Calpastatin Overexpression Preserves Cognitive Function Following Seizures, While Maintaining Post-Injury Neurogenesis

In the adult mammalian brain, new neurons continue to be produced throughout life in two main regions in the brain, the subgranular zone (SGZ) in the hippocampus and the subventricular zone in the walls of the lateral ventricles. Neural stem cells (NSCs) proliferate in these niches, and migrate as neuroblasts, to further differentiate in locations where new neurons are needed, either in normal or pathological conditions. However, the endogenous attempt of brain repair is not very efficient. Calpains are proteases known to be involved in neuronal damage and in cell proliferation, migration and differentiation of several cell types, though their effects on neurogenesis are not well known. Previous work by our group has shown that the absence of calpastatin (CAST), the endogenous inhibitor of calpains, impairs early stages of neurogenesis. Since the hippocampus is highly associated with learning and memory, we aimed to evaluate whether calpain inhibition would help improve cognitive recovery after lesion and efficiency of post-injury neurogenesis in this region. For that purpose, we used the kainic acid (KA) model of seizure-induced hippocampal lesion and mice overexpressing CAST. Selected cognitive tests were performed on the 3rd and 8th week after KA-induced lesion, and cell proliferation, migration and differentiation in the dentate gyrus (DG) of the hippocampus of adult mice were analyzed using specific markers. Cognitive recovery was evaluated by testing the animals for recognition, spatial and associative learning and memory. Cognitive function was preserved by CAST overexpression following seizures, while modulation of post-injury neurogenesis was similar to wild type (WT) mice. Calpain inhibition could still be potentially able to prevent the impairment in the formation of new neurons, given that the levels of calpain activity could be reduced under a certain threshold and other harmful effects from the pathological environment could also be controlled.Foundation for Science and Technology (FCT, Portugal); FCT [SFRH/BD/78050/2011, SFRH/BD/79308/2011]; COMPETE; FEDER [PTDC/SAU-NMC/112183/2009, UID/NEU/04539/2013, UID/BIM/04773/2013]info:eu-repo/semantics/publishedVersio

Differential Regulation of the Variations Induced by Environmental Richness in Adult Neurogenesis as a Function of Time: A Dual Birthdating Analysis

Adult hippocampal neurogenesis (AHN) augments after environmental enrichment (EE) and it has been related to some of the anxiolytic, antidepressant and neuroprotective effects of EE. Indeed, it has been suggested that EE specifically modulates hippocampal neurogenic cell populations over the course of time. Here we have used dual-birthdating to study two subpopulations of newborn neuron in mice (Mus musculus): those born at the beginning and at the end of enrichment. In this way, we demonstrate that while short-term cell survival is upregulated after an initial 1 week period of enrichment in 2 month old female mice, after long-term enrichment (2 months) neither cell proliferation nor the survival of the younger newly born cell populations are distinguishable from that observed in non-enriched control mice. In addition, we show that the survival of older newborn neurons alone (i.e. those born at the beginning of the enrichment) is higher than in controls, due to the significantly lower levels of cell death. Indeed, these parameters are rapidly adjusted to the sudden cessation of the EE conditions. These findings suggest both an early selective, long-lasting effect of EE on the neurons born in the initial stages of enrichment, and a quick response when the environment again becomes impoverished. Therefore, EE induces differential effects on distinct subpopulations of newborn neurons depending on the age of the immature cells and on the duration of the EE itself. The interaction of these two parameters constitutes a new, specific regulation of these neurogenic populations that might account for the long-term enrichment's behavioral effects

Molecular Pathology of Neuro-AIDS (CNS-HIV)

The cognitive deficits in patients with HIV profoundly affect the quality of life of people living with this disease and have often been linked to the neuro-inflammatory condition known as HIV encephalitis (HIVE). With the advent of more effective anti-retroviral therapies, HIVE has shifted from a sub-acute to a chronic condition. The neurodegenerative process in patients with HIVE is characterized by synaptic and dendritic damage to pyramidal neurons, loss of calbindin-immunoreactive interneurons and myelin loss. The mechanisms leading to neurodegeneration in HIVE might involve a variety of pathways, and several lines of investigation have found that interference with signaling factors mediating neuroprotection might play an important role. These signaling pathways include, among others, the GSK3β, CDK5, ERK, Pyk2, p38 and JNK cascades. Of these, GSK3β has been a primary focus of many previous studies showing that in infected patients, HIV proteins and neurotoxins secreted by immune-activated cells in the brain abnormally activate this pathway, which is otherwise regulated by growth factors such as FGF. Interestingly, modulation of the GSK3β signaling pathway by FGF1 or GSK3β inhibitors (lithium, valproic acid) is protective against HIV neurotoxicity, and several pilot clinical trials have demonstrated cognitive improvements in HIV patients treated with GSK3β inhibitors. In addition to the GSK3β pathway, the CDK5 pathway has recently been implicated as a mediator of neurotoxicity in HIV, and HIV proteins might activate this pathway and subsequently disrupt the diverse processes that CDK5 regulates, including synapse formation and plasticity and neurogenesis. Taken together, the GSK3β and CDK5 signaling pathways are important regulators of neurotoxicity in HIV, and modulation of these factors might have therapeutic potential in the treatment of patients suffering from HIVE. In this context, the subsequent sections will focus on reviewing the involvement of the GSK3β and CDK5 pathways in neurodegeneration in HIV

Kuhnian revolutions in neuroscience: the role of tool development.

The terms "paradigm" and "paradigm shift" originated in "The Structure of Scientific Revolutions" by Thomas Kuhn. A paradigm can be defined as the generally accepted concepts and practices of a field, and a paradigm shift its replacement in a scientific revolution. A paradigm shift results from a crisis caused by anomalies in a paradigm that reduce its usefulness to a field. Claims of paradigm shifts and revolutions are made frequently in the neurosciences. In this article I will consider neuroscience paradigms, and the claim that new tools and techniques rather than crises have driven paradigm shifts. I will argue that tool development has played a minor role in neuroscience revolutions.The work received no fundin

Salinity gradient solar pond technology applied to potash solution mining

A solution mining facility at the Eddy Potash Mine, Eddy County, New Mexico has been proposed that will utilize salinity gradient solar pond (SGSP) technology to supply industrial process thermal energy. The process will include underground dissolution of potassium chloride (KCl) from pillars and other reserves remaining after completion of primary room and pillar mining using recirculating solutions heated in the SGSP. Production of KCl will involve cold crystallization followed by a cooling pond stage, with the spent brine being recirculated in a closed loop back to the SGSP for reheating. This research uses SGSP as a renewable, clean energy source to optimize the entire mining process, minimize environmental wastes, provide a safe, more economical extraction process and reduce the need for conventional processing by crushing, grinding and flotation. The applications of SGSP technology will not only save energy in the extraction and beneficiation processes, but also will produce excess energy available for power generation, desalination, and auxiliary structure heating

Effects of structural setting and rock peroperties on amplitudes of surface motions in the vicinity of small explosive tests

A series of small-scale explosive experiments were conducted in a perlite mine near Socorro, New Mexico. These experiments were a joint effort between Los Alamos National Laboratory, New Mexico Institute Of Mining and Technology, Southern Methodist University, and Defense Nuclear Agency. The purpose of these tests was to measure the changes in the shock wave and seismic coupling as a function of depth of burial and structural setting. The size of the explosive charges ranged from 1 to 68 kg. Over 1150 measurements of velocity and acceleration were made on thirteen experiments using three component sensors. The sensors were placed to maximize the azimuthal coverage as well as to provide data at a variety of ranges from {approximately}1 to 130 m. A few far field measurements were made at ranges of {approximately}2 km. While the bulk of the measurements were made on the surface, high g accelerometers were placed in one instrumentation borehole to provide some free-field measurements. Preliminary results indicate that significant differences in the amplitudes of signals can occur when the location of the explosive charges are changed by only meters. Part of the observed difference is attributed to variations in the rock immediately adjacent to the charge affecting the shock coupling; and part to the effects of the site characteristics

Photoperiodic signals repress the transcription of SVP to control gibberellin biosynthesis during floral transition in Arabidopsis

In plants the transition from vegetative growth to flowering is regulated by several environmental stimuli and by the age of the individual. This complexity is conferred by a network of genetic pathways. In Arabidopsis, these pathways include the photoperiodic pathway that promotes flowering in response to long days (LDs) and the response pathway to the growth regulator gibberellins (GA), which has its strongest effect under short days (SDs). FLOWERING LOCUS T (FT) is a positive regulator of flowering that acts in the photoperiodic pathway. Under LDs the FT protein is transported from the leaves to the shoot apical meristem (SAM) where it induces the expression of several floral promoter genes, such as SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) transcription factors. Interestingly, recent studies have shown that GA also induces flowering and affects the expression of the SPLs at the SAM under LDs. However, how the gibberellin pathway is activated in response to photoperiod to promote flowering is still unclear. We have found that mutations in the MADS box transcription factor encoding gene SHORT VEGETATIVE PHASE (SVP) – a well-known repressor of flowering – lead to an increase in the GA content, demonstrating that SVP acts as a negative regulator of the biosynthetic pathway of this hormone. Moreover, our results show that SVP regulates the expression of the SPL genes and flowering time by repressing the transcription of GA20ox2, a rate-limiting enzyme in the biosynthesis of GA. We also show that SVP transcription is repressed by the photoperiodic signals mainly represented by FT, TWIN SISTER OF FT (TSF), and the two MADS box transcription factors SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) and FRUITFULL (FUL), so that inductive LD conditions contribute to the reduction of SVP expression in the shoot apex. Taking our results together, we propose a model to explain how during the floral transition the GA biosynthetic pathway is activated in the SAM in response to inductive photoperiods