modelled in the Hodgkin–Huxley style and Fig. 3B shows the membrane potential of a incorporated known biophysical properties and single post-I neuron in the model under control channel kinetics previously characterized in conditions and after systemic application of a respiratory neurons in vitro and used in our low and higher doses of 8-OH-DPAT as previous models. Two additional types of compared with the corresponding intracellular potassium channels were incorporated in all recording from a post-I neuron of anesthetized respiratory neurons in the present model. One cat in vivo (Fig. 3A). After application of channel type was added to simulate the 8-OH-DPAT the durations of inspiration and hyperpolarizing effect of a higher dose of expiration decrease both in the experiment and 8-OH-DPAT on respiratory neurons and in our simulation. With a lower dose of represented specific K+ leak channels activated 8-OH-DPAT the activity of the post-I neuron by higher doses of the 5-HT-1AR agonist .
shifts to inspiration, whereas with a higher The other channel type included in the model dose the pattern of neuronal activity was an opioid-activated inwardly rectifying K+ transforms into a late-I spiking profile (Kir) channels [1, 2]. The incorporation of Kir associated with significant hyperpolarization.
channels allowed us to simulate the Despite a long history of studies, the experimentally observed opioid-induced specific cellular and/or network mechanisms depression of neuron excitability.
4-Й МЕЖДУНАРОДНЫЙ СИМПОЗИУМ «НЕЙРОИНФОРМАТИКА И НЕЙРОКОМПЬЮТЕРЫ» Fig. 3. Changes in the activity of the post-I neuron with 8-OH-DPAT application in the experiment (A) and in the model (B). Shaded bars show the inspiratory phase.
See text for details. Modified from Fig 5 in .
model, µ-opioid-induced apnea results from an imbalance of inhibitory interactions between inspiratory and expiratory neurons (Fig. 2B1).
Recent findings suggest that activation of 5-HT-1AR, widely expressed in the pre-BtC and BtC [3, 4], promotes breathing recovery after suppression of respiratory activity by opioids. As shown in Fig. 4A1, application of the 8-OH-DPAT to wild-type mice restores respiratory activity from apnea caused by application of the µ-OR agonist. In contrast, breathing in Gly3R knockout mice (Gly3R--) containing Gly1R but lacking Gly3R could not be restored by 8-OH-DPAT Fig. 2. (A) Model performance under control conditions (Fig. 4A2). This recovery was postulated to (A1) and after simulated application of low (A2) and originate from enhanced glycinergic inhibition higher (A3) doses of 8-OH-DPAT. (B) Model via Gly3R modulated by 5-HT-1AR performance after rhythmic activity was suppressed by activation . To simulate the specific role of simulated application of opioids (B1) and after recovery Gly3R and its modulation by 5-HT-1AR, we of rhythmic activity by a low (B2) and a higher dose (B3) of 8-OH-DPAT. The activity of each population is have suggested that dec-E, aug-E(1), and represented by the average spike frequency histogram of early-I(2) neurons co-express Gly3R and neuron activity (bin size, 30 ms). See details in the text.
5-HT-1AR, so activation of 5-HT-1AR amplifies Gly3R-mediated synaptic inhibition underlying respiratory depression (apnea) of these neurons by other glycinergic neurons produced by opioids are poorly understood. It (see dashed connections in Fig. 1B). We have has been suggested that opioids activate Kir also proposed that 8-OH-DPAT activates, in a channels, producing hyperpolarization of dose-dependent manner, 5-HT-1AR-dependent neurons expressing µ-opioid receptors (µ-OR) K+ leak channels that are assumed to be [1, 2]. In our model, we incorporated these present in all neurons of the model. Figure 2B channels, and hypothesized that their maximal shows simulation of suppression of rhythmic conductances in pre-BtC inspiratory neurons activity by opioids acting through µ-ORare larger than the maximal conductances in activated Kir channels followed by the 8-OHBtC expiratory neurons . Thus, in the DPAT-mediated recovery. In Fig. 2B1, the Материалы XVI Международной конференции по нейрокибернетике indicating a necessary role of the 5-HT-1ARmediated Gly3R signalling in this recovery.
Conclusions The developed extended model of the respiratory network reproduces experimentally observed responses to 8-OH-DPAT application and offers a mechanistic explanation for the 8-OH-DPAT-induced recovery of the respiratory rhythm after opioid-evoked apnea, suggesting two distinct mechanisms for recovery of respiratory activity by application of 8-OH-DPAT depending on the low vs. higher dose used.
References 1. Ballanyi, K., Lalley, P. M., Hoch, B. & Richter, D.W.
(1997) cAMP-dependent reversal of opioid- and Fig. 4. (A1) Administration of µ-OR agonist fentanyl prostaglandin mediated depression of the isolated blocked the phrenic nerve (PN) activity in in situ respiratory network in newborn rats. J. Physiol., 504, preparations from wild-type (wt) mice, which then 127–134.
recovered after 8-OH-DPAT application. (A2) In the 2. Lalley, P.M. (2003) µ-Opioid receptor agonist effects same preparations from Gly3R-- mice, respiratory on medullary respiratory neurons in the cat: evidence depression caused by fentanyl could not be reversed by for involvement in certain types of ventilatory 8-OHDPAT. (B1) Simulation of rhythm suppression disturbances. Am. J. Physiol. Regul. Integr. Comp.
followed by its recovery with application of (top) low Physiol., 285, R1287– R1304.
and (bottom) higher doses of 8-OHDPAT in the model.
3. Manzke, T., Dutschmann, M., Schlaf, G., Mrschel, (B2) Simulation shows that after removal of GlyaM., Koch, U.R., Ponimaskin, E., Bidon, O., Lalley, receptors, application of 8-OH-DPAT (any dose) cannot P.M. &. & Richter, D.W. (2009) Serotonin targets restore the rhythm. Modified from Figs. 3 and 13 in .
inhibitory synapses to induce modulation of network functions. Phil. Trans. R. Soc. B, 364, 2589–2602.
excitability of all inspiratory pre-BtC neurons 4. Manzke, T., Niebert, M., Koch, U. R., Caley, A., was reduced by the Kir channel activation and Vogelgesang, S., Hlsmann, S., Ponimaskin, E., they were fully inhibited by the expiratory Mller, U., Smart, T.G., Harvey, R.J. & Richter, D.W.
(2010) Serotonin receptor 1A-modulated phosphory populations of BtC. Application of a low lation of glycine receptor 3 controls breathing in mice.
dose of 8-OH-DPAT (Fig. 2B2) augments J. Clin. Invest., 120, 4118–4128.
inhibition of the dec-E and aug-E(1) 5. Molkov, Y.I., Abdala, A.P.L., Bacak, B.J., populations expressing Gly3R. This induces Smith, J.C., Paton, J.F.R. & Rybak, I.A. (2010) Latedisinhibition of pre-II and early-I(1) neurons expiratory activity: emergence and interactions with the respiratory CPG. J. Neurophysiol., 104, 2713–2729.
and restores respiratory oscillations but with a 6. Richter, D.W. (1996) Neural regulation of two-phase rhythmic pattern (note that the respiration: rhythmogenesis and afferent control. In activity of post-I activity is shifted to Gregor, R., & Windhorst, U. (Eds.), Comprehensive inspiration). At a higher dose of 8-OH-DPAT Human Physiology. Springer-Verlag, Berlin, Vol. 2, pp.
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7. Rybak, I.A., Shevtsova, N.A., Paton, J.F., Dick, T.E., 1AR-mediated potentiating of Gly3R and St-John, W.M., Morschel, M. & Dutschmann, M.
activation of 5-HT-1AR-regulated K+ leak (2004) Modeling the ponto-medullary respiratory channels. The simulated application of higher network. Respir. Physiol. Neurobiol., 143, 307–319.
doses of 8-OH-DPAT produces an increase in 8. Shevtsova, N.A., Manzke, T., Molkov, Y.I., the burst frequency and a decrease in burst Bischoff, A., Smith, J. C., Rybak, I. A., & Richter, D.W.
(2011) Computational modelling of 5-HT receptoramplitude of the ramp-I population (Fig. 4B1).
mediated reorganization of the brainstem respiratory Note also that after elimination of Gly3R in network. Eur. J. Neurosci., 34, 1276-1291.
the model, simulating the situation in Gly3R-- 9. Smith, J.C., Abdala, A.P., Koizumi, H., Rybak, I.A.
mice, application of 8-OH-DPAT (any dose) & Paton, J.F. (2007) Spatial and functional architecture of the mammalian brain stem respiratory network: a cannot restore the rhythm (Fig. 4B2), hierarchy of three oscillatory mechanisms. J.
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4-Й МЕЖДУНАРОДНЫЙ СИМПОЗИУМ «НЕЙРОИНФОРМАТИКА И НЕЙРОКОМПЬЮТЕРЫ» LIGHT ADAPTATION SUBSTATES IN THE RETINA A. Tikidji-Hamburyan, T. Muench Center for Integrative Neuroscience, University of Tuebingen firstname.lastname@example.org There are 3 major adaptation states in the retina, each the light path. The strongest filter, ND8, of which is characterized by photoreceptor actively attenuated light intensity by 8 log units, participating in light responses types (only rods, cones whereas the weakest filter, ND1, attenuated and rods, only cones). In this work, we compare light intensity only by 1 log unit. Each properties of retinal circuits and ganglion cells in different adaptation states and demonstrate that within experiment started with ND8 in the light path.
the photopic regime, there at least 2 distinct substates, Every ~40 minutes, we changed the filter and which we were able to register on both circuit and increased the luminance by 1 log unit. The single ganglion cells levels.
same stimulus set was repeated (i.e. the contrast of the full-field flashes was the same).
Introduction In total, the experiment was performed over log units, ranging from scotopic to high There are 2 photoreceptors types in the photopic levels.
retina: rods and cones. Change of operating ND1 intensity level corresponds to 10^photoreceptor type is one of the main light photoisomerizations/rod*sec. Rods were adaptation mechanisms in the retina. Rods active up to ND5; at ND4 they saturated.
operate at low light level (scotopic vision).
Cones kicked in the response at ND6.
When the light intensity increases, cones kick Therefore, at ND8 and ND7 the retina was in in the responses of ganglion cells (mesopic the scotopic regime, at ND6 and ND5 – in the vision). With further increase of light level, mesopic and at ND4 to ND1 – in the photopic rods saturate and cones operate alone regime.
(photopic vision). However, light adaptation The responses to the 2-sec flashes in the retina is not restricted to that. The recorded on each electrode were low-pass purpose of our study was to compare filtered to obtain local field potentials. This information processing in the retina in type of response reflects summed potential different adaptation states, and to check, changes taking place in both outer and inner whether there are any additional adaptation retina, so that it is a measure of activity over substates within the three major regimes.
all retinal circuits.
A typical local field potential has a Methods negative deflection at a light increment and another negative deflection, followed by a C57Bl/6 mice were dark adapted prior the positive deflection, at a light decrement. We experiment for at least 4 hrs. Multi-electrodemeasured the peaks of the deflections for each array recordings were made from ganglion flash, taking into account contrast sign. We cells of flat-mounted retinas in response to considered these peaks values as a light stimuli. The stimuli set included 20 2-sec characteristic of global retinal response to the full-field flashes of positive and negative light on- and offset.
contrast, presented every 10 seconds and The responses to the white noise were organized in 5 trials, and a full-field Gaussian high-pass filtered. Then a threshold was white noise. Contrast of the 2-sec flashes was applied and spikes extracted. After spike equal to maximal and minimal contrast used in sorting routine, we got responses of single Gaussian white noise. 4 trials of white noise, ganglion cells (units). For each unit, reverse each of which lasted 5 minutes, were correlation (spike-triggered average) was presented. The 2-sec flashes and white noise performed in order to obtain the so-called trials were interleaved.
“linear filter” of the cell . Time to the first To control overall light intensity, we peak of such linear filter was then used to inserted different neutral density filters into characterize temporal properties of ganglion Материалы XVI Международной конференции по нейрокибернетике cells. To reduce susceptibility to noise, we after the transition to ND3, the cells’ latency first fit the linear filter with a Gaussian and decreased as it happened at any other took the mean (µ) as a cell’s latency. brightness increase, but then, in course of Then we compared both local field to 15 minutes, it increased again. In fact, it potential peaks and latency measured 2-10 even exceeded the latency at ND6, the low minutes after the neutral density filter change mesopic level.
and those measured about 15 minutes later. At the next brightness level, ND2, the Also, we compared these values measured at latency dropped quickly and stayed stable over different neutral density filters with each the course of all 40 minutes of the other. presentation.
At the highest brightness level we tested, Results ND1, the latency of ganglion cells dropped quickly as well, but then it began to increase.
As expected, we observed adaptation This increase was not as prominent as at ND3, changes of responses when stepping into the but also significant.
mesopic and into the photopic ranges. On the Strikingly, all ganglion cells we have global level (local field potentials), these recorded from showed the same effect.
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