TY - JOUR
AB - Models of RNA secondary structure folding are widely used to study evolution in theory and simulation. However, systematic studies of the parameters involved are rare. In this paper, we study by simulation how RNA evolution is influenced by three different factors, namely the mutation rate, scaling of the fitness function, and distance measure. We found that for low mutation rates the qualitative evolutionary behavior is robust with respect to the scaling of the fitness function. For efficient mutation rates, which are close to the error threshold, scaling and distance measure have a strong influence on the evolutionary behavior. A global distance measure that takes sequence information additively into account lowers the error threshold. When using a local sequence-structure alignment for the distance, we observed a smoother evolution of the fitness over time. Finally, in addition to the well known error threshold, we identify another threshold of the mutation rate, called divergence threshold, where the qualitative transient behavior changes from a localized to an exploratory search.
AU - Anne Kupczok
AU - Dittrich,Peter
ID - 3767
IS - 3
JF - Journal of Theoretical Biology
TI - Determinants of simulated RNA evolution.
VL - 238
ER -
TY - JOUR
AB - Networks of GABAergic neurons are key elements in the generation of gamma oscillations in the brain. Computational studies suggested that the emergence of coherent oscillations requires hyperpolarizing inhibition. Here, we show that GABA(A) receptor-mediated inhibition in mature interneurons of the hippocampal dentate gyrus is shunting rather than hyperpolarizing. Unexpectedly, when shunting inhibition is incorporated into a structured interneuron network model with fast and strong synapses, coherent oscillations emerge. In comparison to hyperpolarizing inhibition, networks with shunting inhibition show several advantages. First, oscillations are generated with smaller tonic excitatory drive. Second, network frequencies are tuned to the gamma band. Finally, robustness against heterogeneity in the excitatory drive is markedly improved. In single interneurons, shunting inhibition shortens the interspike interval for low levels of drive but prolongs it for high levels, leading to homogenization of neuronal firing rates. Thus, shunting inhibition may confer increased robustness to gamma oscillations in the brain.
AU - Vida, Imre
AU - Bartos, Marlene
AU - Peter Jonas
ID - 3811
IS - 1
JF - Neuron
TI - Shunting inhibition improves robustness of gamma oscillations in hippocampal interneuron networks by homogenizing firing rates
VL - 49
ER -
TY - JOUR
AB - Hyperpolarization-activated channels (Ih or HCN channels) are widely expressed in principal neurons in the central nervous system. However, Ih in inhibitory GABAergic interneurons is less well characterized. We examined the functional properties of Ih in fast-spiking basket cells (BCs) of the dentate gyrus, using hippocampal slices from 17- to 21-day-old rats. Bath application of the Ih channel blocker ZD 7288 at a concentration of 30 microm induced a hyperpolarization of 5.7 +/- 1.5 mV, an increase in input resistance and a correlated increase in apparent membrane time constant. ZD 7288 blocked a hyperpolarization-activated current in a concentration-dependent manner (IC50, 1.4 microm). The effects of ZD 7288 were mimicked by external Cs+. The reversal potential of Ih was -27.4 mV, corresponding to a Na+ to K+ permeability ratio (PNa/PK) of 0.36. The midpoint potential of the activation curve of Ih was -83.9 mV, and the activation time constant at -120 mV was 190 ms. Single-cell expression analysis using reverse transcription followed by quantitative polymerase chain reaction revealed that BCs coexpress HCN1 and HCN2 subunit mRNA, suggesting the formation of heteromeric HCN1/2 channels. ZD 7288 increased the current threshold for evoking antidromic action potentials by extracellular stimulation, consistent with the expression of Ih in BC axons. Finally, ZD 7288 decreased the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal granule cells, the main target cells of BCs, to 70 +/- 4% of the control value. In contrast, the amplitude of mIPSCs was unchanged, consistent with the presence of Ih in inhibitory terminals. In conclusion, our results suggest that Ih channels are expressed in the somatodendritic region, axon and presynaptic elements of fast-spiking BCs in the hippocampus.
AU - Aponte, Yexica
AU - Lien, Cheng-Chang
AU - Reisinger, Ellen
AU - Peter Jonas
ID - 3813
IS - Pt 1
JF - Journal of Physiology
TI - Hyperpolarization-activated cation channels in fast-spiking interneurons of rat hippocampus
VL - 574
ER -
TY - GEN
AB - The axon terminals (mossy fibers) of hippocampal dentate granule cells form characteristic synaptic connections with large spines or excrescences of both hilar mossy cells and CA3 pyramidal neurons. Interneurons of the hilar region and area CA3 are also prominent targets of mossy fibers. The tracing of biocytin-filled mossy fibers and immunolabeling of target cells with interneuron markers has revealed that the majority of mossy fiber synapses project to gamma aminobutyric acid (GABA)-ergic inhibitory interneurons rather than to excitatory principal cells, although the functional implications of these quantitative differences are unclear. Following a brief description of the "classical" mossy fiber synapse on excrescences of CA3 pyramidal cells, the present review focuses on the contacts formed between granule cells and GABAergic interneurons, both normally and after synaptic reorganization. In response to deafferentation of mossy cell target cells, which include both granule cells and interneurons, mossy fibers "sprout" new axon collaterals that form a band of supragranular mossy fibers in the inner molecular layer of the dentate gyrus. Although most newly formed recurrent mossy fibers establish synapses with granule cells, there is an apparently convergent input of new mossy fibers onto GABA-immunoreactive interneuron dendrites that traverse the inner molecular layer. These mossy fiber-interneuron synapses in the dentate gyrus are observed in chronically epileptic rats and may be the structural correlate of the granule cell hyperinhibition observed in these animals in vivo. Together, the findings reviewed here establish mossy fiber synapses as an important component of inhibitory circuits in the hippocampus.
AU - Frotscher, Michael
AU - Peter Jonas
AU - Sloviter, Robert S
ID - 3814
IS - 2
T2 - Cell and Tissue Research
TI - Synapses formed by normal and abnormal hippocampal mossy fibers (Review)
VL - 326
ER -
TY - JOUR
AB - It is widely accepted that the hippocampus plays a major role in learning and memory. The mossy fiber synapse between granule cells in the dentate gyrus and pyramidal neurons in the CA3 region is a key component of the hippocampal trisynaptic circuit. Recent work, partially based on direct presynaptic patch-clamp recordings from hippocampal mossy fiber boutons, sheds light on the mechanisms of synaptic transmission and plasticity at mossy fiber synapses. A high Na(+) channel density in mossy fiber boutons leads to a large amplitude of the presynaptic action potential. Together with the fast gating of presynaptic Ca(2+) channels, this generates a large and brief presynaptic Ca(2+) influx, which can trigger transmitter release with high efficiency and temporal precision. The large number of release sites, the large size of the releasable pool of vesicles, and the huge extent of presynaptic plasticity confer unique strength to this synapse, suggesting a large impact onto the CA3 pyramidal cell network under specific behavioral conditions. The characteristic properties of the hippocampal mossy fiber synapse may be important for pattern separation and information storage in the dentate gyrus-CA3 cell network.
AU - Bischofberger, Josef
AU - Engel, Dominique
AU - Frotscher, Michael
AU - Peter Jonas
ID - 3815
IS - 3
JF - Pflugers Archiv : European Journal of Physiology
TI - Timing and efficacy of transmitter release at mossy fiber synapses in the hippocampal network
VL - 453
ER -
TY - JOUR
AU - Frotscher, Michael
AU - Gundelfinger, Eckart
AU - Peter Jonas
AU - Neher, Erwin
AU - Seeburg, Peter
ID - 3817
IS - 2
JF - Cell and Tissue Research
TI - The most important recent advances in synapse research from my point of view--and what remains to be done
VL - 326
ER -
TY - JOUR
AB - Rigorous analysis of synaptic transmission in the central nervous system requires access to presynaptic terminals. However, cortical terminals have been largely inaccessible to presynaptic patch-clamp recording, due to their small size. Using improved patch-clamp techniques in brain slices, we recorded from mossy fiber terminals in the CA3 region of the hippocampus, which have a diameter of 2-5 microm. The major steps of improvement were the enhanced visibility provided by high-numerical aperture objectives and infrared illumination, the development of vibratomes with minimal vertical blade vibrations and the use of sucrose-based solutions for storage and cutting. Based on these improvements, we describe a protocol that allows us to routinely record from hippocampal mossy fiber boutons. Presynaptic recordings can be obtained in slices from both rats and mice. Presynaptic recordings can be also obtained in slices from transgenic mice in which terminals are labeled with enhanced green fluorescent protein.
AU - Bischofberger, Josef
AU - Engel, Dominique
AU - Li, Liyi
AU - Geiger, Jörg R
AU - Peter Jonas
ID - 3818
IS - 4
JF - Nature Protocols
TI - Patch-clamp recording from mossy fiber terminals in hippocampal slices
VL - 1
ER -
TY - CONF
AB - A stochastic graph game is played by two players on a game graph with probabilistic transitions. We consider stochastic graph games with omega-regular winning conditions specified as Rabin or Streett objectives. These games are NP-complete and coNP-complete, respectively. The value of the game for a player at a state s given an objective Phi is the maximal probability with which the player can guarantee the satisfaction of Phi from s. We present a strategy-improvement algorithm to compute values in stochastic Rabin games, where an improvement step involves solving Markov decision processes (MDPs) and nonstochastic Rabin games. The algorithm also computes values for stochastic Streett games but does not directly yield an optimal strategy for Streett objectives. We then show how to obtain an optimal strategy for Streett objectives by solving certain nonstochastic Streett games.
AU - Krishnendu Chatterjee
AU - Thomas Henzinger
ID - 3888
TI - Strategy improvement for stochastic Rabin and Streett games
VL - 4137
ER -
TY - CONF
AB - We study observation-based strategies for two-player turn-based games on graphs with omega-regular objectives. An observation-based strategy relies on imperfect information about the history of a play, namely, on the past sequence of observations. Such games occur in the synthesis of a controller that does not see the private state of the plant. Our main results are twofold. First, we give a fixed-point algorithm for computing the set of states from which a player can win with a deterministic observation-based strategy for any omega-regular objective. The fixed point is computed in the lattice of antichains of state sets. This algorithm has the advantages of being directed by the objective and of avoiding an explicit subset construction on the game graph. Second, we give an algorithm for computing the set of states from which a player can win with probability 1 with a randomized observation-based strategy for a Buchi objective. This set is of interest because in the absence of perfect information, randomized strategies are more powerful than deterministic ones. We show that our algorithms are optimal by proving matching lower bounds.
AU - Krishnendu Chatterjee
AU - Doyen, Laurent
AU - Thomas Henzinger
AU - Raskin, Jean-François
ID - 3889
TI - Algorithms for omega-regular games with imperfect information
VL - 4207
ER -
TY - CONF
AB - We consider two-player infinite games played on graphs. The games are concurrent, in that at each state the players choose their moves simultaneously and independently, and stochastic, in that the moves determine a probability distribution for the successor state. The value of a game is the maximal probability with which a player can guarantee the satisfaction of her objective. We show that the values of concurrent games with w-regular objectives expressed as parity conditions can be decided in NP boolean AND coNP. This result substantially improves the best known previous bound of 3EXPTIME. It also shows that the full class of concurrent parity games is no harder than the special case of turn-based stochastic reachability games, for which NP boolean AND coNP is the best known bound. While the previous, more restricted NP boolean AND coNP results for graph games relied on the existence of particularly simple (pure memoryless) optimal strategies, in concurrent games with parity objectives optimal strategies may not exist, and epsilon-optimal strategies (which achieve the value of the game within a parameter epsilon > 0) require in general both randomization and infinite memory. Hence our proof must rely on a more detailed analysis of strategies and, in addition to the main result, yields two results that are interesting on their own. First, we show that there exist epsilon-optimal strategies that in the limit coincide with memoryless strategies; this parallels the celebrated result of Mertens-Neyman for concurrent games with limit-average objectives. Second, we complete the characterization of the memory requirements for epsilon-optimal strategies for concurrent games with parity conditions, by showing that memoryless strategies suffice for epsilon-optimality for coBachi conditions.
AU - Krishnendu Chatterjee
AU - de Alfaro, Luca
AU - Thomas Henzinger
ID - 3890
TI - The complexity of quantitative concurrent parity games
ER -
TY - CONF
AB - We study infinite stochastic games played by two-players over a finite state space, with objectives specified by sets of infinite traces. The games are concurrent (players make moves simultaneously and independently), stochastic (the next state is determined by a probability distribution that depends on the current state and chosen moves of the players) and infinite (proceeds for infinite number of rounds). The analysis of concurrent stochastic games can be classified into: quantitative analysis, analyzing the optimum value of the game; and qualitative analysis, analyzing the set of states with optimum value 1. We consider concurrent games with tail objectives, i.e., objectives that are independent of the finite-prefix of traces, and show that the class of tail objectives are strictly richer than the omega-regular objectives. We develop new proof techniques to extend several properties of concurrent games with omega-regular objectives to concurrent games with tail objectives. We prove the positive limit-one property for tail objectives, that states for all concurrent games if the optimum value for a player is positive for a tail objective Phi at some state, then there is a state where the optimum value is 1 for Phi, for the player. We also show that the optimum values of zero-sum (strictly conflicting objectives) games with tail objectives can be related to equilibrium values of nonzero-sum (not strictly conflicting objectives) games with simpler reachability objectives. A consequence of our analysis presents a polynomial time reduction of the quantitative analysis of tail objectives to the qualitative analysis for the sub-class of one-player stochastic games (Markov decision processes).
AU - Krishnendu Chatterjee
ID - 3891
TI - Concurrent games with tail objectives
VL - 4207
ER -