Anomalous diffusion of synaptic vesicles and its influences on spontaneous and evoked neurotransmission.

Neurons in the central nervous system communicate with each other by activating billions of tiny synaptic boutons distributed along their fine axons. These presynaptic varicosities are very crowded environments, comprising hundreds of synaptic vesicles. Only a fraction of these vesicles can be recruited in a single release episode, either spontaneous or evoked by action potentials. Since the seminal work by Fatt and Katz, spontaneous release has been modelled as a memoryless process. Nevertheless, at central synapses, experimental evidence indicates more complex features, including non-exponential distributions of release intervals and power-law behaviour in their rate. To describe these features, we developed a probabilistic model of spontaneous release based on Brownian motion of synaptic vesicles in the presynaptic environment. To account for different diffusion regimes, we based our simulations on fractional Brownian motion. We show that this model can predict both deviation from the Poisson hypothesis and power-law features in experimental quantal release series, thus suggesting that the vesicular motion by diffusion could per se explain the emergence of these properties. We demonstrate the efficacy of our modelling approach using electrophysiological recordings at single synaptic boutons and ultrastructural data. When this approach was used to simulate evoked responses, we found that the replenishment of the readily releasable pool driven by Brownian motion of vesicles can reproduce the characteristic binomial release distributions seen experimentally. We believe that our modelling approach supports the idea that vesicle diffusion and readily releasable pool dynamics are crucial factors for the physiological functioning of neuronal communication. KEY POINTS: We developed a new probabilistic model of spontaneous and evoked vesicle fusion based on simple biophysical assumptions, including the motion of vesicles before they dock to the release site. We provide closed-form equations for the interval distribution of spontaneous releases in the special case of Brownian diffusion of vesicles, showing that a power-law heavy tail is generated. Fractional Brownian motion (fBm) was exploited to simulate anomalous vesicle diffusion, including directed and non-directed motion, by varying the Hurst exponent. We show that our model predicts non-linear features observed in experimental spontaneous quantal release series as well as ultrastructural data of synaptic vesicles spatial distribution. Evoked exocytosis based on a diffusion-replenished readily releasable pool might explain the emergence of power-law behaviour in neuronal activity.

SCAMP5 plays a critical role in axonal trafficking and synaptic localization of NHE6 to adjust quantal size at glutamatergic synapses.

Glutamate uptake into synaptic vesicles (SVs) depends on cation/H+ exchange activity, which converts the chemical gradient (ΔpH) into membrane potential (Δψ) across the SV membrane at the presynaptic terminals. Thus, the proper recruitment of cation/H+ exchanger to SVs is important in determining glutamate quantal size, yet little is known about its localization mechanism. Here, we found that secretory carrier membrane protein 5 (SCAMP5) interacted with the cation/H+ exchanger NHE6, and this interaction regulated NHE6 recruitment to glutamatergic presynaptic terminals. Protein-protein interaction analysis with truncated constructs revealed that the 2/3 loop domain of SCAMP5 is directly associated with the C-terminal region of NHE6. The use of optical imaging and electrophysiological recording showed that small hairpin RNA-mediated knockdown (KD) of SCAMP5 or perturbation of SCAMP5/NHE6 interaction markedly inhibited axonal trafficking and the presynaptic localization of NHE6, leading to hyperacidification of SVs and a reduction in the quantal size of glutamate release. Knockout of NHE6 occluded the effect of SCAMP5 KD without causing additional defects. Together, our results reveal that as a key regulator of axonal trafficking and synaptic localization of NHE6, SCAMP5 could adjust presynaptic strength by regulating quantal size at glutamatergic synapses. Since both proteins are autism candidate genes, the reduced quantal size by interrupting their interaction may underscore synaptic dysfunction observed in autism.

Regulating quantal size of neurotransmitter release through a GPCR voltage sensor.

Current models emphasize that membrane voltage (Vm) depolarization-induced Ca2+ influx triggers the fusion of vesicles to the plasma membrane. In sympathetic adrenal chromaffin cells, activation of a variety of G protein coupled receptors (GPCRs) can inhibit quantal size (QS) through the direct interaction of G protein Gißγ subunits with exocytosis fusion proteins. Here we report that, independently from Ca2+, Vm (action potential) per se regulates the amount of catecholamine released from each vesicle, the QS. The Vm regulation of QS was through ATP-activated GPCR-P2Y12 receptors. D76 and D127 in P2Y12 were the voltage-sensing sites. Finally, we revealed the relevance of the Vm dependence of QS for tuning autoinhibition and target cell functions. Together, membrane voltage per se increases the quantal size of dense-core vesicle release of catecholamine via Vm → P2Y12(D76/D127) → Gißγ → QS → myocyte contractility, offering a universal Vm-GPCR signaling pathway for its functions in the nervous system and other systems containing GPCRs.

Massively parallel classical logic via coherent dynamics of an ensemble of quantum systems with dispersion in size.

Quantum parallelism can be implemented on a classical ensemble of discrete level quantum systems. The nanosystems are not quite identical, and the ensemble represents their individual variability. An underlying Lie algebraic theory is developed using the closure of the algebra to demonstrate the parallel information processing at the level of the ensemble. The ensemble is addressed by a sequence of laser pulses. In the Heisenberg picture of quantum dynamics the coherence between the N levels of a given quantum system can be handled as an observable. Thereby there are N2 logic variables per N level system. This is how massive parallelism is achieved in that there are N2 potential outputs for a quantum system of N levels. The use of an ensemble allows simultaneous reading of such outputs. Due to size dispersion the expectation values of the observables can differ somewhat from system to system. We show that for a moderate variability of the systems one can average the N2 expectation values over the ensemble while retaining closure and parallelism. This allows directly propagating in time the ensemble averaged values of the observables. Results of simulations of electronic excitonic dynamics in an ensemble of quantum dot (QD) dimers are presented. The QD size and interdot distance in the dimer are used to parametrize the Hamiltonian. The dimer N levels include local and charge transfer excitons within each dimer. The well-studied physics of semiconducting QDs suggests that the dimer coherences can be probed at room temperature.

The 'Quantal Newtonian' First Law: A Complementary Perspective to the Stationary-state Quantum Theory of Electrons.

A complementary perspective to the Göttingen-Copenhagen interpretation of stationary-state quantum theory of electrons in an electromagnetic field is described. The perspective, derived from Schrödinger-Pauli theory, is that of the individual electron via its equation of motion or 'Quantal Newtonian' First Law. The Law is in terms of 'classical' fields experienced by each electron: the sum of the external and internal fields vanishes. The external field is a sum of the electrostatic and Lorentz fields. The internal field is a sum of fields' representative of Pauli and Coulomb correlations; kinetic effects; electron density; and internal magnetic component. The energy is obtained from these fields. The sources of the fields are expectation values of Hermitian operators. The perspective is elucidated by application to quantum dots in a magnetic field in a ground, excited singlet and triplet states. The relationship of the perspective to Quantal and traditional density functional theories is briefly explained.

Short-Term Synaptic Plasticity: Microscopic Modelling and (Some) Computational Implications.

Synaptic transmission is transiently adjusted on a spike-by-spike basis, with the adjustments persisting from hundreds of milliseconds up to seconds. Such a short-term plasticity has been suggested to significantly augment the computational capabilities of neuronal networks by enhancing their dynamical repertoire. In this chapter, after reviewing the basic physiology of chemical synaptic transmission, we present a general framework-inspired by the quantal model-to build simple, yet quantitatively accurate models of repetitive synaptic transmission. We also discuss different methods to obtain estimates of the model's parameters from experimental recordings. Next, we show that, indeed, new dynamical regimes appear in the presence of short-term synaptic plasticity. In particular, model neuronal networks exhibit the co-existence of a stable fixed point and a stable limit cycle in the presence of short-term synaptic facilitation. It has been suggested that this dynamical regime is especially relevant in working memory processes. We provide, then, a short summary of the synaptic theory of working memory and discuss some of its specific predictions in the context of experiments. We conclude the chapter with a short outlook.

Keeping Excitation-Inhibition Ratio in Balance.

Unrelated genetic mutations can lead to convergent manifestations of neurological disorders with similar behavioral phenotypes. Experimental data frequently show a lack of dramatic changes in neuroanatomy, indicating that the key cause of symptoms might arise from impairment in the communication between neurons. A transient imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) synaptic transmission (the E/I balance) during early development is generally considered to underlie the development of several neurological disorders in adults. However, the E/I ratio is a multidimensional variable. Synaptic contacts are highly dynamic and the actual strength of synaptic projections is determined from the balance between synaptogenesis and synaptic elimination. During development, relatively slow postsynaptic receptors are replaced by fast ones that allow for fast stimulus-locked excitation/inhibition. Using the binomial model of synaptic transmission allows for the reassessing of experimental data from different mouse models, showing that a transient E/I shift is frequently counterbalanced by additional pre- and/or postsynaptic changes. Such changes-for instance, the slowing down of postsynaptic currents by means of immature postsynaptic receptors-stabilize the average synaptic strength, but impair the timing of information flow. Compensatory processes and/or astrocytic signaling may represent possible targets for medical treatments of different disorders directed to rescue the proper information processing.

Activity-Dependent Global Downscaling of Evoked Neurotransmitter Release across Glutamatergic Inputs in Drosophila.

Within mammalian brain circuits, activity-dependent synaptic adaptations, such as synaptic scaling, stabilize neuronal activity in the face of perturbations. Stability afforded through synaptic scaling involves uniform scaling of quantal amplitudes across all synaptic inputs formed on neurons, as well as on the postsynaptic side. It remains unclear whether activity-dependent uniform scaling also operates within peripheral circuits. We tested for such scaling in a Drosophila larval neuromuscular circuit, where the muscle receives synaptic inputs from different motoneurons. We used motoneuron-specific genetic manipulations to increase the activity of only one motoneuron and recordings of postsynaptic currents from inputs formed by the different motoneurons. We discovered an adaptation which caused uniform downscaling of evoked neurotransmitter release across all inputs through decreases in release probabilities. This "presynaptic downscaling" maintained the relative differences in neurotransmitter release across all inputs around a homeostatic set point, caused a compensatory decrease in synaptic drive to the muscle affording robust and stable muscle activity, and was induced within hours. Presynaptic downscaling was associated with an activity-dependent increase in Drosophila vesicular glutamate transporter expression. Activity-dependent uniform scaling can therefore manifest also on the presynaptic side to produce robust and stable circuit outputs. Within brain circuits, uniform downscaling on the postsynaptic side is implicated in sleep- and memory-related processes. Our results suggest that evaluation of such processes might be broadened to include uniform downscaling on the presynaptic side.SIGNIFICANCE STATEMENT To date, compensatory adaptations which stabilise target cell activity through activity-dependent global scaling have been observed only within central circuits, and on the postsynaptic side. Considering that maintenance of stable activity is imperative for the robust function of the nervous system as a whole, we tested whether activity-dependent global scaling could also manifest within peripheral circuits. We uncovered a compensatory adaptation which causes global scaling within a peripheral circuit and on the presynaptic side through uniform downscaling of evoked neurotransmitter release. Unlike in central circuits, uniform scaling maintains functionality over a wide, rather than a narrow, operational range, affording robust and stable activity. Activity-dependent global scaling therefore operates on both the presynaptic and postsynaptic sides to maintain target cell activity.

TRPM3 expression and control of glutamate release from primary vagal afferent neurons.

Vagal afferent fibers contact neurons in the nucleus of the solitary tract (NTS) and release glutamate via three distinct release pathways: synchronous, asynchronous, and spontaneous. The presence of TRPV1 in vagal afferents is predictive of activity-dependent asynchronous glutamate release along with temperature-sensitive spontaneous vesicle fusion. However, pharmacological blockade or genetic deletion of TRPV1 does not eliminate the asynchronous profile and only attenuates the temperature-dependent spontaneous release at high temperatures (>40°C), indicating additional temperature-sensitive calcium conductance(s) contributing to these release pathways. The transient receptor potential cation channel melastatin subtype 3 (TRPM3) is a calcium-selective channel that functions as a thermosensor (30-37°C) in somatic primary afferent neurons. We predict that TRPM3 is expressed in vagal afferent neurons and contributes to asynchronous and spontaneous glutamate release pathways. We investigated these hypotheses via measurements on cultured nodose neurons and in brainstem slice preparations containing vagal afferent to NTS synaptic contacts. We found histological and genetic evidence that TRPM3 is highly expressed in vagal afferent neurons. The TRPM3-selective agonist, pregnenolone sulfate, rapidly and reversibly activated the majority (∼70%) of nodose neurons; most of which also contained TRPV1. We confirmed the role of TRPM3 with pharmacological blockade and genetic deletion. In the brain, TRPM3 signaling strongly controlled both basal and temperature-driven spontaneous glutamate release. Surprisingly, genetic deletion of TRPM3 did not alter synchronous or asynchronous glutamate release. These results provide convergent evidence that vagal afferents express functional TRPM3 that serves as an additional temperature-sensitive calcium conductance involved in controlling spontaneous glutamate release onto neurons in the NTS.NEW & NOTEWORTHY Vagal afferent signaling coordinates autonomic reflex function and informs associated behaviors. Thermosensitive transient receptor potential (TRP) channels detect temperature and nociceptive stimuli in somatosensory afferent neurons, however their role in vagal signaling remains less well understood. We report that the TRPM3 ion channel provides a major thermosensitive point of control over vagal signaling and synaptic transmission. We conclude that TRPM3 translates physiological changes in temperature to neurophysiological outputs and can serve as a cellular integrator in vagal afferent signaling.

Bounded rational response equilibria in human sensorimotor interactions.

The Nash equilibrium is one of the most central solution concepts to study strategic interactions between multiple players and has recently also been shown to capture sensorimotor interactions between players that are haptically coupled. While previous studies in behavioural economics have shown that systematic deviations from Nash equilibria in economic decision-making can be explained by the more general quantal response equilibria, such deviations have not been reported for the sensorimotor domain. Here we investigate haptically coupled dyads across three different sensorimotor games corresponding to the classic symmetric and asymmetric Prisoner's Dilemma, where the quantal response equilibrium predicts characteristic shifts across the three games, although the Nash equilibrium stays the same. We find that subjects exhibit the predicted deviations from the Nash solution. Furthermore, we show that taking into account subjects' priors for the games, we arrive at a more accurate description of bounded rational response equilibria that can be regarded as a quantal response equilibrium with non-uniform prior. Our results suggest that bounded rational response equilibria provide a general tool to explain sensorimotor interactions that include the Nash equilibrium as a special case in the absence of information processing limitations.

Adrenaline Facilitates Synaptic Transmission by Synchronizing Release of Acetylcholine Quanta from Motor Nerve Endings.

The long history of studies on the effect of catecholamines on synaptic transmission does not answer the main question about the mechanism of their action on quantal release in the neuromuscular junction. Currently, interest in catecholamines has increased not only because of their widespread use in the clinic for the treatment of cardiovascular and pulmonary diseases but also because of recent data on their possible use for the treatment of certain neurodegenerative diseases, muscle weakness and amyotrophic sclerosis. Nevertheless, the effects and mechanisms of catecholamines on acetylcholine release remain unclear. We investigated the action of noradrenaline and adrenaline on the spontaneous and evoked quantal secretion of acetylcholine in the neuromuscular junction of the rat soleus muscle. Noradrenaline (10 µM) did not change the spontaneous acetylcholine quantal release, the number of released quanta after nerve stimulation, or the timing of the quantal secretion. However, adrenaline at the same concentration increased spontaneous secretion by 40%, increased evoked acetylcholine quantal release by 62%, and synchronized secretion. These effects differ from those previously described by us in the synapses of the frog cutaneous pectoris muscle and mouse diaphragm. This indicates specificity in catecholamine action that depends on the functional type of muscle and the need to take the targeted type of muscle into account in clinical practice.

Sympathomimetics regulate quantal acetylcholine release at neuromuscular junctions through various types of adrenoreceptors.

The studies of the interaction between the sympathetic and motor nervous systems are extremely relevant due to therapy for many neurodegenerative and cardiovascular disorders involving adrenergic compounds. Evidences indicate close contact between sympathetic varicosities and neuromuscular synapses. This raises questions about the effects of catecholamines on synaptic transmission. The currently available information is contradictory, and the types of adrenoreceptors responsible for modulation of neurotransmitter release have not been identified in mammalian neuromuscular synapses. Our results have shown that the α1A, α1B, α2A, α2B, α2C, and ß1 adrenoreceptor subtypes are expressed in mouse diaphragm muscle containing neuromuscular synapses and sympathetic varicosities. Pharmacological stimulation of adrenoreceptors affects both spontaneous and evoked acetylcholine quantal secretion. Agonists of the α1, α2 and ß1 adrenoreceptors decrease spontaneous release. Activation of the α2 and ß1 adrenoreceptors reduces the number of acetylcholine quanta released in response to a nerve stimulus (quantal content), but an agonist of the ß2 receptors increases quantal content. Activation of α2 and ß2 adrenoreceptors alters the kinetics of acetylcholine quantal release by desynchronizing the neurosecretory process. Specific blockers of these receptors eliminate the effects of the specific agonists. The action of blockers on quantal acetylcholine secretion indicates possible action of endogenous catecholamines on neuromuscular transmission. Elucidating the molecular mechanisms by which clinically utilized adrenomimetics and adrenoblockers regulate synaptic vesicle release at the motor axon terminal will lead to the creation of improved and safer sympathomimetics for the treatment of various neurodegenerative diseases with synaptic defects.

Statistical inferences on nonconstant relative potency with quantal response data.

Relative potency is widely used in toxicological and pharmacological studies to characterize potency of chemicals. The relative potency of a test chemical compared to a standard chemical is defined as the ratio of equally effective doses (standard divided by test). This classical concept relies on the assumption that the two chemicals are toxicologically similar-that is, they have parallel dose-response curves on log-dose scale-and thus have constant relative potency. Nevertheless, investigators are often faced with situations where the similarity assumption is deemed unreasonable, and hence the classical idea of constant relative potency fails to hold; in such cases, simply reporting a single constant value for relative potency can produce misleading conclusions. Relative potency functions, describing relative potency as a function of the mean response (or other quantities), is seen as a useful tool for handling nonconstant relative potency in the absence of similarity. Often, investigators are interested in assessing nonconstant relative potency at a finite set of some specific response levels for various regulatory concerns, rather than the entire relative potency function; this simultaneous assessment gives rise to multiplicity, which calls for efficient statistical inference procedures with multiplicity adjusted methods. In this paper, we discuss the estimation of relative potency at multiple response levels using the relative potency function, under the log-logistic dose-response model. We further propose and evaluate three approaches to calculating multiplicity-adjusted confidence limits as statistical inference procedures for assessing nonconstant relative potency. Monte Carlo simulations are conducted to evaluate the characteristics of the simultaneous limits.

Adrenoceptors Modulate Cholinergic Synaptic Transmission at the Neuromuscular Junction.

Adrenoceptor activators and blockers are widely used clinically for the treatment of cardiovascular and pulmonary disorders. More recently, adrenergic agents have also been used to treat neurodegenerative diseases. Recent studies indicate a location of sympathetic varicosities in close proximity to neuromuscular junctions. The pressing question is whether there could be any effects of endo- or exogenous catecholamines on cholinergic neuromuscular transmission. It was shown that the pharmacological stimulation of adrenoceptors, as well as sympathectomy, can affect both acetylcholine release from motor nerve terminals and the functioning of postsynaptic acetylcholine receptors. In this review, we discuss the recent data regarding the effects of adrenergic drugs on neurotransmission at the neuromuscular junction. The elucidation of the molecular mechanisms by which the clinically relevant adrenomimetics and adrenoblockers regulate quantal acetylcholine release from the presynaptic nerve terminals and postsynaptic sensitivity may help in the design of highly effective and well-tolerated sympathomimetics for treating a number of neurodegenerative diseases accompanied by synaptic defects.

Benchmark dose risk analysis with mixed-factor quantal data in environmental risk assessment.

Benchmark analysis is a general risk estimation strategy for identifying the benchmark dose (BMD) past which the risk of exhibiting an adverse environmental response exceeds a fixed, target value of benchmark response (BMR). Estimation of BMD and of its lower confidence limit (BMDL) is well understood for the case of an adverse response to a single stimulus. In many environmental settings, however, one or more additional, secondary, qualitative factor(s) may collude to affect the adverse outcome, such that the risk changes with differential levels of the secondary factor. This paper extends the single-dose BMD paradigm to a mixed-factor setting with a secondary qualitative factor possessing two levels. With focus on quantal-response data and using a generalized linear model with a complementary-log link function, we derive expressions for BMD and BMDL. We study the operating characteristics of six different multiplicity-adjusted approaches to calculate the BMDL, using Monte Carlo evaluations. We illustrate the calculations via an example data set from environmental carcinogenicity testing.

A Maximum Entropy Model of Bounded Rational Decision-Making with Prior Beliefs and Market Feedback.

Bounded rationality is an important consideration stemming from the fact that agents often have limits on their processing abilities, making the assumption of perfect rationality inapplicable to many real tasks. We propose an information-theoretic approach to the inference of agent decisions under Smithian competition. The model explicitly captures the boundedness of agents (limited in their information-processing capacity) as the cost of information acquisition for expanding their prior beliefs. The expansion is measured as the Kullblack-Leibler divergence between posterior decisions and prior beliefs. When information acquisition is free, the homo economicus agent is recovered, while in cases when information acquisition becomes costly, agents instead revert to their prior beliefs. The maximum entropy principle is used to infer least biased decisions based upon the notion of Smithian competition formalised within the Quantal Response Statistical Equilibrium framework. The incorporation of prior beliefs into such a framework allowed us to systematically explore the effects of prior beliefs on decision-making in the presence of market feedback, as well as importantly adding a temporal interpretation to the framework. We verified the proposed model using Australian housing market data, showing how the incorporation of prior knowledge alters the resulting agent decisions. Specifically, it allowed for the separation of past beliefs and utility maximisation behaviour of the agent as well as the analysis into the evolution of agent beliefs.

Quantitative Nano-amperometric Measurement of Intravesicular Glutamate Content and its Sub-Quantal Release by Living Neurons.

Quantitative measurements of intravesicular glutamate (Glu) and of transient exocytotic release contents directly from individual living neurons are highly desired for understanding the mechanisms (full or sub-quantal release?) of synaptic transmission and plasticity. However, this could not be achieved so far due to the lack of adequate experimental strategies relying on selective and sensitive Glu nanosensors. Herein, we introduce a novel electrochemical Glu nanobiosensor based on a single SiC nanowire that can selectively measure in real-time Glu fluxes released via exocytosis by large Glu vesicles (ca. 125 nm diameter) present in single hippocampal axonal varicosities as well as their intravesicular content before exocytosis. These measurements revealed a sub-quantal release mode in living hippocampal neurons, viz., only ca. one third to one half of intravesicular Glu molecules are released by individual vesicles during exocytotic events. Importantly, this fraction remained practically the same when hippocampal neurons were pretreated with L-Glu-precursor L-glutamine, while it significantly increased after zinc treatment, although in both cases the intravesicular contents were drastically affected.

Dynamin 1 Restrains Vesicular Release to a Subquantal Mode In Mammalian Adrenal Chromaffin Cells.

Dynamin 1 (dyn1) is required for clathrin-mediated endocytosis in most secretory (neuronal and neuroendocrine) cells. There are two modes of Ca2+-dependent catecholamine release from single dense-core vesicles: full-quantal (quantal) and subquantal in adrenal chromaffin cells, but their relative occurrences and impacts on total secretion remain unclear. To address this fundamental question in neurotransmission area using both sexes of animals, here we report the following: (1) dyn1-KO increased quantal size (QS, but not vesicle size/content) by ≥250% in dyn1-KO mice; (2) the KO-increased QS was rescued by dyn1 (but not its deficient mutant or dyn2); (3) the ratio of quantal versus subquantal events was increased by KO; (4) following a release event, more protein contents were retained in WT versus KO vesicles; and (5) the fusion pore size (dp) was increased from ≤9 to ≥9 nm by KO. Therefore, Ca2+-induced exocytosis is generally a subquantal release in sympathetic adrenal chromaffin cells, implying that neurotransmitter release is generally regulated by dynamin in neuronal cells.SIGNIFICANCE STATEMENT Ca2+-dependent neurotransmitter release from a single vesicle is the primary event in all neurotransmission, including synaptic/neuroendocrine forms. To determine whether Ca2+-dependent vesicular neurotransmitter release is "all-or-none" (quantal), we provide compelling evidence that most Ca2+-induced secretory events occur via the subquantal mode in native adrenal chromaffin cells. This subquantal release mode is promoted by dynamin 1, which is universally required for most secretory cells, including neurons and neuroendocrine cells. The present work with dyn1-KO mice further confirms that Ca2+-dependent transmitter release is mainly via subquantal mode, suggesting that subquantal release could be also important in other types of cells.

Quantal biomechanical effects in speech postures of the lips.

The unique biomechanical and functional constraints on human speech make it a promising area for research investigating modular control of movement. The present article illustrates how a modular control approach to speech can provide insights relevant to understanding both motor control and observed variation across languages. We specifically explore the robust typological finding that languages produce different degrees of labial constriction using distinct muscle groupings and concomitantly distinct lip postures. Research has suggested that these lip postures exploit biomechanical regions of nonlinearity between neural activation and movement, also known as quantal regions, to allow movement goals to be realized despite variable activation signals. We present two sets of computer simulations showing that these labial postures can be generated under the assumption of modular control and that the corresponding modules are biomechanically robust: first to variation in the activation levels of participating muscles, and second to interference from surrounding muscles. These results provide support for the hypothesis that biomechanical robustness is an important factor in selecting the muscle groupings used for speech movements and provide insight into the neurological control of speech movements and how biomechanical and functional constraints govern the emergence of speech motor modules. We anticipate that future experimental work guided by biomechanical simulation results will provide new insights into the neural organization of speech movements.NEW & NOTEWORTHY This article provides additional evidence that speech motor control is organized in a modular fashion and that biomechanics constrain the kinds of motor modules that may emerge. It also suggests that speech can be a fruitful domain for the study of modularity and that a better understanding of speech motor modules will be useful for speech research. Finally, it suggests that biomechanical modeling can serve as a useful complement to experimental work when studying modularity.

Delayed increase of acetylcholine quantal size induced by the activity-dependent release of endogenous CGRP but not ATP in neuromuscular junctions.

In mouse motor synapses tetanic neuromuscular activity (30 Hz, 2 min) led to a delayed posttetanic potentiation of amplitude and duration of spontaneous miniature endplate potentials (MEPPs). Microelectrode recordings of MEPPs before and after nerve stimulation showed an increase in MEPP amplitude and time course by 30% and 15%, respectively, without changes in their frequency. Peak effect was detected 20 min after tetanic activity and progressively faded throughout the next 40 min of recording. The revealed potentiation of MEPPs was fully preserved in preparations from pannexin 1 knockout mice. It means, that myogenic ATP released via pannexin 1 channels from contracting muscle fibers is not likely to participate in the described phenomenon. But posttetanic potentiation of MEPPs was fully prevented by competitive antagonist of calcitonin gene-related peptide (CGRP) receptors CGRP8-37 , ryanodine receptors inhibitor ryanodine and by vesicular acetylcholine transporter inhibitor vesamicol. It is suggested that the combination of intensive synaptic and contractile activity in neuromuscular junctions is required to induce Ca2+ -dependent exocytosis of endogenous CGRP. The accumulation of CGRP in the synaptic cleft and its presynaptic activity may induce posttetanic potentiation of MEPP amplitude due to CGRP-stimulated acetylcholine loading into vesicles and subsequent increase of quantal size.