Improved automatic discovery of subgoals for options in hierarchical

Options have been shown to be a key step in extending reinforcement learning beyond low-level reactionary systems to higher-level, planning systems. Most of the options research involves hand-crafted options; there has been only very limited work in the automated discovery of options. We extend early work in automated option discovery with a flexible and robust method.Facultad de Informátic

Improved automatic discovery of subgoals for options in hierarchical

Options have been shown to be a key step in extending reinforcement learning beyond low-level reactionary systems to higher-level, planning systems. Most of the options research involves hand-crafted options; there has been only very limited work in the automated discovery of options. We extend early work in automated option discovery with a flexible and robust method.Facultad de Informátic

Improved automatic discovery of subgoals for options in hierarchical

Options have been shown to be a key step in extending reinforcement learning beyond low-level reactionary systems to higher-level, planning systems. Most of the options research involves hand-crafted options; there has been only very limited work in the automated discovery of options. We extend early work in automated option discovery with a flexible and robust method.Facultad de Informátic

Neuronal circuitry for pain processing in the dorsal horn

Neurons in the spinal dorsal horn process sensory information, which is then transmitted to several brain regions, including those responsible for pain perception. The dorsal horn provides numerous potential targets for the development of novel analgesics and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation. Despite its obvious importance, we still know little about the neuronal circuits that process sensory information, mainly because of the heterogeneity of the various neuronal components that make up these circuits. Recent studies have begun to shed light on the neuronal organization and circuitry of this complex region

Differences in genotype and virulence among four multidrug-resistant <i>Streptococcus pneumoniae</i> isolates belonging to the PMEN1 clone

We report on the comparative genomics and characterization of the virulence phenotypes of four &lt;i&gt;S. pneumoniae&lt;/i&gt; strains that belong to the multidrug resistant clone PMEN1 (Spain&lt;sup&gt;23F&lt;/sup&gt; ST81). Strains SV35-T23 and SV36-T3 were recovered in 1996 from the nasopharynx of patients at an AIDS hospice in New York. Strain SV36-T3 expressed capsule type 3 which is unusual for this clone and represents the product of an in vivo capsular switch event. A third PMEN1 isolate - PN4595-T23 - was recovered in 1996 from the nasopharynx of a child attending day care in Portugal, and a fourth strain - ATCC700669 - was originally isolated from a patient with pneumococcal disease in Spain in 1984. We compared the genomes among four PMEN1 strains and 47 previously sequenced pneumococcal isolates for gene possession differences and allelic variations within core genes. In contrast to the 47 strains - representing a variety of clonal types - the four PMEN1 strains grouped closely together, demonstrating high genomic conservation within this lineage relative to the rest of the species. In the four PMEN1 strains allelic and gene possession differences were clustered into 18 genomic regions including the capsule, the blp bacteriocins, erythromycin resistance, the MM1-2008 prophage and multiple cell wall anchored proteins. In spite of their genomic similarity, the high resolution chinchilla model was able to detect variations in virulence properties of the PMEN1 strains highlighting how small genic or allelic variation can lead to significant changes in pathogenicity and making this set of strains ideal for the identification of novel virulence determinant

Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal Synaptic Potentiation and Pain Hypersensitivity

Electrophysiological and behavioral experiments in mice reveal that a cGMP-dependent kinase amplifies neurotransmitter release from peripheral pain sensors, potentiates spinal synapses, and leads to exaggerated pain

Sensitization of lamina I spinoparabrachial neurons parallels heat hyperalgesia in the chronic constriction injury model of neuropathic pain

It has been proposed that spinal lamina I neurons with ascending axons that project to the midbrain play a crucial role in hyperalgesia. To test this hypothesis the quantitative properties of lamina I spinoparabrachial neurons in the chronic constriction injury (CCI) model of neuropathic pain were compared to those of unoperated and sham-operated controls. Behavioural testing showed that animals with a CCI exhibited heat hyperalgesia within 4 days of the injury, and this hyperalgesia persisted throughout the 14-day post-operative testing period. In the CCI, nociceptive lamina I spinoparabrachial neurons had heat thresholds that were significantly lower than controls (43.0 ± 2.8°C vs. 46.7 ± 2.6°C; P < 10−4, ANOVA). Nociceptive lamina I spinoparabrachial neurons were also significantly more responsive to graded heat stimuli in the CCI, compared to controls (P < 0.02, 2-factor repeated-measures ANOVA), and increased after-discharges were also observed. Furthermore, the heat-evoked stimulus–response functions of lamina I spinoparabrachial neurons in CCI animals co-varied significantly (P < 0.03, ANCOVA) with the amplitude of heat hyperalgesia determined behaviourally. Taken together these results are consistent with the hypothesis that lamina I spinoparabrachial neurons have an important mechanistic role in the pathophysiology of neuropathic pain

Glycine Inhibitory Dysfunction Turns Touch into Pain through PKCgamma Interneurons

Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. During tactile allodynia, activation of the sensory fibers which normally detect touch elicits pain. Here we provide a new behavioral investigation into the dynamic component of tactile allodynia that developed in rats after segmental removal of glycine inhibition. Using in vivo electrophysiological recordings, we show that in this condition innocuous mechanical stimuli could activate superficial dorsal horn nociceptive specific neurons. These neurons do not normally respond to touch. We anatomically show that the activation was mediated through a local circuit involving neurons expressing the gamma isoform of protein kinase C (PKCγ). Selective inhibition of PKCγ as well as selective blockade of glutamate NMDA receptors in the superficial dorsal horn prevented both activation of the circuit and allodynia. Thus, our data demonstrates that a normally inactive circuit in the dorsal horn can be recruited to convert touch into pain. It also provides evidence that glycine inhibitory dysfunction gates tactile input to nociceptive specific neurons through PKCγ-dependent activation of a local, excitatory, NMDA receptor-dependent, circuit. As a consequence of these findings, we suggest that pharmacological inhibition of PKCγ might provide a new tool for alleviating allodynia in the clinical setting

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG