Dendritic Spine Abnormalities in Hippocampal CA1 Pyramidal Neurons Underlying Memory Deficits in the SAMP8 Mouse Model of Alzheimer's Disease

SAMP8 is a strain of mice with accelerated senescence. These mice have recently been the focus of attention as they show several alterations that have also been described in Alzheimer"s disease (AD) patients. The number of dendritic spines, spine plasticity, and morphology are basic to memory formation. In AD, the density of dendritic spines is severely decreased. We studied memory alterations using the object recognition test. We measured levels of synaptophysin as a marker of neurotransmission and used Golgi staining to quantify and characterize the number and morphology of dendritic spines in SAMP8 mice and in SAMR1 as control animals. While there were no memory differences at 3 months of age, the memory of both 6- and 9-month-old SAMP8 mice was impaired in comparison with age-matched SAMR1 mice or young SAMP8 mice. In addition, synaptophysin levels were not altered in young SAMP8 animals, but SAMP8 aged 6 and 9 months had less synaptophysin than SAMR1 controls and also less than 3-month-old SAMP8 mice. Moreover, while spine density remained stable with age in SAMR1 mice, the number of spines started to decrease in SAMP8 animals at 6 months, only to get worse at 9 months. Our results show that from 6 months onwards SAMP8 mice show impaired memory. This age coincides with that at which the levels of synaptophysin and spine density decrease. Thus, we conclude that together with other studies that describe several alterations at similar ages, SAMP8 mice are a very suitable model for studying AD.

Connecten el cervell d'un humà al d'una mosca

Un equip d"investigadors de la Universitat de Harvard crea una interfície que recull els impulsos nerviosos d"una persona i els envia al cervell d"una rata, de tal manera que es podria provocar que mogués la cua.

Developmental expression of the oligodendrocyte myelin glycoprotein in the mouse telencephalon

The oligodendrocyte myelin glycoprotein is a glycosylphosphatidylinositol-anchored protein expressed by neurons and oligodendrocytes in the CNS. Attempts have been made to identify the functions of the myelin-associated inhibitory proteins (MAIPs) after axonal lesion or in neurodegeneration. However, the developmental roles of some of these proteins and their receptors remain elusive. Recent studies indicate that NgR1 and the recently discovered receptor PirB restrict cortical synaptic plasticity. However, the putative factors that trigger these effects are unknown. Since Nogo-A is mostly associated with the endoplasmic reticulum and MAG appears late during development, the putative participation of OMgp should be considered. Here we examine the pattern of development of OMgp immunoreactive elements during mouse telencephalic development. OMgp immunoreactivity in the developing cortex follows the establishment of the thalamo-cortical barrel-field. At cellular level, we located OMgp neuronal membranes in dendrites and axons as well as in brain synaptosome fractions and axon varicosities. Lastly, the analysis of the barrel-field in OMgp-deficient mice revealed that although thalamo-cortical connections were formed, their targeting in layer IV was altered and numerous axons ectopically invaded layer II-III. Our data support the idea that early-expressed MAIPs play an active role during development and point to OMgp participating in thalamo-cortical connections.

Estimations of topographically correct regeneration to nerve branches and skin after peripheral nerve injury and repair.

Peripheral nerve injury is typically associated with long-term disturbances in sensory localization, despite nerve repair and regeneration. Here, we investigate the extent of correct reinnervation by back-labeling neuronal soma with fluorescent tracers applied in the target area before and after sciatic nerve injury and repair in the rat. The subpopulations of sensory or motor neurons that had regenerated their axons to either the tibial branch or the skin of the third hindlimb digit were calculated from the number of cell bodies labeled by the first and/or second tracer. Compared to the normal control side, 81% of the sensory and 66% of the motor tibial nerve cells regenerated their axons back to this nerve, while 22% of the afferent cells from the third digit reinnervated this digit. Corresponding percentages based on quantification of the surviving population on the experimental side showed 91%, 87%, and 56%, respectively. The results show that nerve injury followed by nerve repair by epineurial suture results in a high but variable amount of topographically correct regeneration, and that proportionally more neurons regenerate into the correct proximal nerve branch than into the correct innervation territory in the skin

Emergence of assortative mixing between clusters of cultured neurons

The analysis of the activity of neuronal cultures is considered to be a good proxy of the functional connectivity of in vivo neuronal tissues. Thus, the functional complex network inferred from activity patterns is a promising way to unravel the interplay between structure and functionality of neuronal systems. Here, we monitor the spontaneous self-sustained dynamics in neuronal cultures formed by interconnected aggregates of neurons (clusters). Dynamics is characterized by the fast activation of groups of clusters in sequences termed bursts. The analysis of the time delays between clusters' activations within the bursts allows the reconstruction of the directed functional connectivity of the network. We propose a method to statistically infer this connectivity and analyze the resulting properties of the associated complex networks. Surprisingly enough, in contrast to what has been reported for many biological networks, the clustered neuronal cultures present assortative mixing connectivity values, meaning that there is a preference for clusters to link to other clusters that share similar functional connectivity, as well as a rich-club core, which shapes a"connectivity backbone" in the network. These results point out that the grouping of neurons and the assortative connectivity between clusters are intrinsic survival mechanisms of the culture.

The Armc10/SVH gene: Genome context, regulation of mitochondrial dynamics and protection against Aβ-induced mitochondrial fragmentation

Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents A beta-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against A beta-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.

The Armc10/SVH gene: Genome context, regulation of mitochondrial dynamics and protection against Aβ-induced mitochondrial fragmentation

Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents A beta-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against A beta-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.

Estudio del desarrollo y conectividad de las neuronas vasotocinérgicas en el prosencéfalo de pollo

En este Trabajo de Fin de Grado se estudia el origen embrionario de las distintas poblaciones neuronales que forman la amígdala medial extendida. La amígdala es una estructura del cerebro anterior involucrada en otorgar un significado emocional a los estímulos ambientales y en el control de distintos aspectos del comportamiento social (p.ej. comportamientos sexual, maternal, agresivo y afiliativo). Ante dichos estímulos, la amígdala pone en marcha una serie de reacciones de carácter motor, autonómico y endocrino que constituyen la respuesta emocional. Algunos desórdenes de carácter neuropsiquiátrico en humanos están relacionados con una disfunción en el control de las emociones y del comportamiento social, y varios de ellos se asocian a alteraciones en el desarrollo de la amígdala. El objetivo del presente trabajo ha sido investigar el origen de las neuronas de la amígdala medial extendida en embriones de pollo (E15 y E18) mediante ensayos de inmunocitoquímica, técnica utilizada para localizar las células que contienen el neuropéptido vasotocina (AVT) y proteínas reguladoras del desarrollo (la producida a partir del gen Otp) para ayudar en la delimitación de los distintos dominios embrionarios del prosencéfalo y distintas subdivisiones de la amígdala extendida. Los resultados de estos ensayos se combinaron con ensayos de trazado de conexiones para analizar la conectividad de las neuronas vasotocinérgicas de esta estructura. Los resultados obtenidos sugieren que las neuronas AVT-positivas podrían derivar del dominio Supra-Opto-Paraventricular (SPV), y algunas poblaciones alcanzarían su posición definitiva dentro del propio dominio por migración radial, mientras que otras invadirían otros dominios cerebrales por migración tangencial. En conclusión, la investigación proporciona importantes datos que clarifican aspectos relevantes del desarrollo y organización adulta de la amígdala extendida, y ayuda a establecer las bases para una mejor comprensión del control neural de las emociones y el comportamiento social en condiciones normales y patológicas.

A feed-forward spiking model of shape-coding by IT cells

The ability to recognize a shape is linked to figure-ground (FG) organization. Cell preferences appear to be correlated across contrast-polarity reversals and mirror reversals of polygon displays, but not so much across FG reversals. Here we present a network structure which explains both shape-coding by simulated IT cells and suppression of responses to FG reversed stimuli. In our model FG segregation is achieved before shape discrimination, which is itself evidenced by the difference in spiking onsets of a pair of output cells. The studied example also includes feature extraction and illustrates a classification of binary images depending on the dominance of vertical or horizontal borders.

Neuronal activity controls the antagonistic between PGC-1α and SMRT in regulating antioxidant defences

Transcriptional coactivators and corepressors often have multiple targets and can have opposing actions on transcription and downstream physiological events. The coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is under-expressed in Huntington's disease and is a regulator of antioxidant defenses and mitochondrial biogenesis. We show that in primary cortical neurons, expression of PGC-1α strongly promotes resistance to excitotoxic and oxidative stress in a cell autonomous manner, whereas knockdown increases sensitivity. In contrast, the transcriptional corepressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) specifically antagonizes PGC-1α-mediated antioxidant effects. The antagonistic balance between PGC-1α and SMRT is upset in favor of PGC-1α by synaptic activity. Synaptic activity triggers nuclear export of SMRT reliant on multiple regions of the protein. Concommitantly, synaptic activity post-translationally enhances the transactivating potential of PGC-1α in a p38-dependent manner, as well as upregulating cyclic-AMP response element binding protein-dependent PGC-1α transcription. Activity-dependent targeting of PGC-1α results in enhanced gene expression mediated by the thyroid hormone receptor, a prototypical transcription factor coactivated by PGC-1α and repressed by SMRT. As a consequence of these events, SMRT is unable to antagonize PGC-1α-mediated resistance to oxidative stress in synaptically active neurons. Thus, PGC-1α and SMRT are antagonistic regulators of neuronal vulnerability to oxidative stress. Further, this coactivatorcorepressor antagonism is regulated by the activity status of the cell, with implications for neuronal viability.

Què hereta el cervell

Tots els animals tenen un sistema nerviós que els relaciona amb l'entorn, però el cervell humà no té parió. No només percebem l'entorn i som capaços de veure, per exemple, com surt el sol, sinó que a diferència de tota la resta d'ani- mals som capaços de percebre i gaudir de tota la bellesa d'aquesta explosió de llum i color. Tampoc no som els únics que vivim en societats organitzades, però la complexitat i la varietat de la nostra és infinitament superior. Ens comuni- quem amb els nostres congèneres, com d'una manera o una altra fan tots els mamífers, però el nostre llenguatge és capaç de crear també poesia. I colpegem pedres i pals, com la resta de primats, però les nostres mans, guiades pel cervell, també són capaces de crear obres d'art magnífiques. I raonem, som conscients de la nostra pròpia existència i hem fet florir les cultures més variades. El nostre comportament, i fins i tot la nostra forma de pensar i de percebre el món, vénen determinats per l'activitat del cervell i per anys d'evolució [...]

La intel·ligència de la col·laboració

Ala natura, les interrelacions entre elements diversos incrementen la complexitat dels sistemes i les seves possibilitats. Per exemple, la intel·ligència que genera el nostre cervell és molt superior a la suma de les capacitats individuals dels 70.000 milions de neurones que conté, cap de les quals és, per ella mateixa, intel·ligent. De la mateixa manera, ja fa molts anys que la ciència no és un afer de persones solitàries sinó el fruit de la col·laboració entre individus i equips de recerca [...]

Migracions neuronals

En més d'una ocasió he defensat en aquestes pàgines que les interpretacions antropomòrfiques dels fenòmens biològics ens poden ajudar a entendre qüestions socials, malgrat que siguin discutibles i puguin portar a conclusions contraposades segons el punt de vista de cadascú. Aquesta me l'ha suggerida una companya de feina, i jo l'he passada pel meu sedàs. Pretenc comparar la migració i integració de les neurones al cervell amb la migració i integració dels nouvinguts a Catalunya [...]

Miralls màgics

Els humans som uns imitadors excel·lents. Som capaços d'imitar els moviments dels altres, les seves expressions i també els seus sentiments. Aquesta és la base de la literatura, la poesia, la música i el teatre, manifestacions culturals cent per cent humanes que ens fan vibrar com si allò que llegim, escoltem o veiem ho estiguéssim vivint realment nosaltres, en un procés d'imitació mental que fa que ens hi sentim reflectits [...].

Progressive Purkinje Cell Degeneration in tambaleante Mutant Mice Is a Consequence of a Missense Mutation in HERC1 E3 Ubiquitin Ligase

The HERC gene family encodes proteins with two characteristic domains: HECT and RCC1-like. Proteins with HECT domain shave been described to function as ubiquitin ligases, and those that contain RCC1-like domains have been reported to function as GTPases regulators. These two activities are essential in a number of important cellular processes such as cell cycle, cell signaling, and membrane trafficking. Mutations affecting these domains have been found associated with retinitis pigmentosa, amyotrophic lateral sclerosis, and cancer. In humans, six HERC genes have been reported which encode two subgroups of HERC proteins: large (HERC1-2) and small (HERC3-6). The giant HERC1 protein was the first to be identified. It has been involved in membrane trafficking and cell proliferation/growth through its interactions with clathrin, M2-pyruvate kinase, and TSC2 proteins. Mutations affecting other members of the HERC family have been found to be associated with sterility and growth retardation. Here, we report the characterization of a recessive mutation named tambaleante, which causes progressive Purkinje cell degeneration leading to severe ataxia with reduced growth and lifespan in homozygous mice aged over two months. We mapped this mutation in mouse chromosome 9 and then performed positional cloning. We found a GuA transition at position 1448, causing a Gly to Glu substitution (Gly483Glu) in the highly conserved N- terminal RCC1-like domain of the HERC1 protein. Successful transgenic rescue, with either a mouse BAC containing the normal copy of Herc1 or with the human HERC1 cDNA, validated our findings. Histological and biochemical studies revealed extensive autophagy associated with an increase of the mutant protein level and a decrease of mTOR activity. Our observations concerning this first mutation in the Herc1 gene contribute to the functional annotation of the encoded E3 ubiquitin ligase and underline the crucial and unexpected role of this protein in Purkinje cell physiology.