Integration of ascending and descending inputs in the auditory midbrain of anurans.

In anurans, the midbrain torus semicircularis is involved in auditory processing and audio-motor integration. In this study, we examined the influence of descending forebrain projections on the auditory response properties and hence the audiomotor transmission of mesencephalic interface neurons. In order to investigate response integration, we performed intracellular recordings from torus neurons in an isolated brain preparation of Discoglossus pictus and Bombina orientalis and stimulated the auditory nerve, striatum, and the dorsal thalamus electrically with single pulses. Stimulation of all three sites could evoke responses in torus neurons that were either excitatory, inhibitory, or a mixture of both, with durations of up to several hundred milliseconds. Further, striatum and thalamus were activated by pulse trains (10-20 Hz, 50 pulses) immediately before stimulating the auditory nerve with single pulses. Thus, responses of torus neurons to "auditory" input were facilitated or suppressed for up to 2 min by striatum stimulation or only suppressed by thalamus stimulation. Intracellular labeling of recorded neurons revealed that response modulation by descending input mostly occurred in laminar nucleus neurons. These results suggest that descending forebrain projections to mesencephalic audiomotor interface neurons may play an important role in modifying acoustically guided behavior in anurans.     

Some state space models of HIV pathogenesis under treatment by anti-viral drugs in HIV-infected individuals

In this paper we have extended the model of HIV pathogenesis under treatment by anti-viral drugs given by Perelson et al. [A.S. Perelson et al., Science 271 (1999) 1582] to a stochastic model. By using this stochastic model as the stochastic system model, we have developed a state space model for the HIV pathogenesis under treatment by anti-viral drugs. In this state space model, the observation model is a statistical model based on the observed numbers of RNA virus copies over different times. For this model we have developed procedures for estimating and predicting the numbers of infectious free HIV and non-infectious free HIV as well as the numbers of different types of T cells through extended Kalman filter method. As an illustration, we have applied the method of this paper to the data of patient Nos. 104, 105 and 107 given by Perelson et al. [A.S. Perelson et al., Science 271 (1999) 1582] under treatment by Ritonavir. For these individuals, it is shown that within two weeks since treatment, most of the free HIV are non-infectious, indicating the usefulness of the treatment. Furthermore, the Kalman filter method revealed a much stronger effect of the treatment within the first 10 to 20 h than that predicted by the deterministic model.     

Probability models and the applicability of statistical procedures in the identification of chromosomal fragile sites

Summary. Böhm et al. (1995, Human Genetics 95 , 249–256) introduced a statistical model (named FSM–fragile site model) specifically designed for the identification of fragile sites from chromosomal breakage data. In response to claims to the contrary (Hou et al., 1999, Human Genetics 104 , 350–355; Hou et al., 2001, Biometrics 57 , 435–440), we show how the FSM model is correctly modified for application under the assumption that the probability of random breakage is proportional to chromosomal band length and how the purportedly alternative procedures proposed by Hou, Chang, and Tai (1999, 2001) are variations of the correctly modified FSM algorithm. With the exception of the test statistic employed, the procedure described by Hou et al. (1999) is shown to be functionally identical to the correctly modified FSM and the application of an incorrectly modified FSM is shown to invalidate all of the comparisons of FSM to the alternatives proposed by Hou et al. (1999, 2001). Last, we discuss the statistical implications of the methodological variations proposed by Hou et al. (2001) and emphasize the logical and statistical necessity for fragile site identifications to be based on data from single individuals.     

A model of the phase-sensitivity of the pacemaking cell in the bullfrog heart.

In this study, mathematical models of the bullfrog sinus venosus (SV) pacemaker cell (Rasmusson et al., 1990, Am. J. Physiol. 259, H352-H369) and the ACh-sensitive K+ channel (Shumaker et al., 1990, Biophys. J. 57, 567-576) are combined to simulate the response of the SV myocyte to brief hyperpolarizing currents or acetylcholine (ACh) pulses. These simulations provide an ionic basis for the interpretation of the response of this pacemaker cell to either single perturbation or periodic stimuli. The model predicts that the effects of ACh stimulation on the pacemaker cycle length are dependent both on the phase and temporal characteristics of the [ACh] waveform. For example, the simulations show that (1) although ACh normally has an inhibitory effect on the pacemaker model, for cases where the rise time and duration of the [ACh] waveform are sufficiently brief, ACh can paradoxically accelerate the beat in which a single stimulus is given; (2) the SV pacemaker normally exhibits type 1 (odd) phase-resetting in response to ACh delivery, however type 0 (even) phase-resetting behavior may be exhibited when the [ACh] waveform is large enough and has a very fast rise time; and (3) the SV pacemaker may become phase-locked to a repetitive ACh stimulus applied with either a constant period or coupling interval. In the latter case, this entrainment phenomenon has implications for the control of the cardiac pacemaker by a neural oscillator (e.g. located in the medullary cardiovascular control center) which provides input to the pacemaker cell via the vagus nerve. In these regions of capture, repetitive ACh stimulation produces a well-known paradoxical accelerative effect on the SV pacemaker cell, similar to that seen in a variety of other species.     

Dynamic Impedance Model of the Skin-Electrode Interface for Transcutaneous Electrical Stimulation

Transcutaneous electrical stimulation can depolarize nerve or muscle cells applying impulses through electrodes attached on the skin. For these applications, the electrode-skin impedance is an important factor which influences effectiveness. Various models describe the interface using constant or current-depending resistive-capacitive equivalent circuit. Here, we develop a dynamic impedance model valid for a wide range stimulation intensities. The model considers electroporation and charge-dependent effects to describe the impedance variation, which allows to describe high-charge pulses. The parameters were adjusted based on rectangular, biphasic stimulation pulses generated by a stimulator, providing optionally current or voltage-controlled impulses, and applied through electrodes of different sizes. Both control methods deliver a different electrical field to the tissue, which is constant throughout the impulse duration for current-controlled mode or have a very current peak for voltage-controlled. The results show a predominant dependence in the current intensity in the case of both stimulation techniques that allows to keep a simple model. A verification simulation using the proposed dynamic model shows coefficient of determination of around 0.99 in both stimulation types. The presented method for fitting electrode-skin impedance can be simple extended to other stimulation waveforms and electrode configuration. Therefore, it can be embedded in optimization algorithms for designing electrical stimulation applications even for pulses with high charges and high current spikes.     

Rats’ (Rattus norvegicus) temporal discrimination of brief auditory stimuli: How does it compare with that of humans (Homo sapiens) and zebra finches (Taeniopygia guttata)?

The present study with rats replicated an experiment on the ability of zebra finches and humans to discriminate among brief auditory stimuli (see Weisman et al., 1999, Experiment 2). We trained rats with 27 3-kHz tones that varied in duration from 10 ms to 1420 ms. Reinforcement was contingent on responding (approaching the food well) to the nine medium-durations range tones (56-255 ms) but not to the nine short-durations range (10-46 ms) or long-durations range tones (309-1420 ms). Rats also received post-discrimination transfer tests with 2 kHz and 4 kHz tones that varied over the same durations as the 3 kHz tones. Rats acquired the temporal discrimination to a slightly lower level of accuracy than seen in finches or humans by Weisman et al. (1999). We tested for transfer of the temporal discrimination to find that rats, similar to humans (data from Weisman et al., 1999), transferred to untrained 2-kHz and 4-kHz tones at levels approaching accuracy to that achieved to the trained 3-kHz tone. By contrast, zebra finches (data from Weisman et al., 1999) failed to transfer their discrimination to the trained tone. We conclude that (a) rats discriminate among tone durations at least as well as they do among auditory frequencies and (b) rats like humans, but unlike finches, are insensitive to absolute pitch in their temporal discrimination.     

Tactile-spatial and cross-modal attention effects in the primary somatosensory cortical areas 3b and 1-2 of rhesus monkeys

Neuronal responses in somatosensory cortical areas 3b and 1-2 (S1) were recorded during an attention task involving cue directed selection of one of three simultaneous stimuli: dual sinewave shaped vibrotactile stimuli applied to mirror sites on both hands or a similarly timed auditory tone. The cued stimulus occurred with one of two equally probable patterns: a constant amplitude vibration or the latter with a superimposed brief sinewave amplitude pulse midway during stimulation. Uncued stimuli always contained amplitude pulses. Two monkeys signaled the absence or presence of an amplitude pulse by appropriately moving a foot pedal up or down. Cues initiated trials by marking the location where the monkey had to discriminate the stimulus pattern. Cue location and stimulus pattern varied randomly per trial. Approximately 50% of cells (44/77 in 3b and 39/77 in 1-2) had significantly different firing rates to stimulation cued to the contralateral hand relative to spatially cuing the ipsilateral hand or cross-modally the auditory stimulus. Relatively suppressed firing rates during times prior to the epoch containing amplitude pulses improved signal-to-noise ratios for responses to amplitude pulses. Instances of significant enhanced activity during and after intervals with amplitude pulses were rare and relative to suppressed activity when cues directed attention to the ipsilateral hand or auditory stimulus. The present findings suggest that attention influences even the earliest stage somatosensory cortical processing. Findings were more modest in S1 than those previously seen in S2 (Burton et al., Somatosens Mot Res 14: 237-267, 1997), which supports the concept of multistage attention processes for touch.     

Updating fearful memories with extinction training during reconsolidation: a human study using auditory aversive stimuli

Learning to fear danger in the environment is essential to survival, but dysregulation of the fear system is at the core of many anxiety disorders. As a consequence, a great interest has emerged in developing strategies for suppressing fear memories in maladaptive cases. Recent research has focused in the process of reconsolidation where memories become labile after being retrieved. In a behavioral manipulation, Schiller et al., (2010) reported that extinction training, administrated during memory reconsolidation, could erase fear responses. The implications of this study are crucial for the possible treatment of anxiety disorders without the administration of drugs. However, attempts to replicate this effect by other groups have been so far unsuccessful. We sought out to reproduce Schiller et al., (2010) findings in a different fear conditioning paradigm based on auditory aversive stimuli instead of electric shock. Following a within-subject design, participants were conditioned to two different sounds and skin conductance response (SCR) was recorded as a measure of fear. Our results demonstrated that only the conditioned stimulus that was reminded 10 minutes before extinction training did not reinstate a fear response after a reminder trial consisting of the presentation of the unconditioned stimuli. For the first time, we replicated Schiller et al., (2010) behavioral manipulation and extended it to an auditory fear conditioning paradigm.     

急性神经损伤引起脊髓背角C-纤维诱发电位长时程增强

神经损伤引起神经病性疼痛,表现为持续性痛超敏和痛觉过敏。目前对神经病性疼痛的机制尚缺乏了解。我们以往的工作表明强直电刺激坐骨神经可引起脊髓背角C-纤维诱发电位的长时程增强(long-term potentiation,LTP),该LTP被认为是病理性疼痛的突触模型。本研究的目的在于探讨急性神经损伤是否能在完整动物的脊髓背角诱发出C-纤维诱发电位LTP。在以测试刺激(10～20V,0．5ms)电刺激坐骨神经的同时在脊髓背角用微电极记录C一纤维诱发电位。分别用强直刺激、剪断或夹捏坐骨神经诱导LTP。结果发现：(1)剪断或夹捏坐骨神经都可以诱导脊髓背角C-纤维诱发电位的LTP,该LTP可持续到实验结束(3～9h),在剪断神经前10min用利多卡因局部阻滞坐骨神经则可完全阻断LTP的产生;(2)神经损伤诱导的LTP可被NMDA受体阻断剂AP5所阻断;(3)用单次强直刺激引起LTP后,切断坐骨神经可使LTP的幅度进一步增大,而用多次强直电刺激使LTP饱和后,损伤神经则不能使LTP进一步增大。切断神经引起LTP后,强直电刺激也不能使LTP进一步增大。这些结果表明,急性神经损伤可以诱导脊髓背角C纤维诱发电位LTP,且切断神经能更有效地诱导LTP。该试验进一步支持我们的设想,即脊髓背角C-纤维诱发电位LTP可能在病理性疼痛的形成中起重要作用。     

Infant Rule Learning: Advantage Language,or Advantage Speech?

Infants appear to learn abstract rule-like regularities (e.g., la la da follows an AAB pattern) more easily from speech than from a variety of other auditory and visual stimuli (Marcus et al., 2007). We test if that facilitation reflects a specialization to learn from speech alone, or from modality-independent communicative stimuli more generally, by measuring 7.5-month-old infants' ability to learn abstract rules from sign language-like gestures. Whereas infants appear to easily learn many different rules from speech, we found that with sign-like stimuli, and under circumstances comparable to those of Marcus et al. (1999), hearing infants were able to learn an ABB rule, but not an AAB rule. This is consistent with results of studies that demonstrate lower levels of infant rule learning from a variety of other non-speech stimuli, and we discuss implications for accounts of speech-facilitation.     

Implications of relaxation dynamics in the synaptic control of olfactory cortex activity.

In a previous work (Ballain et al., 1998. Biol. Cyber. 79, 323-336) we reported the analysis of a model for the piriform cortex activity in rats based on experimental data. In this paper, we study an extension of this model by supplementing it with equations for the post-synaptic conductance and/or the pre-synaptic activation threshold. We use the present model's outputs to account for experimental data based on paired stimulation in the opossum or the rat, obtained either through electrical recording or optical mapping of the cortex activity. The model exhibits great robustness when it comes to large variation in synaptic characteristics. Model outputs mimic satisfactorily the three kind of responses to paired stimuli (Litaudon and Cattarelli, 1996. Eur. J. Neurosci. 8, 21-29) and the recovery of the excitable capacities as demonstrated by Haberly (1973. J. Neurophysiol. 36 (4), 789-802) and Ferreyra-Moyano et al. (1985. Brain Res. Bull. 15, 237 248).     

Structural changes in the neck linker of kinesin explain the load dependence of the motor's mechanical cycle.

The two-headed motor protein kinesin hydrolyzes ATP and moves on microtubule tracks towards the plus end. The motor develops speeds and forces of the order of hundreds of nanometers per second and piconewtons, respectively. Recently, the dependence of the velocity, the dissociation rate and the displacement variance on the load and the ATP concentration were measured in vitro for individual kinesin molecules (Coppin et al., 1997; Visscher et al., 1999) over a wide range of forces. The structural changes in the kinesin motor that drive motility were discovered by Rice et al. (1999). Here we present a phenomenological model for force generation in kinesin based on the bi-stable, nucleotide-dependent behavior of the neck linker. We demonstrate that the model explains the mechanical, kinetic and statistical (experimental) data of Coppin et al. (1997). We also discuss the relationship between the model results and experimental data of Visscher et al. (1999).     

Spike propagation in dendrites with stochastic ion channels

We investigate the effects of the stochastic nature of ion channels on the faithfulness, precision and reproducibility of electrical signal transmission in weakly active, dendritic membrane under in vitro conditions. The properties of forward and backpropagating action potentials (BPAPs) in the dendritic tree of pyramidal cells are the subject of intense empirical work and theoretical speculation (Larkum et al., 1999; Zhu, 2000; Larkum et al., 2001; Larkum and Zhu, 2002; Schaefer et al., 2003; Williams, 2004; Waters et al., 2005). We numerically simulate the effects of stochastic ion channels on the forward and backward propagation of dendritic spikes in Monte-Carlo simulations on a reconstructed layer 5 pyramidal neuron. We report that in most instances there is little variation in timing or amplitude for a single BPAP, while variable backpropagation can occur for trains of action potentials. Additionally, we find that the generation and forward propagation of dendritic Ca²⁺ spikes are susceptible to channel variability. This indicates limitations on computations that depend on the precise timing of Ca²⁺ spikes. Action Editor : Alain Destexhe     

Does nerve impulse activity modulate fast axonal transport?

The possibility that the amount of newly synthesized material made available for fast axonal transport is regulated by nerve impulse activity was examined in an in vitro preparation of bullfrog dorsal root ganglia (DRG) and sciatic nerve. Under conditions that precluded effects of impulse activity on either uptake or incorporation of precursor, patterned stimulation of the sciatic nerve (1 out of every 2 s) produced a frequency- and time-dependent decrease in the amount of radiolabeled protein accumulating at a nerve ligature. The response to patterned stimulation was significantly greater than that to continuous stimulation when the same number of stimuli were delivered. In unligated nerve preparations, patterned stimulation decreased the amplitude of the transport profile with no concomitant change in the wave front distance. Nerve stimulation produced no observable ultrastructural alterations within neuronal cell bodies of the DRG. We propose that the physiological significance of these results is not that nerve impulse activity decreases fast axonal transport, but that the amount of transport increases during periods of electrical quiescence. According to this hypothesis, activity-dependent macromolecules of the axolemma and nerve terminals are replenished during periods when the neuron is firing less frequently. These findings are discussed in light of reports that chronic in vivo stimulation increases the amount of fast-transported, radiolabeled protein (Chan et al., 1989) and that TTX-blockade of neuronal activity has no effect on protein transport (Edwards and Grafstein, 1984; Riccio and Matthews, 1985).     

Application of a NMDA Receptor Conductance in Rat Midbrain Dopaminergic Neurons Using the Dynamic Clamp Technique

Neuroscientists study the function of the brain by investigating how neurons in the brain communicate. Many investigators look at changes in the electrical activity of one or more neurons in response to an experimentally-controlled input. The electrical activity of neurons can be recorded in isolated brain slices using patch clamp techniques with glass micropipettes. Traditionally, experimenters can mimic neuronal input by direct injection of current through the pipette, electrical stimulation of the other cells or remaining axonal connections in the slice, or pharmacological manipulation by receptors located on the neuronal membrane of the recorded cell.Direct current injection has the advantages of passing a predetermined current waveform with high temporal precision at the site of the recording (usually the soma). However, it does not change the resistance of the neuronal membrane as no ion channels are physically opened. Current injection usually employs rectangular pulses and thus does not model the kinetics of ion channels. Finally, current injection cannot mimic the chemical changes in the cell that occurs with the opening of ion channels.Receptors can be physically activated by electrical or pharmacological stimulation. The experimenter has good temporal precision of receptor activation with electrical stimulation of the slice. However, there is limited spatial precision of receptor activation and the exact nature of what is activated upon stimulation is unknown. This latter problem can be partially alleviated by specific pharmacological agents. Unfortunately, the time course of activation of pharmacological agents is typically slow and the spatial precision of inputs onto the recorded cell is unknown.The dynamic clamp technique allows an experimenter to change the current passed directly into the cell based on real-time feedback of the membrane potential of the cell (Robinson and Kawai 1993, Sharp et al., 1993a,b; for review, see Prinz et al. 2004). This allows an experimenter to mimic the electrical changes that occur at the site of the recording in response to activation of a receptor. Real-time changes in applied current are determined by a mathematical equation implemented in hardware.We have recently used the dynamic clamp technique to investigate the generation of bursts of action potentials by phasic activation of NMDA receptors in dopaminergic neurons of the substantia nigra pars compacta (Deister et al., 2009; Lobb et al., 2010). In this video, we demonstrate the procedures needed to apply a NMDA receptor conductance into a dopaminergic neuron.     

Circadian control of neurogenesis

The life-long addition of new neurons has been documented in many regions of the vertebrate and invertebrate brain, including the hippocampus of mammals (Altman and Das, 1965; Eriksson et al., 1998; Jacobs et al., 2000), song control nuclei of birds (Alvarez-Buylla et al., 1990), and olfactory pathway of rodents (Lois and Alvarez-Buylla, 1994), insects (Cayre et al., 1996) and crustaceans (Harzsch and Dawirs, 1996; Sandeman et al., 1998; Harzsch et al., 1999; Schmidt, 2001). The possibility of persistent neurogenesis in the neocortex of primates is also being widely discussed (Gould et al., 1999; Kornack and Rakic, 2001). In these systems, an effort is underway to understand the regulatory mechanisms that control the timing and rate of neurogenesis. Hormonal cycles (Rasika et al., 1994; Harrison et al., 2001), serotonin (Gould, 1999; Brezun and Daszuta, 2000; Beltz et al., 2001), physical activity (Van Praag et al., 1999) and living conditions (Kemperman and Gage, 1999; Sandeman and Sandeman, 2000) influence the rate of neuronal proliferation and survival in a variety of organisms, suggesting that mechanisms controlling life-long neurogenesis are conserved across a range of vertebrate and invertebrate species. The present article extends these findings by demonstrating circadian control of neurogenesis. Data show a diurnal rhythm of neurogenesis among the olfactory projection neurons in the crustacean brain, with peak proliferation during the hours surrounding dusk, the most active period for lobsters. These data raise the possibility that light-controlled rhythms are a primary regulator of neuronal proliferation, and that previously-demonstrated hormonal and activity-driven influences over neurogenesis may be secondary events in a complex circadian control pathway.     

Unique features of the structural model of 'hard' cuticle proteins: implications for chitin-protein interactions and cross-linking in cuticle

Cuticular proteins are one of the determinants of the physical properties of cuticle. A common consensus region (extended R&R Consensus) in these proteins binds to chitin, the other major component of cuticle. We previously predicted the preponderance of beta-pleated sheet in the consensus region and proposed its responsibility for the formation of helicoidal cuticle (Iconomidou et al., Insect Biochem. Mol. Biol. 29 (1999) 285). Subsequently, we verified experimentally the abundance of antiparallel beta-pleated sheet in the structure of cuticle proteins (Iconomidou et al., Insect Biochem. Mol. Biol. 31 (2001) 877). Homology modelling of soft (RR-1) cuticular proteins using bovine plasma retinol binding protein (RBP) as a template revealed an antiparallel beta-sheet half-barrel structure as the basic folding motif (Hamodrakas et al., Insect Biochem. Molec. Biol. 32 (2002) 1577). The RR-2 proteins characteristic of hard cuticle, have a far more conserved consensus and frequently more histidine residues. Extension of modelling to this class of consensus, in this work, reveals in detail several unique features of the proposed structural model to serve as a chitin binding structural motif, thus providing the basis for elucidating cuticle's overall architecture and chitin-protein interactions in cuticle.     

Exhaustive mutagenesis in silico: multicoordinate free energy calculations on proteins and peptides

We have extended and applied a multicoordinate free energy method, chemical Monte Carlo/Molecular Dynamics (CMC/MD), to calculate the relative free energies of different amino acid side-chains. CMC/MD allows the calculation of the relative free energies for many chemical species from a single free energy calculation. We have previously shown its utility in host:guest chemistry (Pitera and Kollman, J Am Chem Soc 1998;120:7557-7567)1 and ligand design (Eriksson et al., J Med Chem 1999;42:868-881)2, and here demonstrate its utility in calculations of amino acid properties and protein stability. We first study the relative solvation free energies of N-methylated and acetylated alanine, valine, and serine amino acids. With careful inclusion of rotameric states, internal energies, and both the solution and vacuum states of the calculation, we calculate relative solvation free energies in good agreement with thermodynamic integration (TI) calculations. Interestingly, we find that a significant amount of the unfavorable solvation of valine seen in prior work (Sun et al., J Am Chem Soc 1992;114:6798-6801)3 is caused by restraining the backbone in an extended conformation. In contrast, the solvation free energy of serine is calculated to be less favorable than expected from experiment, due to the formation of a favorable intramolecular hydrogen bond in the vacuum state. These monomer calculations emphasize the need to accurately consider all significant conformations of flexible molecules in free energy calculations. This development of the CMC/MD method paves the way for computations of protein stability analogous to the biochemical technique of "exhaustive mutagenesis." We have carried out just such a calculation at position 133 of T4 lysozyme, where we use CMC/MD to calculate the relative stability of eight different side-chain mutants in a single free energy calculation. Our T4 calculations show good agreement with the prior free energy calculations of Veenstra et al. (Prot Eng 1997;10:789-807)4 and excellent agreement with the experiments of Mendel et al. (Science 1992;256:1798-1802).     

A Mathematical Model for Simultaneous Spatio-Temporal Dynamics of Calcium and Inositol 1,4,5-Trisphosphate in Madin–Darby Canine Kidney Epithelial Cells

The landmark paper by Hirose et al. (Hirose, K., Kadowaki, S., Tanabe, M., Takeshima, H., Iino, M., Science 284:1527–1530, 1999) presented experimental investigations to show that not only can calcium upregulate IP₃, but that it can also have an inhibitory effect on IP₃. In this paper, we present a preliminary model, which is consistent with these experiments. This model includes positive and negative feedback between calcium and IP₃ and is able to reproduce more precisely the data presented in Hirose et al. (Hirose, K., Kadowaki, S., Tanabe, M., Takeshima, H., Iino, M., Science 284:1527–1530, 1999). In the second part of the paper, the intracellular and intercellular calcium movement in Madin–Darby canine kidney epithelial cells is investigated. With the aid of the model we are able to identify the aspects of IP₃ and calcium signalling, which should be studied further experimentally before refining the model.