Supraspinal modulation of neuronal synchronization by nociceptive stimulation induces an enduring reorganization of dorsal horn neuronal connectivity

Despite a profusion of information on the molecular and cellular mechanisms involved in the central sensitization produced by intense nociceptive stimulation, the changes in the patterns of functional connectivity between spinal neurones associated with the development of secondary hyperalgesia and allodynia remain largely unknown. Here we show that the state of central sensitization produced by the intradermal injection of capsaicin is associated with structured transformations in neuronal synchronization that lead to an enduring reorganization of the functional connectivity within a segmentally distributed ensemble of dorsal horn neurones. These changes are transiently reversed by the systemic administration of small doses of lidocaine, a clinically effective procedure to treat neuropathic pain. Lidocaine also reduces the capsaicin-induced facilitation of the spinal responses evoked by weak mechanical stimulation of the skin in the region of secondary but not primary hyperalgesia. The effects of both intradermic capsaicin and systemic lidocaine on the segmental correlation and coherence between ongoing cord dorsum potentials and on the responses evoked by tactile stimulation in the region of secondary hyperalgesia are greatly attenuated in spinalized preparations, showing that supraspinal influences are involved in the reorganization of the nociceptive-induced structured patterns of dorsal horn neuronal connectivity. We conclude that the structured reorganization of the functional connectivity between the dorsal horn neurones induced by capsaicin nociceptive stimulation results from cooperative interactions between supraspinal and spinal networks, a process that may have a relevant role in the shaping of the spinal state in the pathogenesis of chronic pain and analgesia.Peer ReviewedPostprint (author's final draft

Markovian analysis of the sequential behavior of the spontaneous spinal cord dorsum potentials induced by acute nociceptive stimulation in the anesthetized cat

In a previous study we developed a Machine Learning procedure for the automatic identification and classification of spontaneous cord dorsum potentials (CDPs). This study further supported the proposal that in the anesthetized cat, the spontaneous CDPs recorded from different lumbar spinal segments are generated by a distributed network of dorsal horn neurons with structured (non-random) patterns of functional connectivity and that these configurations can be changed to other non-random and stable configurations after the noceptive stimulation produced by the intradermic injection of capsaicin in the anesthetized cat. Here we present a study showing that the sequence of identified forms of the spontaneous CDPs follows a Markov chain of at least order one. That is, the system has memory in the sense that the spontaneous activation of dorsal horn neuronal ensembles producing the CDPs is not independent of the most recent activity. We used this markovian property to build a procedure to identify portions of signals as belonging to a specific functional state of connectivity among the neuronal networks involved in the generation of the CDPs. We have tested this procedure during acute nociceptive stimulation produced by the intradermic injection of capsaicin in intact as well as spinalized preparations. Altogether, our results indicate that CDP sequences cannot be generated by a renewal stochastic process. Moreover, it is possible to describe some functional features of activity in the cord dorsum by modeling the CDP sequences as generated by a Markov order one stochastic process. Finally, these Markov models make possible to determine the functional state which produced a CDP sequence. The proposed identification procedures appear to be useful for the analysis of the sequential behavior of the ongoing CDPs recorded from different spinal segments in response to a variety of experimental procedures including the changes produced by acute nociceptive stimulation. They are envisaged as a useful tool to examine alterations of the patterns of functional connectivity between dorsal horn neurons under normal and different pathological conditions, an issue of potential clinical concern.Peer ReviewedPostprint (published version

Supraspinal shaping of adaptive transitions in the state of functional connectivity between segmentally distributed dorsal horn neuronal populations in response to nociception and antinociception

In the anesthetized cat the correlation between the ongoing cord dorsum potentials(CDPs) recorded from different lumbar spinal segments has a non-random structure,suggesting relatively stable patterns of functional connectivity between the dorsalhorn neuronal ensembles involved in the generation of these potentials. During thenociception induced by the intradermic injection of capsaicin, the patterns of segmentalcorrelation between the spontaneous CDPs acquire other non-random configurationsthat are temporarily reversed to their pre-capsaicin state by the systemic injectionof lidocaine, a procedure known to decrease the manifestation of neuropathic painin both animals and humans. We have now extended these studies and utilizedmachine learning for the automatic extraction and selection of particular classes ofCDPs according to their shapes and amplitudes. By using a Markovian analysis, wedisclosed the transitions between the different kinds of CDPs induced by capsaicinand lidocaine and constructed a global model based on the changes in the behaviorof the CDPs generated along the whole set of lumbar segments. This allowed theidentification of the different states of functional connectivity within the whole ensembleof dorsal horn neurones attained during nociception and their transitory reversal bysystemic administration of lidocaine in preparations with the intact neuroaxis and afterspinalization. The present observations provide additional information on the stateof self-organized criticality that leads to the adaptive behavior of the dorsal hornneuronal networks during nociception and antinociception both shaped by supraspinaldescending influencesPeer ReviewedPostprint (published version

Glial contribution to excitatory and inhibitory synapse loss in neurodegeneration

Synapse loss is an early feature shared by many neurodegenerative diseases, and it represents the major correlate of cognitive impairment. Recent studies reveal that microglia and astrocytes play a major role in synapse elimination, contributing to network dysfunction associated with neurodegeneration. Excitatory and inhibitory activity can be affected by glia-mediated synapse loss, resulting in imbalanced synaptic transmission and subsequent synaptic dysfunction. Here, we review the recent literature on the contribution of glia to excitatory/inhibitory imbalance, in the context of the most common neurodegenerative disorders. A better understanding of the mechanisms underlying pathological synapse loss will be instrumental to design targeted therapeutic interventions, taking in account the emerging roles of microglia and astrocytes in synapse remodeling

Efectos Genéticos Directo y Materno sobre el Crecimiento de Ovinos de la Raza Junín

In order to estimate the genetic effects – direct and maternal – linked to the expression of growth traits in lambs of Junín breed, four mixed models were applied in the study of the birth weight (PN), weaning weight (PD), first shearing weight (PE) and daily body weight gain from birth to weaning (GPND), through univariate and bivariate analysis. The models used in univariate analysis included as fixed effects year of birth and sex, and as covariates the mother’s weight at mating (for PN and PD), age of lamb at weaning (for PD and GPND), and age at first shearing (for PE). Model 1 included the fixed effects and the direct additive genetic effect (a); Model 2, similar to 1, added additive maternal genetic effect (m), considering Covam=0; Model 3, similar to 2, assumed Covam=Aam; and Model 4, equal to 3, added the maternal permanent environmental effect (c). All bivariate models were extensions of the univariate ones. In all the analyses, the restricted maximum likelihood (REML) method, implemented in the ASReml program was applied. Univariate Model 2 and bivariate Model 3 estimated the best genetic parameters, including correlations between direct and maternal additive effects for the traits. The estimated heritability values ranged from low to moderate, indicating the possibility of its application in genetic improvement plans for Junín sheep, which would increase its efficiency when the estimated, moderate to high genetic and phenotypic correlations are also included.Con el objetivo de estimar los efectos genéticos – directo y materno – vinculados a la expresión de características de crecimiento en corderos de la raza Junín, se aplicaron cuatro modelos mixtos en el estudio de sus pesos de nacimiento (PN), destete (PD), primera esquila (PE) y ganancia diaria del nacimiento al destete (GPND), a través de análisis univariado y bivariado. Los modelos usados en análisis univariado incluyeron como efectos fijos el año de nacimiento y sexo, y como covariables el peso de la madre al empadre (para PN y PD), la edad del cordero al destete (para PD y GPND) y la edad a la primera esquila (para PE). El Modelo 1 incluyó los efectos fijos y el efecto genético aditivo directo (a); el Modelo 2, similar al 1, adicionó el efecto genético aditivo materno (m), considerando la Covam=0; en el Modelo 3, igual al 2, se asumió la Covam=Aóam; y el Modelo 4, igual al 3, se adicionó el efecto del ambiente permanente materno (c). Los modelos para el análisis bivariado fueron extensiones del univariado, empleándose en todos los análisis el método de máxima verosimilitud restringida (REML), instrumentado en el programa ASReml. En el análisis univariado, el Modelo 2, y en el bivariado el Modelo 3, estimaron mejor los parámetros genéticos, incluidas las correlaciones entre los efectos aditivos directos y maternos para las características. Los valores estimados de heredabilidad variaron entre bajos y moderados, indicando la posibilidad de ser aplicados en planes de mejora genética del ovino Junín, los mismos que incrementarían su eficiencia al adicionarse a ellos los valores, entre moderados y altos, de las correlaciones genéticas y fenotípicas estimadas

Intersegmental synchronization of spontaneous cord dorsum potentials as a clinical parameter to evaluate changes in neuronal connectivity produced by peripheral nerve and spinal cord damage

We describe here automatic selection method to retrieve spontaneous cord dorsum potentials from the spiral cord in the anesthetized cat. Previous studies have indicated that some of these potentials appear synchronized in several spinal segments and are generated by the activation of specific sets of dorsal horn neurons. Since their synchronization is affected in a characteristic manner by acute peripheral nerve and spinal lesions, as well as during capsaicin-induced skin inflammation, they can be used to describe the patterns of functional interconnectivity between specific sets of dorsal horn neurons, which makes them of potential clinical interest

Supraspinal modulation of neuronal synchronization by nociceptive stimulation induces an enduring reorganization of dorsal horn neuronal connectivity

Despite a profusion of information on the molecular and cellular mechanisms involved in the central sensitization produced by intense nociceptive stimulation, the changes in the patterns of functional connectivity between spinal neurones associated with the development of secondary hyperalgesia and allodynia remain largely unknown. Here we show that the state of central sensitization produced by the intradermal injection of capsaicin is associated with structured transformations in neuronal synchronization that lead to an enduring reorganization of the functional connectivity within a segmentally distributed ensemble of dorsal horn neurones. These changes are transiently reversed by the systemic administration of small doses of lidocaine, a clinically effective procedure to treat neuropathic pain. Lidocaine also reduces the capsaicin-induced facilitation of the spinal responses evoked by weak mechanical stimulation of the skin in the region of secondary but not primary hyperalgesia. The effects of both intradermic capsaicin and systemic lidocaine on the segmental correlation and coherence between ongoing cord dorsum potentials and on the responses evoked by tactile stimulation in the region of secondary hyperalgesia are greatly attenuated in spinalized preparations, showing that supraspinal influences are involved in the reorganization of the nociceptive-induced structured patterns of dorsal horn neuronal connectivity. We conclude that the structured reorganization of the functional connectivity between the dorsal horn neurones induced by capsaicin nociceptive stimulation results from cooperative interactions between supraspinal and spinal networks, a process that may have a relevant role in the shaping of the spinal state in the pathogenesis of chronic pain and analgesia.Peer Reviewe

Intersegmental synchronization of spontaneous cord dorsum potentials as a clinical parameter to evaluate changes in neuronal connectivity produced by peripheral nerve and spinal cord damage

We describe here automatic selection method to retrieve spontaneous cord dorsum potentials from the spiral cord in the anesthetized cat. Previous studies have indicated that some of these potentials appear synchronized in several spinal segments and are generated by the activation of specific sets of dorsal horn neurons. Since their synchronization is affected in a characteristic manner by acute peripheral nerve and spinal lesions, as well as during capsaicin-induced skin inflammation, they can be used to describe the patterns of functional interconnectivity between specific sets of dorsal horn neurons, which makes them of potential clinical interest

Studies of the 3-phosphoglycerate kinase gene of Penicillium chrysogenum

SIGLEAvailable from British Library Document Supply Centre- DSC:D174210 / BLDSC - British Library Document Supply CentreGBUnited Kingdo