Brain atlas of the annual Garcialebias charrua fish.

Annual fish have become attractive study models for a wide range of disciplines, including neurobiology. These fish have developed different survival strategies. As a result, their nervous system is under considerable selective pressure when facing extreme environmental situations. Fish from the Austrolebias group exhibit rapid neurogenesis in different brain regions, possibly as a result of the demanding conditions of a changing habitat. Knowledge of cerebral histology is essential for detecting ontogenic, anatomical, or cytoarchitectonic changes in the brain during the short lifespan of these fish, such as those reflecting functional adaptive plasticity in different systems, including sensory structures. The generation of an atlas of Garcialebias charrua (previously known as Austrolebias charrua) establishes its anatomical basis as a representative of a large group of fish that share similarities in their way of life. In this work, we present a detailed study of both gross anatomy and microscopic anatomy obtained through serial sections stained with the Nissl technique in three orientations: transverse, horizontal, and parasagittal planes. This atlas includes accurate drawings of the entire adult brain of the male fish Garcialebias charrua, showing dorsal, ventral, and lateral views, including where emergence and origin of cranial nerves. This brain atlas allows us to understand histoarchitecture as well as the location of neural structures that change during adult neurogenesis, enabling comparisons within the genus. Simultaneously, this atlas constitutes a valuable tool for comparing the brains of other fish species with different behaviors and neuroecologies.

Morphological evidence of the protective effects of a synthetic chalcone against the striatal myelin damage induced by glutaric acid.

Ultrastructural features of striatal white matter and cells in an in vivo model of glutaric acidemia type I created by intracerebral injection of glutaric acid (GA) were analyzed by transmission electron microscopy and immunohistochemistry. To test if the white matter damage observed in this model could be prevented, we administered the synthetic chemopreventive molecule CH38 ((E)-3-(4-methylthiophenyl)-1-phenyl-2-propen-1-one) to newborn rats, previous to an intracerebroventricular injection of GA. The study was done when striatal myelination was incipient and when it was already established (at 12 and 45 days post-injection [DPI], respectively). Results obtained indicate that that the ultrastructure of astrocytes and neurons did not appear significantly affected by the GA bolus. Instead, in oligodendrocytes, the most prominent GA-dependent injury defects included endoplasmic reticulum (ER) stress and nuclear envelope swelling at 12 DPI. Altered and reduced immunoreactivities against heavy neurofilament (NF), proteolipid protein (PLP), and myelin-associated glycoprotein (MAG) together with axonal bundle fragmentation and decreased myelin were also found at both ages analyzed. CH38 by itself did not affect striatal cells or axonal packages. However, the group of rats that received CH38 before GA did not show evidence neither of ER stress nor nuclear envelope dilation in oligodendrocytes, and axonal bundles appeared less fragmented. In this group, labeling of NF and PLP was similar to the controls. These results suggest that the CH38 molecule is a candidate drug to prevent or decrease the neural damage elicited by a pathological increase of GA in the brain. Optimization of the treatments and identification of the mechanisms underlying CH38 protective effects will open new therapeutic windows to protect myelin, which is a vulnerable target of numerous nervous system diseases.

Superior Thermoelectric Performance of SiGe Nanowires Epitaxially Integrated into Thermal Micro-Harvesters.

Semiconductor nanowires have demonstrated fascinating properties with applications in a wide range of fields, including energy and information technologies. Particularly, increasing attention has focused on SiGe nanowires for applications in a thermoelectric generation. In this work, a bottom-up vapour-liquid-solid chemical vapour Deposition methodology is employed to integrate heavily boron-doped SiGe nanowires on thermoelectric generators. Thermoelectrical properties -, i.e., electrical and thermal conductivities and Seebeck coefficient - of grown nanowires are fully characterized at temperatures ranging from 300 to 600 K, allowing the complete determination of the Figure-of-merit, zT, with obtained values of 0.4 at 600 K for optimally doped nanowires. A correlation between doping level, thermoelectric performance, and elemental distribution is established employing advanced elemental mapping (synchrotron-based nano-X-ray fluorescence). Moreover, the operation of p-doped SiGe NWs integrated into silicon micromachined thermoelectrical generators is shown over standalone and series- and parallel-connected arrays. Maximum open circuit voltage of 13.8 mV and power output as high as 15.6 µW cm-2 are reached in series and parallel configurations, respectively, operating upon thermal gradients generated with hot sources at 200 °C and air flows of 1.5 m s-1 . These results pave the way for direct application of SiGe nanowire-based micro-thermoelectric generators in the field of the Internet of Things.

Plasticity of cell proliferation in the retina of Austrolebias charrua fish under light and darkness conditions.

Austrolebias annual fishes exhibit cell proliferation and neurogenesis throughout life. They withstand extreme environmental changes as their habitat dries out, pressuring nervous system to adapt. Their visual system is challenged to adjust as the water becomes turbid. Therefore, this study focused on how change in photic environment can lead to an increased cell proliferation in the retina. We administered 5-chloro-2'- deoxyuridine (CldU) and 5-iodo-2'-deoxyuridine (IdU) at different temporal windows to detect cell proliferation in natural light and permanent darkness. Stem/progenitor cells were recognized as IdU+/CldU + nuclei co-labeled with Sox2, Pax6 or BLBP found in the ciliary marginal zone (CMZ). The expression pattern of BLBP + glial cells and ultrastructural analysis indicates that CMZ has different cell progenitors. In darkness, the number of dividing cells significantly increased, compared to light conditions. Surprisingly, CMZ IdU+/CldU + cell number was similar under light and darkness, suggesting a stable pool of stem/progenitor cells possibly responsible for retinal growth. Therefore, darkness stimulated cell progenitors outside the CMZ, where Müller glia play a crucial role to generate rod precursors and other cell types that might integrate rod-dependent circuits to allow darkness adaptation. Thus, the Austrolebias fish retina shows great plasticity, with cell proliferation rates significantly higher than that of brain visual areas.

Nanoscaled LiMn2O4 for Extended Cycling Stability in the 3 V Plateau.

Extending the potential window toward the 3 V plateau below the typically used range could boost the effective capacity of LiMn2O4 spinel cathodes. This usually leads to an "overdischarge" of the cathode, which can cause severe material damage due to manganese dissolution into the electrolyte and a critical volume expansion (induced by Jahn-Teller distortions). As those factors determine the stability and cycling lifetime for all-solid-state batteries, the operational window of LiMn2O4 is usually limited to 3.5-4.5 V versus Li/Li+ in common battery cells. However, it has been reported that nano-shaped particles and thin films can potentially mitigate these detrimental effects. We demonstrate here that porous LiMn2O4 thin-film cathodes with a certain level of off-stoichiometry show improved cycling stability for the extended cycling range of 2.0-4.5 V versus Li/Li+. We argue through operando spectroscopic ellipsometry that the origin of this stability lies in the surprisingly small volume change in the layer during lithiation.

Colocalization Analysis of Peripheral Myelin Protein-22 and Lamin-B1 in the Schwann Cell Nuclei of Wt and TrJ Mice.

Myelination of the peripheral nervous system requires Schwann cells (SC) differentiation into the myelinating phenotype. The peripheral myelin protein-22 (PMP22) is an integral membrane glycoprotein, expressed in SC. It was initially described as a growth arrest-specific (gas3) gene product, up-regulated by serum starvation. PMP22 mutations were pathognomonic for human hereditary peripheral neuropathies, including the Charcot-Marie-Tooth disease (CMT). Trembler-J (TrJ) is a heterozygous mouse model carrying the same pmp22 point mutation as a CMT1E variant. Mutations in lamina genes have been related to a type of peripheral (CMT2B1) or central (autosomal dominant leukodystrophy) neuropathy. We explore the presence of PMP22 and Lamin B1 in Wt and TrJ SC nuclei of sciatic nerves and the colocalization of PMP22 concerning the silent heterochromatin (HC: DAPI-dark counterstaining), the transcriptionally active euchromatin (EC), and the nuclear lamina (H3K4m3 and Lamin B1 immunostaining, respectively). The results revealed that the number of TrJ SC nuclei in sciatic nerves was greater, and the SC volumes were smaller than those of Wt. The myelin protein PMP22 and Lamin B1 were detected in Wt and TrJ SC nuclei and predominantly in peripheral nuclear regions. The level of PMP22 was higher, and those of Lamin B1 lower in TrJ than in Wt mice. The level of PMP22 was higher, and those of Lamin B1 lower in TrJ than in Wt mice. PMP22 colocalized more with Lamin B1 and with the transcriptionally competent EC, than the silent HC with differences between Wt and TrJ genotypes. The results are discussed regarding the probable nuclear role of PMP22 and the relationship with TrJ neuropathy.

Photo-enhanced ionic conductivity across grain boundaries in polycrystalline ceramics.

Grain boundary conductivity limitations are ubiquitous in material science. We show that illumination with above-bandgap light can decrease the grain boundary resistance in solid ionic conductors. Specifically, we demonstrate the increase of the grain boundary conductance of a 3 mol% Gd-doped ceria thin film by a factor of approximately 3.5 at 250 °C and the reduction of its activation energy from 1.12 to 0.68 eV under illumination, while light-induced heating and electronic conductivity could be excluded as potential sources for the observed opto-ionic effect. The presented model predicts that photo-generated electrons decrease the potential barrier heights associated with space charge zones depleted in charge carriers between adjacent grains. The discovered opto-ionic effect could pave the way for the development of new electrochemical storage and conversion technologies operating at lower temperatures and/or higher efficiencies and could be further used for fast and contactless control or diagnosis of ionic conduction in polycrystalline solids.

Toward Controlling Filament Size and Location for Resistive Switches via Nanoparticle Exsolution at Oxide Interfaces.

Memristive devices are among the most prominent candidates for future computer memory storage and neuromorphic computing. Though promising, the major hurdle for their industrial fabrication is their device-to-device and cycle-to-cycle variability. These occur due to the random nature of nanoionic conductive filaments, whose rupture and formation govern device operation. Changes in filament location, shape, and chemical composition cause cycle-to-cycle variability. This challenge is tackled by spatially confining conductive filaments with Ni nanoparticles. Ni nanoparticles are integrated on the bottom La0.2 Sr0.7 Ti0.9 Ni0.1 O3- δ electrode by an exsolution method, in which, at high temperatures under reducing conditions, Ni cations migrate to the perovskite surface, generating metallic nanoparticles. This fabrication method offers fine control over particle size and density and ensures strong particle anchorage in the bottom electrode, preventing movement and agglomeration. In devices based on amorphous SrTiO3 , it is demonstrated that as the exsolved Ni nanoparticle diameter increases up to ≈50 nm, the ratio between the ON and OFF resistance states increases from single units to 180 and the variability of the low resistance state reaches values below 5%. Exsolution is applied for the first time to engineer solid-solid interfaces extending its realm of application to electronic devices.

Nanoscale Correlations between Metal-Insulator Transition and Resistive Switching Effect in Metallic Perovskite Oxides.

Strongly correlated perovskite oxides are a class of materials with fascinating intrinsic physical functionalities due to the interplay of charge, spin, orbital ordering, and lattice degrees of freedom. Among the exotic phenomena arising from such an interplay, metal-insulator transitions (MITs) are fundamentally still not fully understood and are of large interest for novel nanoelectronics applications, such as resistive switching-based memories and neuromorphic computing devices. In particular, rare-earth nickelates and lanthanum strontium manganites are archetypical examples of bandwidth-controlled and band-filling-controlled MIT, respectively, which are used in this work as a playground to correlate the switching characteristics of the oxides and their MIT properties by means of local probe techniques in a systematic manner. These findings suggest that an electric-field-induced MIT can be triggered in these strongly correlated systems upon generation of oxygen vacancies and establish that lower operational voltages and larger resistance ratios are obtained in those films where the MIT lies closer to room temperature. This work demonstrates the potential of using MITs in the next generation of nanoelectronics devices.

Lithium-Battery Anode Gains Additional Functionality for Neuromorphic Computing through Metal-Insulator Phase Separation.

Specialized hardware for neural networks requires materials with tunable symmetry, retention, and speed at low power consumption. The study proposes lithium titanates, originally developed as Li-ion battery anode materials, as promising candidates for memristive-based neuromorphic computing hardware. By using ex- and in operando spectroscopy to monitor the lithium filling and emptying of structural positions during electrochemical measurements, the study also investigates the controlled formation of a metallic phase (Li7 Ti5 O12 ) percolating through an insulating medium (Li4 Ti5 O12 ) with no volume changes under voltage bias, thereby controlling the spatially averaged conductivity of the film device. A theoretical model to explain the observed hysteretic switching behavior based on electrochemical nonequilibrium thermodynamics is presented, in which the metal-insulator transition results from electrically driven phase separation of Li4 Ti5 O12 and Li7 Ti5 O12 . Ability of highly lithiated phase of Li7 Ti5 O12 for Deep Neural Network applications is reported, given the large retentions and symmetry, and opportunity for the low lithiated phase of Li4 Ti5 O12 toward Spiking Neural Network applications, due to the shorter retention and large resistance changes. The findings pave the way for lithium oxides to enable thin-film memristive devices with adjustable symmetry and retention.

Electrochemical Tuning of Metal Insulator Transition and Nonvolatile Resistive Switching in Superconducting Films.

Modulation of carrier concentration in strongly correlated oxides offers the unique opportunity to induce different phases in the same material, which dramatically change their physical properties, providing novel concepts in oxide electronic devices with engineered functionalities. This work reports on the electric manipulation of the superconducting to insulator phase transition in YBa2Cu3O7-δ thin films by electrochemical oxygen doping. Both normal state resistance and the superconducting critical temperature can be reversibly manipulated in confined active volumes of the film by gate-tunable oxygen diffusion. Vertical and lateral oxygen mobility may be finely modulated, at the micro- and nano-scale, by tuning the applied bias voltage and operating temperature thus providing the basis for the design of homogeneous and flexible transistor-like devices with loss-less superconducting drain-source channels. We analyze the experimental results in light of a theoretical model, which incorporates thermally activated and electrically driven volume oxygen diffusion.

Stem cells distribution, cellular proliferation and migration in the adult Austrolebias charrua brain.

Our previous studies demonstrated that Austrolebias charrua annual fish is an excellent model to study adult brain cell proliferation and neurogenesis due to the presence of active and fast neurogenesis in several regions during its short lifespan. Our main goal was to identify and localize the cells that compose the neurogenic areas throughout the Austrolebias brain. To do this, we used two thymidine halogenated analogs to detect cell proliferation at different survival times: 5-chloro-2'-deoxyuridine (CldU) at 1day and 5-iodo-2'-deoxyuridine (IdU) at 30days. Three types of proliferating cells were identified: I - transient amplifying or fast cycling cells that uptake CldU; II - stem cells or slow cycling cells, that were labeled with both CldU and IdU and did not migrate; and III - migrant cells that uptake IdU. Mapping and 3D-reconstruction of labeled nuclei showed that type I and type II cells were preferentially found close to ventricle walls. Type III cells appeared widespread and migrating in tangential and radial routes. Use of proliferation markers together with Vimentin or Nestin evidenced that type II cells are the putative stem cells that are located at the ventricular lumen. Double label cells with IdU+ and NeuN or HuC/D allowed us identify migrant neurons. Quantitation of labeled nuclei indicates that the proportion of putative stem cells is around 10% in all regions of the brain. This percentage of stem cells suggests the existence of a constant brain cell population in Austrolebias charrua that seems functional to the maintainance of adult neurogenesis.

Astrocyte Dysfunction in Developmental Neurometabolic Diseases.

Astrocytes play crucial roles in maintaining brain homeostasis and in orchestrating neural development, all through tightly coordinated steps that cooperate to maintain the balance needed for normal development. Here, we review the alterations in astrocyte functions that contribute to a variety of developmental neurometabolic disorders and provide additional data on the predominant role of astrocyte dysfunction in the neurometabolic neurodegenerative disease glutaric acidemia type I. Finally, we describe some of the therapeutical approaches directed to neurometabolic diseases and discuss if astrocytes can be possible therapeutic targets for treating these disorders.

Telencephalic-olfactory bulb ventricle wall organization in Austrolebias charrua: Cytoarchitecture, proliferation dynamics, neurogenesis and migration.

Adult neurogenesis participates in fish olfaction sensitivity in response to environmental challenges. Therefore, we investigated if several populations of stem/progenitor cells that are retained in the olfactory bulbs (OB) may constitute different neurogenic niches that support growth and functional demands. By electron microscopy and combination cell proliferation and lineage markers, we found that the telencephalic ventricle wall (VW) at OB level of Austrolebias charrua fish presents three neurogenic niches (transitional 1, medial 2 and ventral 3). The main cellular types described in other vertebrate neurogenic niches were identified (transient amplifying cells, stem cells and migrating neuroblasts). However, elongated vimentin/BLBP+ radial glia were the predominant cells in transitional and ventral zones. Use of halogenated thymidine analogs chloro- and iodo-deoxyuridine administered at different experimental times showed that both regions have the highest cell proliferation and migration rates. Zone 1 migration was toward the OB and telencephalon, whereas in zone 3, migration was directed toward the OB rostral portion constituting the equivalent of the mammal rostral migratory band. Medial zone (MZ) has fewer proliferating non-migrant cells that are the putative stem cells as indicated by short and long proliferation assays as well as cell lineage markers. Sparse migration observed suggests MZ may collaborate with VW growth. Scanning electron microscopy evidenced that the whole VW has only monociliated cells with remarkable differences in cilium length among regions. In OB there are monociliated cells with dwarf cilium whereas ventral telencephalon shows long cilium. Summarizing, we identified three neurogenic niches that might serve different functional purposes.

Spontaneous formation of spiral-like patterns with distinct periodic physical properties by confined electrodeposition of Co-In disks.

Spatio-temporal patterns are ubiquitous in different areas of materials science and biological systems. However, typically the motifs in these types of systems present a random distribution with many possible different structures. Herein, we demonstrate that controlled spatio-temporal patterns, with reproducible spiral-like shapes, can be obtained by electrodeposition of Co-In alloys inside a confined circular geometry (i.e., in disks that are commensurate with the typical size of the spatio-temporal features). These patterns are mainly of compositional nature, i.e., with virtually no topographic features. Interestingly, the local changes in composition lead to a periodic modulation of the physical (electric, magnetic and mechanical) properties. Namely, the Co-rich areas show higher saturation magnetization and electrical conductivity and are mechanically harder than the In-rich ones. Thus, this work reveals that confined electrodeposition of this binary system constitutes an effective procedure to attain template-free magnetic, electric and mechanical surface patterning with specific and reproducible shapes.

White matter injury induced by perinatal exposure to glutaric acid.

Glutaric acid (GA) is a neurotoxic metabolite that accumulates in the CNS of patients with glutaric acidemia-I (GA-I), a neurometabolic disease caused by deficient activity of glutaryl-CoA dehydrogenase. Most GA-I patients display characteristic CNS lesions, mainly in the gray and white matter of basal ganglia and cerebral cortex. Neurons and astrocytes are believed to be vulnerable to millimolar concentrations of GA. However, little is known about the effects of GA on oligodendrocytes (OL) and the myelination process in the postnatal brain. Here, we show that a single intracerebroventricular administration of GA to rat neonatal pups induced a selective and long-lasting myelination failure in the striatum but no deleterious effect in the myelination of the corpus callosum. At 45 days post-GA injection, the myelinated area of striatal axonal bundles was decreased by 35 %, and the expression of myelin basic protein and myelin-associated glycoprotein (MAG) reduced by 25 and 60 %, respectively. This was accompanied by long lasting cytopathology features in MAG and CC-1-expressing OLs, which was confirmed by transmission electron microscopy. Remarkably, GA did not induce acute loss of pre-OLs in the striatum as assessed by NG2 or PDGFRα immunohistochemistry, suggesting an indirect and progressive mechanism for OL damage. In accordance, GA-induced white matter injury was restricted to the striatum and associated to GA-induced astrocytosis and neuronal loss. In conclusion, the current evidence indicates a pathogenic mechanism by which GA can permanently affect myelin status.

Neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia-I.

BACKGROUND: We have investigated whether an acute metabolic damage to astrocytes during the neonatal period may critically disrupt subsequent brain development, leading to neurodevelopmental disorders. Astrocytes are vulnerable to glutaric acid (GA), a dicarboxylic acid that accumulates in millimolar concentrations in Glutaric Acidemia I (GA-I), an inherited neurometabolic childhood disease characterized by degeneration of striatal neurons. While GA induces astrocyte mitochondrial dysfunction, oxidative stress and subsequent increased proliferation, it is presently unknown whether such astrocytic dysfunction is sufficient to trigger striatal neuronal loss. METHODOLOGY/PRINCIPAL FINDINGS: A single intracerebroventricular dose of GA was administered to rat pups at postnatal day 0 (P0) to induce an acute, transient rise of GA levels in the central nervous system (CNS). GA administration potently elicited proliferation of astrocytes expressing S100ß followed by GFAP astrocytosis and nitrotyrosine staining lasting until P45. Remarkably, GA did not induce acute neuronal loss assessed by FluoroJade C and NeuN cell count. Instead, neuronal death appeared several days after GA treatment and progressively increased until P45, suggesting a delayed onset of striatal degeneration. The axonal bundles perforating the striatum were disorganized following GA administration. In cell cultures, GA did not affect survival of either striatal astrocytes or neurons, even at high concentrations. However, astrocytes activated by a short exposure to GA caused neuronal death through the production of soluble factors. Iron porphyrin antioxidants prevented GA-induced astrocyte proliferation and striatal degeneration in vivo, as well as astrocyte-mediated neuronal loss in vitro. CONCLUSIONS/SIGNIFICANCE: Taken together, these results indicate that a transient metabolic insult with GA induces long lasting phenotypic changes in astrocytes that cause them to promote striatal neuronal death. Pharmacological protection of astrocytes with antioxidants during encephalopatic crisis may prevent astrocyte dysfunction and the ineluctable progression of disease in children with GA-I.

Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: possible implications for GAI pathogenesis.

Glutaric (GA) and 3-hydroxyglutaric (OHGA) acids accumulate in glutaric acidemia I (GAI), a neurometabolic disease characterized by acute striatal degeneration and chronic progressive cortical atrophy. To explore the hypothesis that astrocytes are involved in GAI pathogenesis and targets of accumulating metabolites, we determined the effects of GA and OHGA on cultured rat cortical astrocytes. Remarkably, both acids induced mitochondria depolarization and stimulated proliferation in confluent cultures without apparent cell toxicity. Newborn rats injected with GA systemically also showed increased cell proliferation in different brain regions. Most of the proliferating cells displayed markers of immature astrocytes. Antioxidant iron porphyrins prevented both mitochondria dysfunction and increased in vitro and in vivo proliferation, suggesting a role of oxidative stress in inducing astrocytosis. Taken together, the data suggest that mitochondrial dysfunction induced by GA metabolites causes astrocytes to adopt a proliferative phenotype, which may underlie neuronal loss, white matter abnormalities and macrocephalia characteristics of GAI.