse visual cortex plasticity

The chromosome make-up of mouse embryonic stem cells is predictive of somatic and germ cell chimerism.

Mouse pluripotent embryonic stem (ES) cells, once reintroduced into a mouse blastocyst, can contribute to the formation of all tissues, including the germline, of an organism referred to as a chimaeric. However, the reasons why this contribution often appears erratic are poorly understood. We have tested the notion that the chromosome make-up may be important in contributing both to somatic cell chimaerism and to germ line transmission. We found that the percentage of chimaerism of ES cell-embryo chimaeras, the absolute number of chimaeras and the ratio of chimaeras to total pups born all correlate closely with the percentage of euploid metaphases in the ES cell clones injected into the murine blastocyst. The majority of the ES cell clones that we tested, which were obtained from different gene targeting knockout experiments and harboured 50 to 100% euploid metaphases, did transmit to the germline; in contrast, none of the ES cell clones with more than 50% of chromosomally abnormal metaphases transmitted to the germline. Euploid ES cell clones cultured in vitro for more than 20 passages rapidly became severely aneuploid, and again this correlated closely with the percentage of chimaerism and with the number of ES cell-embryo chimaeras obtained per number of blastocysts injected. At the same time, the ability of these clones to contribute to the germline was lost when the proportion of euploid cells dropped below 50%. This study suggests that aneuploidy, rather than 'loss of totipotency', in ES cells, is the major cause of failure in obtaining contributions to all tissues of the adult chimaera, including the germline. Because euploidy is predictive of germline transmission, karyotype analysis is crucial and time/cost saving in any gene-targeting experiment

Novel p75 neurotrophin receptor ligand stabilizes neuronal calcium, preserves mitochondrial movement and protects against HIV associated neuropathogenesis

Human immunodeficiency virus (HIV) rapidly penetrates into the brain and establishes a persistent infection of macrophages/microglia. Activation of these cells by HIV results in the secretion of soluble factors that destabilize neuronal calcium homeostasis, encourage oxidative stress and result in neural damage. This damage is thought to underlie the cognitive-motor dysfunction that develops in many HIV-infected patients. Studies have suggested that neurotrophins may protect neurons from the toxic effects of HIV-associated proteins. To better understand the pathogenic mechanisms and the neuroprotective potential of neurotrophin ligands, we evaluated neuronal damage, calcium homeostasis and mitochondrial functions after exposure of cultured rat neurons directly to HIV gp120 or to conditioned medium from human monocyte-derived macrophages treated with gp120. We then assessed the ability of a new non-peptide p75 neurotrophin receptor ligand, LM11A-31, to stabilize calcium homeostasis and prevent the development of pathology. Each toxic challenge resulted in a delayed accumulation of intracellular calcium coupled to a decrease in the rate of calcium clearance from the cell. The delayed calcium accumulation correlated with the development of focal dendritic swellings (beading), cytoskeletal damage and impaired movement of mitochondria. Addition of LM11A-31 to the cultures at nanomolar concentrations eliminated cell death, significantly reduced the pathology, suppressed the delayed accumulation of calcium and restored mitochondrial movements. The potent neuroprotection and the stabilization of calcium homeostasis indicate that LM11A-31 may have excellent potential for the treatment of HIV-associated neurodegeneration

Cytophotometric determinations of nuclear DNA content in tissues of the wax moth larva, Galleria mellonella Linnaeus

The present study was undertaken to determine, by measurement of nuclear DNA, the degrees and frequencies of ploidy in the last larval instar of the moth Galleria mellonella Linnaeus. While such data have been amassed for a wide variety of vertebrate tissues, few studies have been concerned with invertebrates and especially insects where somatic polyploidy is developed to an unusually high degree. Relative amounts of DNA were determined cytophotometrically on individual Feulgen-stained nuclei of hypodermis, ventriculus, fat cells, blood cells, anterior silk gland, and proventriculus. Graphs of the determined DNA values indicated the presence of nuclear classes falling into polyploid ratios, The majority of blood cell and fat cell nuclei had class I values (= diploid), while class II and III (= tetraploid and octoploid) DNA values represented about 17 to 20 percent of the total nuclear population. The majority of DNA values of the ventriculus nuclei fell into the second class while 6.8 percent were considered as class I. The hypodermal nuclei were mostly of class I, while class II values represented 5.5 percent of the total number of determinations. Nuclei of the proventriculus and the anterior silk gland showed a broad spectrum of DNA values ranging from classes IV to VIII including many intermediate values. The method of measurement was analyzed for sources of error. Various interpretations were offered for the variations in DNA values including the role of endomitosis, definitive polyploidy, aneuploidy, differential gene replication, etc. In the case of the anterior silk gland and the proventriculus a possible relationship between DNA amounts and ceIl activity is indicated

Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants

Many chemotherapy drugs are known to cause significant clinical neurotoxicity, which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. In the present study, we examine the effects of paclitaxel (taxol), cisplatin, and methotrexate on primary rat neurons including hippocampal, cortical, and dorsal horn/dorsal root ganglion neuronal cultures. We found that all of these anti-cancer drugs induce substantial neurotoxicity evidenced by neurite degeneration. The neurons are capable of recovering after treatment withdrawal, but taxol exerts a biphasic effect that results in the collapse of processes days after treatment is withdrawn. After cisplatin and methotrexate treatment, we observed the degeneration of neuronal processes including the reduction of dendritic branching, length, and altered growth cone formation, indicating an abnormal arrangement of the actin cytoskeleton consistent with the involvement of Rho family small GTPases. Inhibiting RhoA downstream effector p160ROCK/Rho kinase using Y-27632, or activating p75 neurotrophin receptor (p75NTR) using non-peptide mimetic LM11A-31, were able to reverse the degeneration caused by cisplatin and methotrexate. Therefore, the neurotoxicity resulting from exposure to the anti-cancer drugs cisplatin and methotrexate can be alleviated by inhibiting Rho signaling pathway. Originally published Neurotoxicology, Vol. 29, No. 4, July 200

Comparing mortality risk reduction, life expectancy gains, and probability of achieving full life span, as alternatives for presenting CVD mortality risk reduction: a discrete choice study of framing risk and health behaviour change

The growing rate of obesity has recently required governments to divert considerable resources in the promotion of healthy lifestyles. We explored the relative effectiveness in inducing healthy behaviour change of three different communication strategies about the benefits of an intervention that reduces the mortality risks of cardiovascular disease (CVD) and encourages respondents to embrace healthier lifestyles. We designed a Discrete Choice Experiments questionnaire to analyse the trade-off between lifestyles, defined in terms of diet and exercise, and reduction in cardiovascular disease (CVD) mortality risk. We set three ways of framing an identical benefit: (A) as a reduction in mortality risk from cardiovascular disease, (B) as an increase in months of life expectancy, and (C) as an increase in the probability of reaching an individual's full lifespan. The experiment was tailored for each subject in the sample according to his/her individual's baseline information on diet and physical activity. During the period February 2010–July 2011, we interviewed 1008 individuals in Northern Ireland, split randomly into three samples for the three CVD risk reduction frames. Considering the models' goodness of fit and significance, we conclude that the most effective way of communicating these CVD health benefits is using an increase in life expectancy, since with this frame individuals are more inclined to state that they would change to a healthier lifestyle

Nerve Growth Factor Pathobiology During The Progression Of Alzheimer\u27s Disease

The current review summarizes the pathobiology of nerve growth factor (NGF) and its cognate receptors during the progression of Alzheimer’s disease (AD). Both transcript and protein data indicate that cholinotrophic neuronal dysfunction is related to an imbalance between TrkA-mediated survival signaling and the NGF precursor (proNGF)/p75NTR-mediated pro-apoptotic signaling, which may be related to alteration in the metabolism of NGF. Data indicate a spatiotemporal pattern of degeneration related to the evolution of tau pathology within cholinotrophic neuronal subgroups located within the nucleus basalis of Meynert (nbM). Despite these degenerative events the cholinotrophic system is capable of cellular resilience and/or plasticity during the prodromal and later stages of the disease. In addition to neurotrophin dysfunction, studies indicate alterations in epigenetically regulated proteins occur within cholinotrophic nbM neurons during the progression of AD, suggesting a mechanism that may underlie changes in transcript expression. Findings that increased cerebrospinal fluid levels of proNGF mark the onset of MCI and the transition to AD suggests that this proneurotrophin is a potential disease biomarker. Novel therapeutics to treat NGF dysfunction include NGF gene therapy and the development of small molecule agonists for the cognate prosurvival NGF receptor TrkA and antagonists against the pan-neurotrophin p75NTR death receptor for the treatment of AD