Fast Inhibition Alters First Spike Timing in Auditory Brainstem Neurons

2004 ◽  
Vol 92 (4) ◽  
pp. 2615-2621 ◽  
Author(s):  
Antonio G. Paolini ◽  
Janine C. Clarey ◽  
Karina Needham ◽  
Graeme M. Clark
Keyword(s):  
Lateral Inhibition ◽  
Cochlear Nucleus ◽  
Stellate Cell ◽  
Discharge Rate ◽  
Stellate Cells ◽  
Auditory Pathway ◽  
Auditory Brainstem ◽  
Spike Timing ◽  
Inhibitory Neurons

Within the first processing site of the central auditory pathway, inhibitory neurons (D stellate cells) broadly tuned to tonal frequency project on narrowly tuned, excitatory output neurons (T stellate cells). The latter is thought to provide a topographic representation of sound spectrum, whereas the former is thought to provide lateral inhibition that improves spectral contrast, particularly in noise. In response to pure tones, the overall discharge rate in T stellate cells is unlikely to be suppressed dramatically by D stellate cells because they respond primarily to stimulus onset and provide fast, short-duration inhibition. In vivo intracellular recordings from the ventral cochlear nucleus (VCN) showed that, when tones were presented above or below the characteristic frequency (CF) of a T stellate neuron, they were inhibited during depolarization. This resulted in a delay in the initial action potential produced by T stellate cells. This ability of fast inhibition to alter the first spike timing of a T stellate neuron was confirmed by electrically activating the D stellate cell pathway that arises in the contralateral cochlear nucleus. Delay was also induced when two tones were presented: one at CF and one outside the frequency response area of the T stellate neuron. These findings suggest that the traditional view of lateral inhibition within the VCN should incorporate delay as one of its principle outcomes.

scholarly journals Chemical synaptic transmission onto superficial stellate cells of the mouse dorsal cochlear nucleus

2014 ◽  
Vol 111 (9) ◽  
pp. 1812-1822 ◽  
Author(s):  
Pierre F. Apostolides ◽  
Laurence O. Trussell
Keyword(s):  
Cochlear Nucleus ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Dorsal Cochlear Nucleus ◽  
Fine Tuning ◽  
In Vivo Studies ◽  
Inhibitory Synapses ◽  
Inhibitory Interneurons ◽  
Sensory Stimuli

The dorsal cochlear nucleus (DCN) is a cerebellum-like auditory brain stem region whose functions include sound localization and multisensory integration. Although previous in vivo studies have shown that glycinergic and GABAergic inhibition regulate the activity of several DCN cell types in response to sensory stimuli, data regarding the synaptic inputs onto DCN inhibitory interneurons remain limited. Using acute DCN slices from mice, we examined the properties of excitatory and inhibitory synapses onto the superficial stellate cell, a poorly understood cell type that provides inhibition to DCN output neurons (fusiform cells) as well as to local inhibitory interneurons (cartwheel cells). Excitatory synapses onto stellate cells activated both NMDA receptors and fast-gating, Ca2+-permeable AMPA receptors. Inhibition onto superficial stellate cells was mediated by glycine and GABAA receptors with different temporal kinetics. Paired recordings revealed that superficial stellate cells make reciprocal synapses and autapses, with a connection probability of ∼18–20%. Unexpectedly, superficial stellate cells co-released both glycine and GABA, suggesting that co-transmission may play a role in fine-tuning the duration of inhibitory transmission.

scholarly journals Alpha-single chains of collagen type VI inhibit the fibrogenic effects of triple helical collagen VI in hepatic stellate cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0254557
Author(s):  
Christian Freise ◽  
Hyunho Lee ◽  
Christopher Chronowski ◽  
Doug Chan ◽  
Jessica Cziomer ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Collagen Type ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Collagen Type I ◽  
Serum Starvation ◽  
Type I ◽  
Linear Peptide

The interaction of extracellular matrix (ECM) components with hepatic stellate cells (HSCs) is thought to perpetuate fibrosis by stimulating signaling pathways that drive HSC activation, survival and proliferation. Consequently, disrupting the interaction between ECM and HSCs is considered a therapeutical avenue although respective targets and underlying mechanisms remain to be established. Here we have interrogated the interaction between type VI collagen (CVI) and HSCs based on the observation that CVI is 10-fold upregulated during fibrosis, closely associates with HSCs in vivo and promotes cell proliferation and cell survival in cancer cell lines. We exposed primary rat HSCs and a rat hepatic stellate cell line (CFSC) to soluble CVI and determined the rate of proliferation, apoptosis and fibrogenesis in the absence of any additional growth factors. We find that CVI in nanomolar concentrations prevents serum starvation-induced apoptosis. This potent anti-apoptotic effect is accompanied by induction of proliferation and acquisition of a pronounced pro-fibrogenic phenotype characterized by increased α-smooth muscle actin, TGF-β, collagen type I and TIMP-1 expression and diminished proteolytic MMP-13 expression. The CVI-HSC interaction can be disrupted with the monomeric α2(VI) and α3(VI) chains and abrogates the activating CVI effects. Further, functional relevant α3(VI)—derived 30 amino acid peptides lead to near-complete inhibition of the CVI effect. In conclusion, CVI serves as a potent mitogen and activating factor for HSCs. The antagonistic effects of the CVI monomeric chains and peptides point to linear peptide sequences that prevent activation of CVI receptors which may allow a targeted antifibrotic therapy.

Regulation of peroxisome proliferator-activated receptor-γ in liver fibrosis

2006 ◽  
Vol 291 (5) ◽  
pp. G902-G911 ◽  
Author(s):  
Liu Yang ◽  
Che-Chang Chan ◽  
Oh-Sang Kwon ◽  
Songling Liu ◽  
Jason McGhee ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Liver Injury ◽  
Mrna Expression ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Collagen I ◽  
Peroxisome Proliferator ◽  
Actin Mrna

The peroxisome proliferator-activated receptors (PPARs) impart diverse cellular effects in biological systems. Because stellate cell activation during liver injury is associated with declining PPARγ expression, we hypothesized that its expression is critical in stellate cell-mediated fibrogenesis. We therefore modulated its expression during liver injury in vivo. PPARγ was depleted in rat livers by using an adenovirus-Cre recombinase system. PPARγ was overexpressed by using an additional adenoviral vector (AdPPARγ). Bile duct ligation was utilized to induce stellate cell activation and liver fibrosis in vivo; phenotypic effects (collagen I, smooth muscle α-actin, hydroxyproline content, etc.) were measured. PPARγ mRNA levels decreased fivefold and PPARγ protein was undetectable in stellate cells after culture-induced activation. During activation in vivo, collagen accumulation, assessed histomorphometrically and by hydroxyproline content, was significantly increased after PPARγ depletion compared with controls (1.28 ± 0.14 vs. 1.89 ± 0.21 mg/g liver tissue, P < 0.03). In isolated stellate cells, AdPPARγ overexpression resulted in significantly increased adiponectin mRNA expression and decreased collagen I and smooth muscle α-actin mRNA expression compared with controls. During in vivo fibrogenesis, rat livers exposed to AdPPARγ had significantly less fibrosis than controls. Collagen I and smooth muscle α-actin mRNA expression were significantly reduced in AdPPARγ-infected rats compared with controls ( P < 0.05, n = 10). PPARγ-deficient mice exhibited enhanced fibrogenesis after liver injury, whereas PPARγ receptor overexpression in vivo attenuated stellate cell activation and fibrosis. The data highlight a critical role for PPARγ during in vivo fibrogenesis and emphasize the importance of the PPARγ pathway in stellate cells during liver injury.

Hepatic and pancreatic stellate cells in focus

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Claus Kordes ◽  
Iris Sawitza ◽  
Dieter Häussinger
Keyword(s):  
Cell Biology ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Differentiation Potential ◽  
Undifferentiated Cells ◽  
Cell Niche ◽  
Space Of Disse

Abstract Stellate cells are vitamin A-storing cells of liver and pancreas and have been described in all vertebrates ranging from lampreys (primitive fish) to humans, demonstrating their major importance. This cell type is thought to contribute to fibrosis, a condition characterized by an excess deposition of extracellular matrix proteins. Recently, the expression of stem/progenitor cell markers, such as CD133 (prominin-1) and Oct4, was discovered in hepatic stellate cells (HSCs) of rats. Moreover, HSCs possess signaling pathways important for maintenance of stemness and cell differentiation, such as hedgehog, β-catenin-dependent Wnt, and Notch signaling, and are resistant to CD95-mediated apoptosis. In analogy to a stem cell niche, some characteristics of quiescent HSC are maintained by aid of a special microenvironment located in the space of Dissé. Finally, stellate cells display a differentiation potential as investigated in vitro and in vivo. Collectively all these properties are congruently found in stem/progenitor cells and support the concept that stellate cells are undifferentiated cells, which might play an important role in liver regeneration. The present review highlights findings related to this novel aspect of stellate cell biology.

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

2003 ◽  
Vol 285 (3) ◽  
pp. G652-G660 ◽  
Author(s):  
H. Hendrickson ◽  
S. Chatterjee ◽  
S. Cao ◽  
M. Morales Ruiz ◽  
W. C. Sessa ◽  
...  
Keyword(s):  
Rat Liver ◽  
Hepatic Stellate Cells ◽  
Fluorescent Protein ◽  
Stellate Cell ◽  
Active Form ◽  
Stellate Cells ◽  
Liver Cells ◽  
No Production

Diminished endothelial nitric oxide (NO) synthase (eNOS)-derived NO production from the hepatic vascular endothelium contributes to hepatic vasoconstriction in portal hypertension. The aim of this study was to examine the mechanism of this process by testing the influence of a constitutively active form of eNOS (S1179DeNOS) in both primary and propagated liver cells in vitro and in the sham and bile duct ligated (BDL) rat liver in vivo, using an adenoviral vector encoding green fluorescent protein (AdGFP) and S1179DeNOS (AdS1179DeNOS). AdS1179DeNOS transduction augmented basal and agonist-stimulated NO generation in nonparenchymal liver cells. Sham rats transduced in vivo with AdS1179DeNOS evidenced a decreased pressor response to incremental doses of the vasoconstrictor methoxamine compared with sham rats transduced with AdGFP. However, BDL rats transduced with AdS1179DeNOS did not display improved vasodilatory responses as evidenced by similar flow-dependent pressure increases to that observed in BDL rats transduced with AdGFP, despite similar levels of viral transgene expression. We next examined the influence of the eNOS inhibitory protein caveolin on S1179DeNOS dysfunction in cirrhotic liver. Immunogold electron microscopic analysis of caveolin in BDL liver demonstrated prominent expression not only in liver endothelial cells, but also in hepatic stellate cells. In vitro studies in the LX2 hepatic stellate cell line demonstrate that caveolin precipitates recombinant S1179DeNOS in LX2 cells, that recombinant S1179DeNOS coprecipitates caveolin, and that binding is enhanced in the presence of overexpression of caveolin. Furthermore, caveolin overexpression inhibits recombinant S1179DeNOS activity. These studies indicate that recombinant S1179DeNOS protein functions appropriately in normal liver cells and tissue but evidences dysfunction in the cirrhotic rat liver and that caveolin expression and inhibition in BDL nonparenchymal cells, including hepatic stellate cells, may account for this dysfunction.

Level dependence of cochlear nucleus onset unit responses and facilitation by second tones or broadband noise

1995 ◽  
Vol 73 (1) ◽  
pp. 141-159 ◽  
Author(s):  
I. M. Winter ◽  
A. R. Palmer
Keyword(s):  
Cochlear Nucleus ◽  
Discharge Rate ◽  
Nerve Fibers ◽  
Sound Level ◽  
Spike Timing ◽  
Broadband Noise ◽  
Sound System ◽  
Rate Level ◽  
Sound Levels ◽  
Level Function

1. The responses of onset units in the cochlear nucleus of the anesthetized guinea pig have been measured to single tones, two-tone complexes, and broadband noise (BBN; 20-kHz bandwidth). The onset units were subdivided into three groups, onset-I (OnI), onset-L (OnL), and onset-C (OnC), on the basis of a decision tree using their peristimulus time histogram (PSTH) shape and discharge rate in response to suprathreshold best-frequency (BF) tone bursts. 2. PSTHs were constructed from responses either to single tones at a unit's BF or to BBN as a function of level. When sufficient sustained activity could be elicited from the unit, arbitrarily defined as > 100 spikes/s, a coefficient of variation (CV) was calculated; the majority were characterized by a CV that was similar to transient chopper units (0.35 < CV < 0.5). First spike latency decreased monotonically with increasing sound level. For the majority of onset units, the first spike timing was very precise. 3. BF rate-level functions recorded from OnL and OnC units did not show any signs of discharge rate saturation at the highest sound levels we have used (100-115 dB SPL). No systematic relationship was observed between the threshold at BF and the shape of the rate-level function. BBN rate-level functions were typically characterized by higher discharge rates than in response to BF tones. However, for OnI units and a minority of other onset units, there was little difference in the shape of their rate-level functions in response to BF tones or BBN. 4. The threshold of most onset units to BBN was similar to the threshold to a BF tone that had similar overall root-mean-square (RMS) energy. The BBN threshold was, on average, 5.5 dB greater than the BF threshold. This result contrasts with that found in auditory-nerve fibers recorded in the same species, with the use of an identical sound system, where the threshold to BBN was, on average, 19.4 dB higher. The mean threshold difference between BBN and BF tones for a population of chopper units recorded in the same series of experiments was 17.7 dB. The relative thresholds to BBN and BF tones indicated that the bandwidths near the onset units' BF threshold were broader than could be estimated with the use of single tones. Ten units were characterized by bimodal response areas.(ABSTRACT TRUNCATED AT 400 WORDS)

Regularity analysis in a compartmental model of chopper units in the anteroventral cochlear nucleus

1991 ◽  
Vol 65 (3) ◽  
pp. 606-629 ◽  
Author(s):  
M. I. Banks ◽  
M. B. Sachs
Keyword(s):  
Cochlear Nucleus ◽  
Auditory Nerve ◽  
Compartmental Model ◽  
Dendritic Tree ◽  
Stellate Cells ◽  
Physiological Data ◽  
Response Patterns ◽  
Anteroventral Cochlear Nucleus

1. We investigate the discharge patterns of chopper units in the anteroventral cochlear nucleus (AVCN) by developing an equivalent cylinder compartmental model of AVCN stellate cells, which are the sources of the chopper response pattern. The model consists of a passive dendritic tree connected to somatic and axonal compartments with voltage-sensitive channels. Synaptic inputs to the model are simulated auditory nerve fiber responses to best-frequency tones. 2. We adjust the anatomic and electrical parameters of the model to agree with available intracellular data from stellate cells in the AVCN of the mouse and the cat and compare the response of the model to injected current with responses recorded in vitro. The model shows approximately linear current-voltage characteristics for small hyperpolarizing currents. The model's input resistance and the time course of its response to hyperpolarizing current applied at the soma are comparable with those measured from stellate cells in vitro. In response to sustained depolarizing current, the model fires repetitively with nearly perfect regularity, a property also observed in vitro. 3. Auditory nerve inputs to the cell are modeled as deadtime-modified Poisson processes with a multiexponential adaptation in the Poisson rate. We are able to adjust the number, rate, and location of excitatory and inhibitory inputs to the model and succeed in simulating chopper response patterns seen in vivo. 4. Chopper units exhibit a variety of regularity and adaptation patterns in response to tone stimuli. Physiological data from brain slice experiments and experiments in vivo imply that this heterogeneity is primarily due to differences in input configurations. By systematically varying the number and position of excitatory and inhibitory inputs, we can simulate a range of chopper response patterns. 5. We quantify the regularity of the model's response using the coefficient of variation (CV) of the interspike interval. We find that the CV decreases, i.e., the regularity increases, as the number of converging inputs or their distance from the soma increases. The regularity of the output is more sensitive to the number of converging inputs than to their location on the dendritic tree. The statistics of the first spike latency (FSL) are also sensitive to the configuration of excitatory inputs. The mean and minimum FSL are more sensitive to the electrotonic distance of the inputs from the soma than to the number of inputs, whereas the standard deviation of the FSL is highly dependent on the number of converging inputs and is nearly independent of their location.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Pregnenolone-16α-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms

2005 ◽  
Vol 387 (3) ◽  
pp. 601-608 ◽  
Author(s):  
Carylyn J. MAREK ◽  
Steven J. TUCKER ◽  
Dimitrios K. KONSTANTINOU ◽  
Lucy J. ELRICK ◽  
Dee HAEFNER ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Direct Interaction ◽  
Pregnane X Receptor ◽  
Stellate Cells ◽  
Liver Growth ◽  
Liver Fibrogenesis

The effect of liver growth stimulation [using the rodent PXR (pregnane X receptor) activator PCN (pregnenolone-16α-carbonitrile)] in rats chronically treated with carbon tetrachloride to cause repeated hepatocyte necrosis and liver fibrogenesis was examined. PCN did not inhibit the hepatotoxicity of carbon tetrachloride. However, transdifferentiation of hepatic stellate cells and the extent of fibrosis caused by carbon tetrachloride treatment was significantly inhibited by PCN in vivo. In vitro, PCN directly inhibited hepatic stellate cell transdifferentiation to a profibrogenic phenotype, although the cells did not express the PXR (in contrast with hepatocytes), suggesting that PCN acts independently of the PXR. Mice with a functionally disrupted PXR gene (PXR−/−) did not respond to the antifibrogenic effects of PCN, in contrast with wild-type (PXR+/+) mice, demonstrating an antifibrogenic role for the PXR in vivo. However, PCN inhibited the transdifferentiation of PXR−/−-derived mouse hepatic stellate cells in vitro, confirming that there is also a PXR-independent antifibrogenic effect of PCN through a direct interaction with hepatic stellate cells. These data suggest that the PXR is antifibrogenic in rodents in vivo and that a PXR-independent target for PXR activators exists in hepatic stellate cells that also functions to inhibit fibrosis.

scholarly journals Inhibitory networks orchestrate the self-organization of computational function in cortical microcircuit motifs through STDP

2017 ◽  
Author(s):  
Stefan Häusler ◽  
Wolfgang Maass
Keyword(s):  
Lateral Inhibition ◽  
Network Motif ◽  
Pyramidal Cells ◽  
Theoretical Work ◽  
Spike Timing ◽  
The Self ◽  
Inhibitory Neurons ◽  
Self Organization ◽  
Interacting Networks ◽  
Inhibitory Networks

AbstractInterneurons have diverse morphological and physiological characteristics that potentially contribute to the emergence of powerful computational properties of cortical networks. We investigate the functional role of inhibitory subnetworks in the arguably most common network motif of cortical microcircuits: ensembles of pyramidal cells (PCs) with lateral inhibition, commonly referred to as Winner-Take-All networks. Recent theoretical work has shown that spike-timing-dependent plasticity installs in this network motif an important and ubiquitously useful self-organization process: The emergence of sparse codes and Bayesian inference for repeatedly occurring high-dimensional input patterns. However, this link has so far only been established for strongly simplified models with a symbolic implementation of lateral inhibition, rather than through the interaction of PCs with known types of interneurons. We close this gap in this article, and show that the interaction of PCs with two types of inhibitory networks, that reflect salient properties of somatic-targeting neurons (e.g. basket cells) and dendritic-targeting neurons (e.g. Martinotti cells), provides a good approximation to the theoretically optimal lateral inhibition needed for the self-organization of these network motifs. We provide a step towards unraveling the functional roles of interacting networks of excitatory and inhibitory neurons from the perspective of emergent neural computation.

scholarly journals Identification of an inhibitory neuron subtype, the L-stellate cell of the cochlear nucleus

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Tenzin Ngodup ◽  
Gabriel E Romero ◽  
Laurence O Trussell
Keyword(s):  
Auditory Processing ◽  
Cochlear Nucleus ◽  
Stellate Cell ◽  
Imaging Techniques ◽  
Inhibitory Neuron ◽  
Stellate Cells ◽  
Projection Neuron ◽  
Transgenic Mouse Line ◽  
Soma Size ◽  
Inhibitory Signaling

Auditory processing depends upon inhibitory signaling by interneurons, even at its earliest stages in the ventral cochlear nucleus (VCN). Remarkably, to date only a single subtype of inhibitory neuron has been documented in the VCN, a projection neuron termed the D-stellate cell. With the use of a transgenic mouse line, optical clearing, and imaging techniques, combined with electrophysiological tools, we revealed a population of glycinergic cells in the VCN distinct from the D-stellate cell. These multipolar glycinergic cells were smaller in soma size and dendritic area, but over ten-fold more numerous than D-stellate cells. They were activated by auditory nerve and T-stellate cells, and made local inhibitory synaptic contacts on principal cells of the VCN. Given their abundance, combined with their narrow dendritic fields and axonal projections, it is likely that these neurons, here termed L-stellate cells, play a significant role in frequency-specific processing of acoustic signals.

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