A Top-down Systems Analysis Identifies an Innate Feed-forward Inflammatory Circuit Leading to Lethal Influenza Infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE42641 | GEO | 2013/07/03
SECONDARY ACCESSION(S): PRJNA182485
REPOSITORIES: GEO
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2013-07-03 | E-GEOD-42641 | biostudies-arrayexpress
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Project description:Neuropathic pain is characterized by mechanical allodynia induced by low-threshold myelinated A?-fiber activation. The original gate theory of pain proposes that inhibitory interneurons in the lamina II of the spinal dorsal horn (DH) act as "gate control" units for preventing the interaction between innocuous and nociceptive signals. However, our understanding of the neuronal circuits underlying pain signaling and modulation in the spinal DH is incomplete. Using a rat model, we have shown that the convergence of glycinergic inhibitory and excitatory A?-fiber inputs onto PKC?+ neurons in the superficial DH forms a feed-forward inhibitory circuit that prevents A? input from activating the nociceptive pathway. This feed-forward inhibition was suppressed following peripheral nerve injury or glycine blockage, leading to inappropriate induction of action potential outputs in the nociceptive pathway by A?-fiber stimulation. Furthermore, spinal blockage of glycinergic synaptic transmission in vivo induced marked mechanical allodynia. Our findings identify a glycinergic feed-forward inhibitory circuit that functions as a gate control to separate the innocuous mechanoreceptive pathway and the nociceptive pathway in the spinal DH. Disruption of this glycinergic inhibitory circuit after peripheral nerve injury has the potential to elicit mechanical allodynia, a cardinal symptom of neuropathic pain.
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Project description:BACKGROUND:Egg laying in Caenorhabditis elegans has been well studied at the genetic and behavioral levels. However, the neural basis of egg-laying behavior is still not well understood; in particular, the roles of specific neurons and the functional nature of the synaptic connections in the egg-laying circuit remain uncharacterized. RESULTS:We have used in vivo neuroimaging and laser surgery to address these questions in intact, behaving animals. We have found that the HSN neurons play a central role in driving egg-laying behavior through direct excitation of the vulval muscles and VC motor neurons. The VC neurons play a dual role in the egg-laying circuit, exciting the vulval muscles while feedback-inhibiting the HSNs. Interestingly, the HSNs are active in the absence of synaptic input, suggesting that egg laying may be controlled through modulation of autonomous HSN activity. Indeed, body touch appears to inhibit egg laying, in part by interfering with HSN calcium oscillations. CONCLUSIONS:The egg-laying motor circuit comprises a simple three-component system combining feed-forward excitation and feedback inhibition. This microcircuit motif is common in the C. elegans nervous system, as well as in the mammalian cortex; thus, understanding its functional properties in C. elegans may provide insight into its computational role in more complex brains.
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Project description:In embryos, multipotent progenitors divide to produce distinct progeny and express their full potential. In vertebrates, multipotent cardiopharyngeal progenitors produce second-heart-field-derived cardiomyocytes, and branchiomeric skeletal head muscles. However, the mechanisms underlying these early fate choices remain largely elusive. The tunicate Ciona emerged as an attractive model to study early cardiopharyngeal development at high resolution: through two asymmetric and oriented divisions, defined cardiopharyngeal progenitors produce distinct first and second heart precursors, and pharyngeal muscle (aka atrial siphon muscle, ASM) precursors. Here, we demonstrate that differential FGF-MAPK signaling distinguishes between heart and ASM precursors. We characterize a feed-forward circuit that promotes the successive activations of essential ASM determinants, Hand-related, Tbx1/10 and Ebf. Finally, we show that coupling FGF-MAPK restriction and cardiopharyngeal network deployment with cell divisions defines the timing of gene expression and permits the emergence of diverse cell types from multipotent progenitors.
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Project description:Prior studies have shown that repetitive presentation of acoustic stimuli results in an alignment of ongoing neuronal oscillations to the sequence rhythm via oscillatory entrainment by external cues. Our study aimed to explore the neural correlates of the perceptual parsing and grouping of complex repeating auditory patterns that occur based solely on statistical regularities, or context. Human psychophysical studies suggest that the recognition of novel auditory patterns amid a continuous auditory stimulus sequence occurs automatically halfway through the first repetition. We hypothesized that once repeating patterns were detected by the brain, internal rhythms would become entrained, demarcating the temporal structure of these repetitions despite lacking external cues defining pattern on- or offsets. To examine the neural correlates of pattern perception, neuroelectric activity of primary auditory cortex (A1) and thalamic nuclei was recorded while nonhuman primates passively listened to streams of rapidly presented pure tones and bandpass noise bursts. At arbitrary intervals, random acoustic patterns composed of 11 stimuli were repeated five times without any perturbance of the constant stimulus flow. We found significant delta entrainment by these patterns in the A1, medial geniculate body, and medial pulvinar. In A1 and pulvinar, we observed a statistically significant, pattern structure-aligned modulation of neuronal firing that occurred earliest in the pulvinar, supporting the idea that grouping and detecting complex auditory patterns is a top-down, context-driven process. Besides electrophysiological measures, a pattern-related modulation of pupil diameter verified that, like humans, nonhuman primates consciously detect complex repetitive patterns that lack physical boundaries.
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Project description:Myocyte enhancer factor 2c (MEF2C) is the MADS-box type transcription factor involved in the differentiation of cardiac and skeletal muscle and synaptic formation. Alternatively spliced transcripts of the MEF2C gene were proven to encode isoforms which exert distinct functions in transcriptional regulation. During the differentiation of brown adipocytes, upregulated RBM4 enhanced skipping of the MEF2C? region which functions as a transcriptional repressor. The presence of an overexpressed MEF2C?- isoform in turn induced transcriptional activity of the RBM4 promoter, constituting a positive feedback circuit in differentiating brown adipocytes. The RBM4-MEF2C?- network induced the expression of "myogenic" miR-1 to a greater extent than did PRDM17, BMP7 C/EBP?, or UCP1 transcripts in C3H10T1/2 cells. Overexpression of miR-1 independently exerted the same activity as RBM4 and the MEF2C?- isoform of upregulating brown adipocyte-specific factors in C3H10T1/2 cells, which suggests a potential effect of miR-1 on brown adipocytes. These results indicated that the RBM4-MEF2C-miR-1 network constitutes a novel mechanism which programs the gene expression profile toward the development of brown adipocytes.
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Project description:BackgroundLeadership has been identified as an influential factor in implementation processes in healthcare organizations. However, the processes through which leaders affect implementation outcomes are largely unknown. The purpose of this study is to analyse how managers interpret and make sense of a large scale top-down implementation initiative and what implications this has for the implementation process. This was studied at the implementation of an academic primary healthcare initiative covering 210 primary healthcare centres in central Sweden. The aim of the initiative was to integrate research and education into regular primary healthcare services.MethodsThe study builds on 16 in-depth individual semi-structured interviews with all managers (n?=?8) who had operative responsibility for the implementation. Each manager was interviewed twice during the initial phase of the implementation. Data were analysed using a thematic approach guided by theory on managerial role taking based on the Transforming Experience Framework.ResultsHow the managers interpreted and made sense of the implementation task built on three factors: how they perceived the different parts of the initiative, how they perceived themselves in relation to these parts, and the resources available for the initiative. Based on how they combined these three factors the managers chose to integrate or separate the different parts of the initiative in their management of the implementation process.ConclusionsThis research emphasizes that managers in healthcare seem to have a substantial impact on how and to what extent different tasks are addressed and prioritized in top-down implementation processes. This has policy implications. To achieve intended implementation outcomes, the authors recognize the necessity of an early and on-going dialogue about how the implementation is perceived by the managers responsible for the implementation.
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