extracellular-recording-neuronal-activity-combined-with

Extracellular Recording of Neuronal Activity Combined with Microiontophoretic Application of Neuroactive Substances in Awake Mice

Differences in the activity of neurotransmitters and neuromodulators, and consequently different neural responses, can be found between anesthetized and ...

University of Salamanca

University of Maryland

Some of the pitfalls that may befall molecular simulations of interfaces are discussed. They are all related to the calculation of the pressure tensor profiles, which are needed in order to compute surface tensions. We focus on three controversial points: (1) the calculation of the pressure tensor profiles for polyatomic systems, in particular, when the SHAKE algorithm is employed, (2) the addition of long-range corrections to compensate the truncation of the potential, and (3) the importance of including adequate error intervals with the results. Most of the conclusions are general, but some specifically apply to multiple site molecular-dynamics simulations.

Some issues on the calculation of interfacial properties by molecular simulation.

We perform a series of molecular dynamics simulations of Lennard-Jones chains systems, up to tetramers, in order to investigate the influence of temperature and chain length on their phase separation and interfacial properties. Simulation results serve as a test to check the accuracy of a statistical associated fluid theory (soft-SAFT) coupled with the density gradient theory. We focus on surface tension and density profiles. The simulations allow us to discuss the success and limitations of the theory and how to estimate the only adjustable parameter, the influence parameter. This parameter is obtained by fitting the surface tension, and then used to obtain the density profiles in a predictive manner. A good agreement is found if the temperature dependence of this parameter is neglected.(c) 2004 American Institute of Physics.

Interfacial properties of Lennard-Jones chains by direct simulation and density gradient theory.

Density gradient theory (DGT) and molecular-dynamics (MD) simulations have been used to predict subcritical phase and interface behaviors in type-I and type-V equal-size Lennard-Jones mixtures. Type-I mixtures exhibit a continuum critical line connecting their pure critical components, which implies that their subcritical phase equilibria are gas liquid. Type-V mixtures are characterized by two critical lines and a heteroazeotropic line. One of the two critical lines begins at the more volatile pure component critical point up to an upper critical end point and the other one comes from the less volatile pure component critical point ending at a lower critical end point. The heteroazeotropic line connects both critical end points and is characterized by gas-liquid-liquid equilibria. Therefore, subcritical states of this type exhibit gas-liquid and gas-liquid-liquid equilibria. In order to obtain a correct characterization of the phase and interface behaviors of these types of mixtures and to directly compare DGT and MD results, the global phase diagram of equal-size Lennard-Jones mixtures has been used to define the molecular parameters of these mixtures. According to our results, DGT and MD are two complementary methodologies able to obtain a complete and simultaneous prediction of phase equilibria and their interfacial properties. For the type of mixtures analyzed here, both approaches have shown excellent agreement in their phase equilibrium and interface properties in the full concentration range.

Phase and interface behaviors in type-I and type-V Lennard-Jones mixtures: theory and simulations.

We present here molecular-dynamics simulation results of the vapor-liquid coexistence curve, surface tension, and self-diffusion coefficients of sulfur hexafluoride. Sulfur hexafluoride is modeled as a rigid molecule, following the model proposed by Pawley [Mol. Phys. 43, 1321 (1981)]. Vapor-liquid coexistence curve and surface tension are obtained through direct molecular-dynamic simulations in the NVT ensemble. Simulation results are able to reproduce the qualitative shape of the vapor-liquid envelope. However, lower densities, a higher critical temperature, and an overestimated surface tension are obtained here. Those deviations are explained on the basis of the rigidity of the molecular model used. Self-diffusion coefficients are calculated from simulations in the NVE ensemble for different gas states at atmospheric pressure. The rigid model performs better for dynamical properties since simulation results provide very good agreement with available experimental data in this case.

Sulfur hexafluoride's liquid-vapor coexistence curve, interfacial properties, and diffusion coefficients as predicted by a simple rigid model.

We discuss the calculation of the force between surfaces coated with anchored molecules. This force is related to the pressure and can therefore be calculated by the usual means: either by summing over all surface-particle forces or from the virial. However, we argue that the grafting of the molecule must be included by means of a restraining potential-otherwise, nonphysical results can be obtained, such as the appearance of a net force even when the particles are spaced very far away. Bond-stretching potentials are also required if the virial is employed.

Calculation of the force between surfaces coated with grafted molecules by molecular simulation.

Recently, the intrinsic sampling method has been developed in order to obtain, from molecular simulations, the intrinsic structure of the liquid-vapor interface that is presupposed in the classical capillary wave theory. Our purpose here is to study dynamical processes at the liquid-vapor interface, since this method allows tracking down and analyzing the movement of surface molecules, thus providing, with great accuracy, dynamical information on molecules that are "at" the interface. We present results for the coefficients for diffusion parallel and perpendicular to the liquid-vapor interface of the Lennard-Jones fluid, as well as other time and length parameters that characterize the diffusion process in this system. We also obtain statistics of permanence and residence time. The generality of our results is tested by varying the system size and the temperature; for the latter case, an existing model for alkali metals is also considered. Our main conclusion is that, even if diffusion coefficients can still be computed, the turnover processes, by which molecules enter and leave the intrinsic surface, are as important as diffusion. For example, the typical time required for a molecule to traverse a molecular diameter is very similar to its residence time at the surface.

Diffusion at the liquid-vapor interface.

The identification of the interfacial molecules in fluid-fluid equilibrium is a long-standing problem in the area of simulation. We here propose an alternative point of view, making use of concepts taken from the field of computational geometry, where the definition of the "shape" of a set of points is a well-known problem. In particular, we employ the alpha -shape construction which, applied to the positions of the molecules, selects a shape and identifies its boundary points, which we will take to define our interfacial molecules. A single parameter needs to be fixed (the "alpha" of the alpha shape), and several proposals are examined, all leading to very similar choices. Results of this methodology are evaluated against previous proposals, and seen to be reasonable.

Applications of computational geometry to the molecular simulation of interfaces.

The ability to detect unexpected sounds within the environment is an important function of the auditory system, as a rapid response may be required for the organism to survive. Previous studies found a decreased response to repetitive stimuli (standard), but an increased response to rare or less frequent sounds (deviant) in individual neurons in the inferior colliculus (IC) and at higher levels. This phenomenon, known as stimulus-specific adaptation (SSA) has been suggested to underpin change detection. Currently, it is not known how SSA varies within a single neuron receptive field, i.e., it is unclear whether SSA is a unique property of the neuron or a feature that is frequency and/or intensity dependent. In the present experiments, we used the common SSA index (CSI) to quantify and compare the degree of SSA under different stimulation conditions in the IC of the rat. We calculated the CSI at different intensities and frequencies for each individual IC neuron to map the neuronal CSI within the receptive field. Our data show that high SSA is biased toward the high-frequency and low-intensity regions of the receptive field. We also find that SSA is better represented in the earliest portions of the response, and there is a positive correlation between the width of the frequency response area of the neuron and the maximum level of SSA. The present data suggest that SSA in the IC is not mediated by the intrinsic membrane properties of the neurons and instead might be related to an excitatory and/or inhibitory input segregation.

Topographic distribution, frequency, and intensity dependence of stimulus-specific adaptation in the inferior colliculus of the rat.

Auditory neurons that exhibit stimulus-specific adaptation (SSA) decrease their response to common tones while retaining responsiveness to rare ones. We recorded single-unit responses from the inferior colliculus (IC) where SSA is known to occur and we explored for the first time SSA in the cochlear nucleus (CN) of rats. We assessed an important functional outcome of SSA, the extent to which frequency discriminability depends on sensory context. For this purpose, pure tones were presented in an oddball sequence as standard (high probability of occurrence) or deviant (low probability of occurrence) stimuli. To study frequency discriminability under different probability contexts, we varied the probability of occurrence and the frequency separation between tones. The neuronal sensitivity was estimated in terms of spike-count probability using signal detection theory. We reproduced the finding that many neurons in the IC exhibited SSA, but we did not observe significant SSA in our CN sample. We concluded that strong SSA is not a ubiquitous phenomenon in the CN. As predicted, frequency discriminability was enhanced in IC when stimuli were presented in an oddball context, and this enhancement was correlated with the degree of SSA shown by the neurons. In contrast, frequency discrimination by CN neurons was independent of stimulus context. Our results demonstrated that SSA is not widespread along the entire auditory pathway, and suggest that SSA increases frequency discriminability of single neurons beyond that expected from their tuning curves.

Frequency discrimination and stimulus deviance in the inferior colliculus and cochlear nucleus.

Dithiocarb (diethyldithiocarbamate, DEDTC) belongs to the group of dithiocarbamates and is the main metabolite of disulphiram, a drug of choice for the treatment of alcohol dependence. Its therapeutic potential relays on its ability to create an unpleasant aversive reaction following the ingestion of alcohol, and this effect is usually accompanied by neurobehavioural symptoms. Most of these can be attributed to the impaired metabolism of brain biogenic amines.

Dithiocarb (N,N-diethyldithiocarbamate, DEDTC) decreases levels of biogenic monoamines in the adult mouse brain.

Stimulus-specific adaptation (SSA), which describes adaptation to repeated sounds concurrent with the maintenance of responsiveness to uncommon ones, may be an important neuronal mechanism for the detection of and attendance to rare stimuli or for the detection of deviance. It is well known that GABAergic neurotransmission regulates several different response properties in central auditory system neurons and that GABA is the major inhibitory neurotransmitter acting in the medial geniculate body (MGB). The mechanisms underlying SSA are still poorly understood; therefore, the primary aim of the present study was to examine what role, if any, MGB GABAergic circuits play in the generation and/or modulation of SSA. Microiontophoretic activation of GABA(A) receptors (GABA(A)Rs) with GABA or with the selective GABA(A)R agonist gaboxadol significantly increased SSA (computed with the common SSA index, CSI) by decreasing responses to common stimuli while having a lesser effect on responses to novel stimuli. In contrast, GABA(A)R blockade using gabazine resulted in a significant decrease in SSA. In all cases, decreases in the CSI during gabazine application were accompanied by an increase in firing rate to the stimulus paradigm. The present findings, in conjunction with those of previous studies, suggest that GABA(A)-mediated inhibition does not generate the SSA response, but can regulate the level of SSA sensitivity in a gain control manner. The existence of successive hierarchical levels of processing through the auditory system suggests that the GABAergic circuits act to enhance mechanisms to reduce redundant information.

Modulation of stimulus-specific adaptation by GABA(A) receptor activation or blockade in the medial geniculate body of the anaesthetized rat.

Rapid behavioral responses to unexpected events in the acoustic environment are critical for survival. Stimulus-specific adaptation (SSA) is the process whereby some auditory neurons respond better to rare stimuli than to repetitive stimuli. Most experiments on SSA have been performed under anesthesia, and it is unknown if SSA sensitivity is altered by the anesthetic agent. Only a direct comparison can answer this question. Here, we recorded extracellular single units in the inferior colliculus of awake and anesthetized mice under an oddball paradigm that elicits SSA. Our results demonstrate that SSA is similar, but not identical, in the awake and anesthetized preparations. The differences are mostly due to the higher spontaneous activity observed in the awake animals, which also revealed a high incidence of inhibitory receptive fields. We conclude that SSA is not an artifact of anesthesia and that spontaneous activity modulates neuronal SSA differentially, depending on the state of arousal. Our results suggest that SSA may be especially important when nervous system activity is suppressed during sleep-like states. This may be a useful survival mechanism that allows the organism to respond to danger when sleeping.

Stimulus-specific adaptation in the inferior colliculus of the mouse: anesthesia and spontaneous activity effects.

A remarkable ability of animals that is critical for survival is to detect and respond to to unexpected stimuli in an ever-changing world. Auditory neurons that show stimulus-specific adaptation (SSA), i.e., a decrease in their response to frequently occurring stimuli while maintaining responsiveness when different stimuli are presented, might participate in the coding of deviance occurrence. Traditionally, deviance detection is measured by the mismatch negativity (MMN) potential in studies of evoked local field potentials. We present a review of the state-of-the-art of SSA in auditory subcortical nuclei, i.e., the inferior colliculus and medial geniculate body of the thalamus, and link the differential receptor distribution and neural connectivity of those regions in which extreme SSA has been found. Furthermore, we review both SSA and MMN-like responses in auditory and non-auditory areas that exhibit multimodal sensitivities that we suggest conform to a distributed network encoding for deviance detection. The understanding of the neurochemistry and response similarities across these different regions will contribute to a better understanding of the neural mechanism underlying deviance detection.

Deviance detection in auditory subcortical structures: what can we learn from neurochemistry and neural connectivity?

Electrophysiological and psychophysical responses to a low-intensity probe sound tend to be suppressed by a preceding high-intensity adaptor sound. Nevertheless, rare low-intensity deviant sounds presented among frequent high-intensity standard sounds in an intensity oddball paradigm can elicit an electroencephalographic mismatch negativity (MMN) response. This has been taken to suggest that the MMN is a correlate of true change or "deviance" detection. A key question is where in the ascending auditory pathway true deviance sensitivity first emerges. Here, we addressed this question by measuring low-intensity deviant responses from single units in the inferior colliculus (IC) of anesthetized rats. If the IC exhibits true deviance sensitivity to intensity, IC neurons should show enhanced responses to low-intensity deviant sounds presented among high-intensity standards. Contrary to this prediction, deviant responses were only enhanced when the standards and deviants differed in frequency. The results could be explained with a model assuming that IC neurons integrate over multiple frequency-tuned channels and that adaptation occurs within each channel independently. We used an adaptation paradigm with multiple repeated adaptors to measure the tuning widths of these adaption channels in relation to the neurons' overall tuning widths.

Article	Year
Some issues on the calculation of interfacial properties by molecular simulation. The Journal of chemical physics\| PubMed ID: 15511187	2004
Interfacial properties of Lennard-Jones chains by direct simulation and density gradient theory. The Journal of chemical physics\| PubMed ID: 15634099	2004
Phase and interface behaviors in type-I and type-V Lennard-Jones mixtures: theory and simulations. The Journal of chemical physics\| PubMed ID: 16080742	2005
Sulfur hexafluoride's liquid-vapor coexistence curve, interfacial properties, and diffusion coefficients as predicted by a simple rigid model. The Journal of chemical physics\| PubMed ID: 16321101	2005
Calculation of the force between surfaces coated with grafted molecules by molecular simulation. The Journal of chemical physics\| PubMed ID: 16438596	2006
Diffusion at the liquid-vapor interface. The Journal of chemical physics\| PubMed ID: 18397091	2008
Applications of computational geometry to the molecular simulation of interfaces. Physical review. E, Statistical, nonlinear, and soft matter physics\| PubMed ID: 19518382	2009
Topographic distribution, frequency, and intensity dependence of stimulus-specific adaptation in the inferior colliculus of the rat. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 23223296	2012
Frequency discrimination and stimulus deviance in the inferior colliculus and cochlear nucleus. Frontiers in neural circuits\| PubMed ID: 23335885	2012
Dithiocarb (N,N-diethyldithiocarbamate, DEDTC) decreases levels of biogenic monoamines in the adult mouse brain. Neuropathology and applied neurobiology\| PubMed ID: 24033405	2014
Modulation of stimulus-specific adaptation by GABA(A) receptor activation or blockade in the medial geniculate body of the anaesthetized rat. The Journal of physiology\| PubMed ID: 24099802	2014
Stimulus-specific adaptation in the inferior colliculus of the mouse: anesthesia and spontaneous activity effects. Brain structure & function\| PubMed ID: 25115620	2015
Deviance detection in auditory subcortical structures: what can we learn from neurochemistry and neural connectivity? Cell and tissue research\| PubMed ID: 25749993	2015
Neurons in the inferior colliculus of the rat show stimulus-specific adaptation for frequency, but not for intensity. Scientific reports\| PubMed ID: 27066835	2016

Daniel Duque

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