Enrico Cataldo

Inhibition of Na+/K+ ATPase potentiates synaptic transmission in tactile sensory neurons of the leech

Increasing evidence indicates that modulation of Na+/K+ ATPase activity is involved in forms of neuronal and synaptic plasticity. In tactile (T) neurons of the leech Hirudo medicinalis, Na+/K+ ATPase is the main determinant of the afterhyperpolarization (AHP), which characterizes the firing of these mechanosensory neurons. Previously, it has been reported that cAMP (3′,5′‐cyclic adenosine monophosphate), which mediates the effects of serotonin (5HT) in some forms of learning in the leech, negatively modulates Na+/K+ ATPase activity, thereby reducing the AHP amplitude in T neurons. Here, we show that a transient inhibition of Na+/K+ ATPase can affect the synaptic connection between two ipsilateral T neurons. Bath application of 10 nm dihydroouabain (DHO), an ouabain analogue, causes an increase in the amplitude of the synaptic potential (SP) recorded in the postsynaptic element when a test stimulus is applied in the presynaptic neuron. Iontophoretic injection of cAMP into the presynaptic T neuron also produces an increase of SP. Simulations carried out by using a computational model of the T neuron suggest that a reduction of the pump rate and a consequent depression of the AHP might facilitate the conduction of action potentials to the synaptic terminals. Moreover, nearly intact leeches injected with 10 nm DHO respond with a swimming episode more quickly to an electrical stimulation, which selectively activates T neurons exhibiting sensitization of swimming induction. Collectively, our results show that inhibition of Na+/K+ ATPase is critical for short‐term plasticity.

Acetyl-l-carnitine induces a sustained potentiation of the afterhyperpolarization

Acetyl-L-carnitine is known to improve many aspects of the neural activity even if its exact role in neurotransmission is still unknown. This study investigates the effects of acetyl-L-carnitine in T segmental sensory neurons of the leech Hirudo medicinalis. These neurons are involved in some forms of neural plasticity associated with learning processes. Their physiological firing is accompanied by a large afterhyperpolarization that is mainly due to the Na+/K+ ATPase activity and partially to a Ca2+ -dependent K+ current. A clear-cut hyperpolarization and a significant increase of the afterhyperpolarization have been recorded in T neurons of leeches injected with 2 mM acetyl-L-carnitine some days before. Acute treatments of 50 microM acetyl-L-carnitine induced similar effects in T cells of naive animals. In the presence of apamin, a pharmacological blocker of Ca2+ -dependent K+ channel, acetyl-L-carnitine still enhanced the residual afterhyperpolarization, suggesting an effect of the drug on the Na+/K+ATPase. Acetyl-L-carnitine also increased the hyperpolarization induced by intracellular injection of Na+ ions. Therefore, acetyl-L-carnitine seems to be able to exert a positive sustained effect on the Na+/K+ ATPase activity in leech T sensory neurons. Moreover, in these cells, widely arborized, the afterhyperpolarization seems to play an important role in determining the action potential transmission at neuritic bifurcations. A computational model of a T cell has been previously developed considering detailed data for geometry and the modulation of the pump current. Herein, we showed that to a larger afterhyperpolarization, due to the acetyl-L-carnitine-induced effects, corresponds a decrement in the number of action potentials reaching synaptic terminals.

Sensitization and dishabituation of swim induction in the leech Hirudo medicinalis: role of serotonin and cyclic AMP

In this paper the role of serotonin (5HT) and cyclic AMP (cAMP) in sensitization and dishabituation of swim induction (SI) has been investigated in the leech Hirudo medicinalis. Electrical stimulation of the body wall evokes swimming activity with a constant latency. In animals with a disconnection between head ganglion and segmental ganglia, repetitive stimulation induces habituation of swimming whereas brushing on the dorsal skin provokes sensitization of a naïve response or dishabituation of a previously habituated response. Our findings indicate that 5HT is the neurotransmitter underlying both sensitization and dishabituation of SI. Injection of the 5HT receptor blocking agent methysergide impaires the onset of sensitization and dishabituation induced by brushing. Moreover, injection of 5HT mimics these forms of nonassociative learning, whereas injection of dopamine does not. Finally, the effects of 5HT are mediated by cAMP: (1) after injections of specific adenylate cyclase inhibitors such as MDL 12.330A or SQ22536, brushing becomes ineffective in facilitating the SI in either non-habituated or habituated animals. (2) 8Br-cAMP application mimics both sensitization and dishabituation of SI.

Computational Model of Touch Sensory Cells (T Cells) of the Leech: Role of the Afterhyperpolarization (AHP) in Activity-Dependent Conduction Failure

Bursts of spikes in T cells produce an AHP, which results from activation of a Na+/K+ pump and a Ca2+-dependent K+ current. Activity-dependent increases in the AHP are believed to induce conduction block of spikes in several regions of the neuron, which in turn, may decrease presynaptic invasion of spikes and thereby decrease transmitter release. To explore this possibility, we used the neurosimulator SNNAP to develop a multi-compartmental model of the T cell. The model incorporated empirical data that describe the geometry of the cell and activity-dependent changes of the AHP. Simulations indicated that at some branching points, activity-dependent increases of the AHP reduced the number of spikes transmitted from the minor receptive fields to the soma and beyond. More importantly, simulations also suggest that the AHP could modulate, under some circumstances, transmission from the soma to the synaptic terminals, suggesting that the AHP can regulate spike conduction within the presynaptic arborizations of the cell and could in principle contribute to the synaptic depression that is correlated with increases in the AHP.

Stochastic models for the in silico simulation of synaptic processes

BackgroundResearch in life sciences is benefiting from a large availability of formal description techniques and analysis methodologies. These allow both the phenomena investigated to be precisely modeled and virtual experiments to be performed in silico. Such experiments may result in easier, faster, and satisfying approximations of their in vitro/vivo counterparts. A promising approach is represented by the study of biological phenomena as a collection of interactive entities through process calculi equipped with stochastic semantics. These exploit formal grounds developed in the theory of concurrency in computer science, account for the not continuous, nor discrete, nature of many phenomena, enjoy nice compositional properties and allow for simulations that have been demonstrated to be coherent with data in literature.ResultsMotivated by the need to address some aspects of the functioning of neural synapses, we have developed one such model for synaptic processes in the calyx of Held, which is a glutamatergic synapse in the auditory pathway of the mammalia. We have developed such a stochastic model starting from existing kinetic models based on ODEs of some sub-components of the synapse, integrating other data from literature and making some assumptions about non-fully understood processes. Experiments have confirmed the coherence of our model with known biological data, also validating the assumptions made. Our model overcomes some limitations of the kinetic ones and, to our knowledge, represents the first model of synaptic processes based on process calculi. The compositionality of the approach has permitted us to independently focus on tuning the models of the pre- and post- synaptic traits, and then to naturally connect them, by dealing with “interface” issues. Furthermore, we have improved the expressiveness of the model, e.g. by embedding easy control of element concentration time courses. Sensitivity analysis over several parameters of the model has provided results that may help clarify the dynamics of synaptic transmission, while experiments with the model of the complete synapse seem worth explaining short-term plasticity mechanisms.ConclusionsSpecific presynaptic and postsynaptic mechanisms can be further analysed under various conditions, for instance by studying the presynaptic behaviour under repeated activations. The level of details of the description can be refined, for instance by further specifying the neurotransmitter generation and release steps. Taking advantage of the compositionality of the approach, an enhanced model could then be composed with other neural models, designed within the same framework, in order to obtain a more detailed and comprehensive model. In the long term, we are interested, in particular, in addressing models of synaptic plasticity, i.e. activity dependent mechanisms, which are the bases of memory and learning processes.More on the computer science side, we plan to follow some directions to improve the underlying computational model and the linguistic primitives it provides as suggested by the experiments carried out, e.g. by introducing a suitable notion of (spatial) locality.

In the Rat Brain Acetyl-l-carnitine Treatment Modulates the Expression of Genes Involved in Neuronal Ceroid Lipofuscinosis

Acetyl-l-carnitine (ALC) is a naturally occurring substance that, when administered at supraphysiological concentration, is neuroprotective. It is a molecule of considerable interest for its clinical application in various neural disorders, including Alzheimer’s disease and painful neuropathies. Suppression subtractive hybridization methodology was used for the generation of subtracted cDNA libraries and the subsequent identification of differentially expressed transcripts in the rat brain after ALC treatment. The method generates an equalized representation of differentially expressed genes irrespective of their relative abundance and it is based on the construction of forward and reverse cDNA libraries that allow the identification of the genes which are regulated by ALC. We report that ALC treatment: (1) upregulates lysosomal H+/ATPase gene expression and (2) downregulates myelin basic protein gene expression. The expression of these genes is altered in some forms of neuronal ceroid lipofuscinosis (NCL) pathologies. In this case, ALC might rebalance the disorders underlying NCL disease represented by a disturbance in pH homeostasis affecting the acidification of vesicles transported to lysosomal compartment for degradation. This study provides evidence that ALC controls genes involved in these serious neurological pathologies and provides insights into the ways in which ALC might exert its therapeutic benefits.

Oral Implant-Prostheses: New Teeth for a Brighter Brain

Several studies have demonstrated that chewing can be regarded as a preventive measure for cognitive impairment, whereas masticatory deficiency, associated with soft-diet feeding, is a risk factor for the development of dementia. At present the link between orofacial sensorimotor activity and cognitive functions is unknown. In subjects with unilateral molar loss we have shown asymmetries in both pupil size and masticatory muscles electromyographic (EMG) activity during clenching: the molar less side was characterized by a lower EMG activity and a smaller pupil. Since implant-prostheses, greatly reduced both the asymmetry in EMG activity and in pupil’s size, trigeminal unbalance, leading to unbalance in the activity of the Locus Coeruleus (LC), may be responsible for the pupil’s asymmetry. According to the findings obtained in animal models, we propose that the different activity of the right and left LC may induce an asymmetry in brain activity, thus leading to cognitive impairment. According to this hypothesis, prostheses improved the performance in a complex sensorimotor task and increased the mydriasis associated with haptic tasks. In conclusion, the present study indicates that the implant-prosthesis therapy, which reduces the unbalance of trigeminal proprioceptive afferents and the asymmetry in pupil’s size, may improve arousal, boosting performance in a complex sensorimotor task.

Computational model of a central pattern generator

The buccal ganglia of Aplysia contain a central pattern generator (CPG) that mediates rhythmic movements of the foregut during feeding. This CPG is a multifunctional circuit and generates at least two types of buccal motor patterns (BMPs), one that mediates ingestion (iBMP) and another that mediates rejection (rBMP). The present study used a computational approach to examine the ways in which an ensemble of identified cells and synaptic connections function as a CPG. Hodgkin-Huxley-type models were developed that mimicked the biophysical properties of these cells and synaptic connections. The results suggest that the currently identified ensemble of cells is inadequate to produce rhythmic neural activity and that several key elements of the CPG remain to be identified.

Synapses as stochastic concurrent systems

We present a stochastic model of the presynaptic terminal in the calyx of Held synapse. This model exploits process calculi as a representation language and has a direct computational implementation that supports quantitative simulation trials of the behaviour of the synapse. To our knowledge, it represents the first model of synaptic activity based on process calculi. The model builds upon available data, the fitting of some parameters and developed working hypotheses. Experiments about plasticity have been carried out regarding synaptic facilitation and potentiation. Also, synaptic depression has been considered in a model exhibiting dynamical equilibrium. Overall, the simulation results are coherent with the experimental findings appearing in the literature about the modeled reality. These results represent a quite detailed description of the presynaptic activity. This multidisciplinary work validates some aspects of the approach based on process calculi with respect to the new application domain, such as abstraction, expressiveness and compositionality.

Circular plate capacitor with different discs

In this paper, we write a system of integral equations for a capacitor composed of two discs of different radii, generalizing Love’s equation for equal discs. We compute the complete asymptotic form of the capacitance matrix for both large and small distances obtaining a generalization of Kirchhoff’s formula for the latter case.