bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Sensory Suppression: Implications for Receptive Field Sizes in the Human Visual Cortex
Authors: Kastner Sabine , De Weerd Peter , Pinsk Mark A. , Elizondo M. Idette , Desimone Robert , Ungerleider Leslie G.
Published: December 2017

Neurophysiological studies in monkeys show that when multiple visual stimuli appear simultaneously in the visual field, they are not processed independently, but rather interact in a mutually suppressive way. This suggests that multiple stimuli compete for neural representation. Consistent with this notion, we have previously found in humans that functional magnetic resonance imaging (fMRI) signals in V1 and ventral extrastriate areas V2, V4, and TEO are smaller for simultaneously presented (i.e., competing) stimuli than for the same stimuli presented sequentially (i.e., not competing). Here we report that suppressive interactions between stimuli are also present in dorsal extrastriate areas V3A and MT, and we compare these interactions to those in areas V1 through TEO. To exclude the possibility that the differences in responses to simultaneously and sequentially presented stimuli were due to differences in the number of transient onsets, we tested for suppressive interactions in area V4, in an experiment that held constant the number of transient onsets. We found that the fMRI response to a stimulus in the upper visual field was suppressed by the presence of nearby stimuli in the lower visual field. Further, we excluded the possibility that the greater fMRI responses to sequential compared with simultaneous presentations were due to exogeneous attentional cueing by having our subjects count T's or L's at fixation, an attentionally demanding task. Behavioral testing demonstrated that neither condition interfered with performance of the T/L task. Our previous findings suggested that suppressive interactions among nearby stimuli in areas V1 through TEO were scaled to the receptive field (RF) sizes of neurons in those areas. Here we tested this idea by parametrically varying the spatial separation among stimuli in the display. Display sizes ranged from 2 × 2° to 7 × 7° and were centered at 5.5° eccentricity. Based on the effects of display size on the magnitude of suppressive interactions, we estimated that RF sizes at an eccentricity of 5.5° were <2° in V1, 2–4° in V2, 4–6° in V4, larger than 7° (but still confined to a quadrant) in TEO, and larger than 6° (confined to a quadrant) in V3A. These estimates of RF sizes in human visual cortex are strikingly similar to those measured in physiological mapping studies in the homologous visual areas in monkeys.
Central Positional Nystagmus Simulated by a Mathematical Ocular Motor Model of Otolith-Dependent Modification of Listing's Plane
Authors: Glasauer S. , Dieterich M. , Brandt Th.
Published: December 2017

To find an explanation of the mechanisms of central positional nystagmus in neurological patients with posterior fossa lesions, we developed a three-dimensional (3-D) mathematical model to simulate head position-dependent changes in eye position control relative to gravity. This required a model implementation of saccadic burst generation, of the neural velocity to eye position integrator, which includes the experimentally demonstrated leakage in the torsional component, and of otolith-dependent neural control of Listing's plane. The validity of the model was first tested by simulating saccadic eye movements in different head positions. Then the model was used to simulate central positional nystagmus in off-vertical head positions. The model simulated lesions of assumed otolith inputs to the burst generator or the neural integrator, both of which resulted in different types of torsional-vertical nystagmus that only occurred during head tilt in roll plane. The model data qualitatively fit clinical observations of central positional nystagmus. Quantitative comparison with patient data were not possible, since no 3-D analyses of eye movements in various head positions have been reported in the literature on patients with positional nystagmus. The present model, prompted by an open clinical question, proposes a new hypothesis about the generation of pathological nystagmus and about neural control of Listing's plane.
Investigation Into Non-Monosynaptic Corticospinal Excitation of Macaque Upper Limb Single Motor Units
Authors: Olivier E. , Baker S. N. , Nakajima K. , Brochier T. , Lemon R. N.
Published: December 2017

There has been considerable recent debate as to relative importance, in the primate, of propriospinal transmission of corticospinal excitation to upper limb motoneurons. Previous studies in the anesthetized macaque monkey suggested that, compared with the cat, the transmission of such excitation via a system of C3–C4 propriospinal neurons may be relatively weak. However, it is possible that in the anesthetized preparation, propriospinal transmission of cortical inputs to motoneurons may be depressed. To address this issue, the current study investigated the responses of single motor units (SMUs) to corticospinal inputs in either awake ( n = 1) or lightly sedated ( n = 3) macaque monkeys. Recordings in the awake state were made during performance of a precision grip task. The responses of spontaneously discharging SMUs to electrical stimulation of the pyramidal tract (PT) via chronically implanted electrodes were examined for evidence of non-monosynaptic, presumed propriospinal, effects. Single PT stimuli (up to 250 μA; duration, 0.2 ms, 2 Hz) were delivered during steady discharge of the SMU (10–30 imp/s). SMUs were recorded from muscles acting on the thumb (adductor pollicis and abductor pollicis brevis, n = 18), wrist (extensor carpi radialis, n = 29) and elbow (biceps, n = 9). In all SMUs, the poststimulus time histograms to PT stimulation consisted of a single peak at a fixed latency and with a brief duration [0.74 ± 0.25 (SD) ms, n = 56], consistent with the responses being mediated by monosynaptic action of cortico-motoneuronal (CM) impulses. Later peaks, indicating non-monosynaptic action, were not present even when the probability of the initial peak response was low and when there was no evidence for suppression of ongoing SMU activity following this peak ( n = 20 SMUs). Even when repetitive (double-pulse) PT stimuli were used to facilitate transmission through oligosynaptic linkages, no later peaks were observed (16 SMUs). In some thumb muscle SMUs ( n = 8), responses to PT stimulation were compared with those evoked by transcranial magnetic stimulation, using a figure-eight coil held over the motor cortex. Responses varied according the orientation of the coil: in the latero-medial position, single peak responses similar to those from the PT were obtained; their latencies confirmed direct excitation of CM cells, and there were no later peaks. In the posterio-anterior orientation, responses had longer latencies and consisted of two to three subpeaks. At least under the conditions that we have tested, the results provide no positive evidence for transmission of cortical excitation to upper limb motoneurons by non-monosynaptic pathways in the macaque monkey.
Grasp With Hand and Mouth: A Kinematic Study on Healthy Subjects
Authors: Gentilucci Maurizio , Benuzzi Francesca , Gangitano Massimo , Grimaldi Silvia
Published: December 2017

Neurons involved in grasp preparation with hand and mouth were previously recorded in the premotor cortex of monkey. The aim of the present kinematic study was to determine whether a unique planning underlies the act of grasping with hand and mouth in humans as well. In a set of four experiments, healthy subjects reached and grasped with the hand an object of different size while opening the mouth ( experiments 1 and 3), or extending the other forearm ( experiment 4), or the fingers of the other hand ( experiment 5). In a subsequent set of three experiments, subjects grasped an object of different size with the mouth, while opening the fingers of the right hand ( experiments 6–8). The initial kinematics of mouth and finger opening, but not of forearm extension, was affected by the size of the grasped object congruently with the size effect on initial grasp kinematics. This effect was due neither to visual presentation of the object, without the successive grasp motor act ( experiment 2) nor to synchronism between finger and mouth opening ( experiments 3, 7, and 8). In experiment 9 subjects grasped with the right hand an object of different size while pronouncing a syllable printed on the target. Mouth opening and sound production were affected by the grasped object size. The results of the present study are discussed according to the notion that in an action each motor act is prepared before the beginning of the motor sequence. Double grasp preparation can be used for successive motor acts on the same object as, for example, grasping food with the hand and ingesting it after bringing it to the mouth. We speculate that the circuits involved in double grasp preparation might have been the neural substrate where hand motor patterns used as primitive communication signs were transferred to mouth articulation system. This is in accordance with the hypothesis that Broca's area derives phylogenetically from the monkey premotor area where hand movements are controlled.
Local Correlation-Based Circuitry Can Account for Responses to Multi-Grating Stimuli in a Model of Cat V1
Authors: Lauritzen T. Z. , Krukowski A. E. , Miller K. D.
Published: December 2017

In cortical simple cells of cat striate cortex, the response to a visual stimulus of the preferred orientation is partially suppressed by simultaneous presentation of a stimulus at the orthogonal orientation, an effect known as “cross-orientation inhibition.” It has been argued that this is due to the presence of inhibitory connections between cells tuned for different orientations, but intracellular studies suggest that simple cells receive inhibitory input primarily from cells with similar orientation tuning. Furthermore, response suppression can be elicited by a variety of nonpreferred stimuli at all orientations. Here we study a model circuit that was presented previously to address many aspects of simple cell orientation tuning, which is based on local intracortical connectivity between cells of similar orientation tuning. We show that this model circuit can account for many aspects of cross-orientation inhibition and, more generally, of response suppression by nonpreferred stimuli and of other nonlinear properties of responses to stimulation with multiple gratings.
Neural Basis of a Perceptual Decision in the Parietal Cortex (Area LIP) of the Rhesus Monkey
Authors: Shadlen Michael N. , Newsome William T.
Published: December 2017

We recorded the activity of single neurons in the posterior parietal cortex (area LIP) of two rhesus monkeys while they discriminated the direction of motion in random-dot visual stimuli. The visual task was similar to a motion discrimination task that has been used in previous investigations of motion-sensitive regions of the extrastriate cortex. The monkeys were trained to decide whether the direction of motion was toward one of two choice targets that appeared on either side of the random-dot stimulus. At the end of the trial, the monkeys reported their direction judgment by making an eye movement to the appropriate target. We studied neurons in LIP that exhibited spatially selective persistent activity during delayed saccadic eye movement tasks. These neurons are thought to carry high-level signals appropriate for identifying salient visual targets and for guiding saccadic eye movements. We arranged the motion discrimination task so that one of the choice targets was in the LIP neuron's response field (RF) while the other target was positioned well away from the RF. During motion viewing, neurons in LIP altered their firing rate in a manner that predicted the saccadic eye movement that the monkey would make at the end of the trial. The activity thus predicted the monkey's judgment of motion direction. This predictive activity began early in the motion-viewing period and became increasingly reliable as the monkey viewed the random-dot motion. The neural activity predicted the monkey's direction judgment on both easy and difficult trials (strong and weak motion), whether or not the judgment was correct. In addition, the timing and magnitude of the response was affected by the strength of the motion signal in the stimulus. When the direction of motion was toward the RF, stronger motion led to larger neural responses earlier in the motion-viewing period. When motion was away from the RF, stronger motion led to greater suppression of ongoing activity. Thus the activity of single neurons in area LIP reflects both the direction of an impending gaze shift and the quality of the sensory information that instructs such a response. The time course of the neural response suggests that LIP accumulates sensory signals relevant to the selection of a target for an eye movement.
Synchronization of Neuronal Activity in the Human Primary Motor Cortex by Transcranial Magnetic Stimulation: An EEG Study
Authors: Paus T. , Sipila P. K. , Strafella A. P.
Published: December 2017

Using multichannel electroencephalography (EEG), we investigated temporal dynamics of the cortical response to transcranial magnetic stimulation (TMS). TMS was applied over the left primary motor cortex (M1) of healthy volunteers, intermixing single suprathreshold pulses with pairs of sub- and suprathreshold pulses and simultaneously recording EEG from 60 scalp electrodes. Averaging of EEG data time locked to the onset of TMS pulses yielded a waveform consisting of a positive peak (30 ms after the pulse P30), followed by two negative peaks [at 45 (N45) and 100 ms]. Peak-to-peak amplitude of the P30–N45 waveform was high, ranging from 12 to 70 μV; in most subjects, the N45 potential could be identified in single EEG traces. Spectral analysis revealed that single-pulse TMS induced a brief period of synchronized activity in the beta range (15–30 Hz) in the vicinity of the stimulation site; again, this oscillatory response was apparent not only in the EEG averages but also in single traces. Both the N45 and the oscillatory response were lower in amplitude in the 12-ms (but not 3-ms) paired-pulse trials, compared with the single-pulse trials. These findings are consistent with the possibility that TMS applied to M1 induces transient synchronization of spontaneous activity of cortical neurons within the 15- to 30-Hz frequency range. As such, they corroborate previous studies of cortical oscillations in the motor cortex and point to the potential of the combined TMS/EEG approach for further investigations of cortical rhythms in the human brain.
Human Cortical Activity Correlates With Stereoscopic Depth Perception
Authors: Backus Benjamin T. , Fleet David J. , Parker Andrew J. , Heeger David J.
Published: December 2017

Stereoscopic depth perception is based on binocular disparities. Although neurons in primary visual cortex (V1) are selective for binocular disparity, their responses do not explicitly code perceived depth. The stereoscopic pathway must therefore include additional processing beyond V1. We used functional magnetic resonance imaging (fMRI) to examine stereo processing in V1 and other areas of visual cortex. We created stereoscopic stimuli that portrayed two planes of dots in depth, placed symmetrically about the plane of fixation, or else asymmetrically with both planes either nearer or farther than fixation. The interplane disparity was varied parametrically to determine the stereoacuity threshold (the smallest detectable disparity) and the upper depth limit (largest detectable disparity). fMRI was then used to quantify cortical activity across the entire range of detectable interplane disparities. Measured cortical activity covaried with psychophysical measures of stereoscopic depth perception. Activity increased as the interplane disparity increased above the stereoacuity threshold and dropped as interplane disparity approached the upper depth limit. From the fMRI data and an assumption that V1 encodes absolute retinal disparity, we predicted that the mean response of V1 neurons should be a bimodal function of disparity. A post hoc analysis of electrophysiological recordings of single neurons in macaques revealed that, although the average firing rate was a bimodal function of disparity (as predicted), the precise shape of the function cannot fully explain the fMRI data. Although there was widespread activity within the extrastriate cortex (consistent with electrophysiological recordings of single neurons), area V3A showed remarkable sensitivity to stereoscopic stimuli, suggesting that neurons in V3A may play a special role in the stereo pathway.
Functional Organization of Macaque V3 for Stereoscopic Depth
Authors: Adams Daniel L. , Zeki Semir
Published: December 2017

Recordings were made from single and small groups of cells in prestriate area V3 of the visual cortex of the Cynomolgus macaque (Macaca fascicularis). The majority of cells in V3 were selective for orientation and stereoscopic depth, these cells being segregated into two sets of functionally distinct columns. Orientation columns in V3 have been previously demonstrated; here we show that V3 also contains columns of segregated disparity-selective cells. On the basis of its cellular properties, functional organization, and intra-cortical connections, we propose that V3 contributes to the processing of stereoscopic depth information and that the parietal areas to which it projects use this information for the analysis of object depth and three-dimensional form.
Activation of Group I mGluRs Is Necessary for Induction of Long-Term Depression at Striatal Synapses
Authors: Sung Ki-Wug , Choi Sukwoo , Lovinger David M.
Published: December 2017

Activation of metabotropic glutamate receptors (mGluRs), which are coupled to G proteins, has important roles in certain forms of synaptic plasticity including corticostriatal long-term depression (LTD). In the present study, extracellular field potential and whole cell voltage-clamp recording techniques were used to investigate the effect of mGluR antagonists with different subtype specificity on high-frequency stimulation (HFS)-induced LTD of synaptic transmission in the striatum of brain slices obtained from 15-to 25-day-old rats. Induction of LTD was prevented during exposure to the nonselective mGluR antagonist (RS)-α-methyl-4-carboxyphenylglycine (500 μM). The group I mGluR-selective antagonists ( S)-4-carboxy-phenylglycine (50 μM) and (RS)-1-aminoindan-1,5-dicarboxylic acid (100 μM) prevented induction of LTD when applied before and during HFS. The mGluR1-selective antagonist 7-(Hydroxyimino) cyclopropa[b]chromen-1a-carboxylate ethyl ester (80 μM) also blocked LTD induction. Unexpectedly, the mGluR5-selective antagonist 2-methyl-6-(phenylethyl)-pyridine (10 μM) also prevented LTD induction. The group II mGluR antagonist LY307452 (10 μM) did not block LTD induction at corticostriatal synapses, but LY307452 was able to block transient synaptic depression induced by the group II agonist LY314593. None of the antagonists had any effect on basal synaptic transmission at the concentrations used, and mGluR antagonists did not reverse LTD when applied beginning 20 min after HFS. These results suggest that both group I mGluR subtypes contribute to the induction of LTD at corticostriatal synapses.
Facilitation of Smooth Pursuit Initiation by Electrical Stimulation in the Supplementary Eye Fields
Authors: Missal M. , Heinen S. J.
Published: December 2017

The role of the supplementary eye fields (SEF) during smooth pursuit was investigated with electrical microstimulation. We found that stimulation in the SEF increased the acceleration and velocity of the eyes in the direction of target motion during smooth pursuit initiation but not during sustained pursuit. The increase in eye velocity during initiation will be referred to as pursuit facilitation and was observed at sites where saccades could not be evoked with the same stimulation parameters. On average, electrical stimulation increased eye velocity by ∼20%. At most sites, the threshold for a significant facilitation was 50 μA with a stimulation frequency of 300 Hz. Facilitation of pursuit initiation depended on the timing of stimulation trains. The effect was most pronounced if the stimulation was delivered before smooth pursuit initiation. On average, eye velocity in stimulation trials increased linearly as a function of eye velocity in control trials, and this function had a slope greater than one, suggesting a multiplicative influence of the stimulation. Stimulation during a fixation task did not evoke smooth eye movements. The latency of catch-up saccades was increased during facilitation, but their accuracy was not affected. Saccades toward stationary targets were not affected by the stimulation. The results are further evidence that the SEF plays a role in smooth pursuit in addition to its known role in saccade planning and suggest that this role may be to control the gain of smooth pursuit during initiation. The covariance between pursuit facilitation and the timing of the catch-up saccade as a result of stimulation suggests that these different eye movements systems are coordinated to achieve a common goal.
Effect of Lamotrigine on the Ca2+-Sensing Cation Current in Cultured Hippocampal Neurons
Authors: Xiong Zhi-Gang , Chu Xiang-Ping , MacDonald J. F.
Published: December 2017

Concentrations of extracellular calcium ([Ca2+]e) in the CNS decrease substantially during seizure activity. We have demonstrated previously that decreases in [Ca2+]e activate a novel calcium-sensing nonselective cation (csNSC) channel in hippocampal neurons. Activation of csNSC channels is responsible for a sustained membrane depolarization and increased neuronal excitability. Our study has suggested that the csNSC channel is likely involved in generating and maintaining seizure activities. In the present study, the effects of anti-epileptic agent lamotrigine (LTG) on csNSC channels were studied in cultured mouse hippocampal neurons using patch-clamp techniques. At a holding potential of −60 mV, a slow inward current through csNSC channels was activated by a step reduction of [Ca2+]e from 1.5 to 0.2 mM. LTG decreased the amplitude of csNSC currents dose dependently with an IC50 of 171 ± 25.8 (SE) μM. The effect of LTG was independent of membrane potential. In the presence of 300 μM LTG, the amplitude of csNSC current was decreased by 31 ± 3% at −60 mV and 29 ± 2.9% at +40 mV ( P > 0.05). LTG depressed csNSC current without affecting the potency of Ca2+ block of the current (IC50 for Ca2+block of csNSC currents in the absence of LTG: 145 ± 18 μM; in the presence of 300 μM LTG: 136 ± 10 μM. n = 5, P > 0.05). In current-clamp recordings, activation of csNSC channel by reducing the [Ca2+]e caused a sustained membrane depolarization and an increase in the frequency of spontaneous firing of action potentials. LTG (300 μM) significantly inhibited csNSC channel-mediated membrane depolarization and the excitation of neurons. Fura-2 ratiometric Ca2+imaging experiment showed that LTG also inhibited the increase in intracellular Ca2+ concentration induced by csNSC channel activation. The effect of LTG on csNSC channels may partially contribute to its broad spectrum of anti-epileptic actions.
Target Selection for Saccadic Eye Movements: Prelude Activity in the Superior Colliculus During a Direction-Discrimination Task
Authors: Horwitz Gregory D. , Newsome William T.
Published: December 2017

We investigated the role of the superior colliculus (SC) in saccade target selection while macaque monkeys performed a direction-discrimination task. The monkeys selected one of two possible saccade targets based on the direction of motion in a stochastic random-dot display; the difficulty of the task was varied by adjusting the strength of the motion signal in the display. One of the two saccade targets was positioned within the movement field of the SC neuron under study while the other target was positioned well outside the movement field. Approximately 30% of the neurons in the intermediate and deep layers of the SC discharged target-specific preludes of activity that “predicted” target choices well before execution of the saccadic eye movement. Across the population of neurons, the strength of the motion signal in the display influenced the intensity of this “predictive” prelude activity: SC activity signaled the impending saccade more reliably when the motion signal was strong than when it was weak. The dependence of neural activity on motion strength could not be explained by small variations in the metrics of the saccadic eye movements. Predictive activity was particularly strong in a subpopulation of neurons with directional visual responses that we have described previously. For a subset of SC neurons, therefore, prelude activity reflects the difficulty of the direction discrimination in addition to the target of the impending saccade. These results are consistent with the notion that a restricted network of SC neurons plays a role in the process of saccade target selection.
Extraretinal Inputs to Neurons in the Rostral Superior Colliculus of the Monkey During Smooth-Pursuit Eye Movements
Authors: Krauzlis Richard J.
Published: December 2017

The intermediate and deep layers of the monkey superior colliculus (SC) are known to be important for the generation of saccadic eye movements. Recent studies have also provided evidence that the rostral SC might be involved in the control of pursuit eye movements. However, because rostral SC neurons respond to visual stimuli used to guide pursuit, it is also possible that the pursuit-related activity is simply a visual response. To test this possibility, we recorded the activity of neurons in the rostral SC as monkeys smoothly pursued a target that was briefly extinguished. We found that almost all rostral SC neurons in our sample maintained their pursuit-related activity during a brief visual blink, which was similar to the maintained activity they also exhibited during blinks imposed during fixation. These results indicate that discharge of rostral SC neurons during pursuit is not simply a visual response, but includes extraretinal signals.
Distinct NMDA and AMPA Receptor–Mediated Responses in Mouse and Human Cajal-Retzius Cells
Authors: Lu Shao-Ming , Zecevic Nada , Yeh Hermes H.
Published: December 2017

This study examined glutamate-activated current responses of mouse and human Cajal-Retzius (C-R) cells. Thin cortical slices were prepared from the brains of mice 4–6 days after birth and from those of midgestational human fetuses. Both human and mouse C-R cells displayed glutamate-induced whole-cell current responses that were voltage-dependent and included an N-methyl-d-aspartate (NMDA) receptor–mediated component that was differentially sensitive to blockade by the NMDA receptor antagonists 2-amino-5-phosphonovaleric acid and ifenprodil. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), a non-NMDA glutamate receptor agonist, induced current responses in human but not in mouse C-R cells. These results, taken together, lead us to conclude that human C-R cells express both NMDA and AMPA types of glutamate receptors very early during development of the cortex. In contrast, mouse C-R cells express only the NMDA type of glutamate receptor. Thus we demonstrate a species-dependent sensitivity of C-R cells to glutamate and postulate that this differential sensitivity may account in part for a species-dependent difference in the persistence of C-R cells during cortical development.
Altered Dentate Filtering During the Transition to Seizure in the Rat Tetanus Toxin Model of Epilepsy
Authors: Finnerty G. T. , Whittington M. A. , Jefferys J.G.R.
Published: December 2017

The dentate gyrus is thought to be a key area in containing the spread of seizure discharges in temporal lobe epilepsy. We investigated whether it actively contributes to the transition to seizure in vivo using the tetanus toxin chronic experimental epilepsy. Brief epileptic discharges lasted <2 s in freely moving animals and were clearly distinguishable from spontaneous seizures that lasted tens of seconds. This suggested that the changes underpinning the transition to seizure started within the first few seconds of seizure onset. During this period, we found that the amplitude of dentate gyrus population spikes depressed initially, but from 1.1 s after seizure onset, they potentiated. The amplitude and number of CA3 population spikes paralleled the pattern found in the dentate gyrus. We used hippocampal slices to study dentate filtering in more detail. The perforant pathway was stimulated repetitively at the frequency of field postsynaptic potentials found during epileptic discharges in vivo. The amplitude of dentate gyrus population spikes decreased to a steady state in naı̈ve hippocampal slices. In hippocampal slices prepared from rats previously injected with tetanus toxin, population spike amplitude decreased transiently and then potentiated. We found that the biphasic profile and rate of potentiation of dentate population spikes in vivo can be reproduced in naı̈ve hippocampal slices by blocking GABAB receptors. We conclude that the filtering properties of the dentate gyrus are altered in the tetanus toxin model of epilepsy and propose how this contributes to the transition to seizure in our animals.
Disruption of GABAA Receptors on GABAergic Interneurons Leads to Increased Oscillatory Power in the Olfactory Bulb Network
Authors: Nusser Zoltan , Kay Leslie M. , Laurent Gilles , Homanics Gregg E. , Mody Istvan
Published: December 2017

Synchronized neural activity is believed to be essential for many CNS functions, including neuronal development, sensory perception, and memory formation. In several brain areas GABAA receptor–mediated synaptic inhibition is thought to be important for the generation of synchronous network activity. We have used GABAA receptor β3 subunit deficient mice (β3−/−) to study the role of GABAergic inhibition in the generation of network oscillations in the olfactory bulb (OB) and to reveal the role of such oscillations in olfaction. The expression of functional GABAA receptors was drastically reduced (>93%) in β3−/− granule cells, the local inhibitory interneurons of the OB. This was revealed by a large reduction of muscimol-evoked whole-cell current and the total current mediated by spontaneous, miniature inhibitory postsynaptic currents (mIPSCs). In β3−/− mitral/tufted cells (principal cells), there was a two-fold increase in mIPSC amplitudes without any significant change in their kinetics or frequency. In parallel with the altered inhibition, there was a significant increase in the amplitude of theta (80% increase) and gamma (178% increase) frequency oscillations in β3−/− OBs recorded in vivo from freely moving mice. In odor discrimination tests, we found β3−/− mice to be initially the same as, but better with experience than β3+/+ mice in distinguishing closely related monomolecular alcohols. However, β3−/− mice were initially better and then worse with practice than control mice in distinguishing closely related mixtures of alcohols. Our results indicate that the disruption of GABAAreceptor–mediated synaptic inhibition of GABAergic interneurons and the augmentation of IPSCs in principal cells result in increased network oscillations in the OB with complex effects on olfactory discrimination, which can be explained by an increase in the size or effective power of oscillating neural cell assemblies among the mitral cells of β3−/− mice.
Synaptic Regulation of the Slow Ca2+-Activated K+ Current in Hippocampal CA1 Pyramidal Neurons: Implication in Epileptogenesis
Authors: Martín Eduardo D. , Araque Alfonso , Buño Washington
Published: December 2017

The slow Ca2+-activated K+ current (sIAHP) plays a critical role in regulating neuronal excitability, but its modulation during abnormal bursting activity, as in epilepsy, is unknown. Because synaptic transmission is enhanced during epilepsy, we investigated the synaptically mediated regulation of the sIAHP and its control of neuronal excitability during epileptiform activity induced by 4-aminopyridine (4AP) or 4AP+Mg2+-free treatment in rat hippocampal slices. We used electrophysiological and photometric Ca2+ techniques to analyze the sIAHP modifications that parallel epileptiform activity. Epileptiform activity was characterized by slow, repetitive, spontaneous depolarizations and action potential bursts and was associated with increased frequency and amplitude of spontaneous excitatory postsynaptic currents and a reduced sIAHP. The metabotropic glutamate receptor (mGluR) antagonist (S)-α-methyl-4-carboxyphenylglycine did not modify synaptic activity enhancement but did prevent sIAHP inhibition and epileptiform discharges. The mGluR-dependent regulation of the sIAHP was not caused by modulated intracellular Ca2+ signaling. Histamine, isoproterenol, and (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid reduced the sIAHP but did not increase synaptic activity and failed to evoke epileptiform activity. We conclude that 4AP or 4AP+Mg-free–induced enhancement of synaptic activity reduced the sIAHP via activation of postsynaptic group I/II mGluRs. The increased excitability caused by the lack of negative feedback provided by the sIAHP contributes to epileptiform activity, which requires the cooperative action of increased synaptic activity.
Hand Synergies During Reach-to-Grasp
Authors: Mason C. R. , Gomez J. E. , Ebner T. J.
Published: December 2017

An emerging viewpoint is that the CNS uses synergies to simplify the control of the hand. Previous work has shown that static hand postures for mimed grasps can be described by a few principal components in which the higher order components explained only a small fraction of the variance yet provided meaningful information. Extending that earlier work, this study addressed whether the entire act of grasp can be described by a small number of postural synergies and whether these synergies are similar for different grasps. Five right-handed adults performed five types of reach-to-grasps including power grasp, power grasp with a lift, precision grasp, and mimed power grasp and mimed precision grasp of 16 different objects. The object shapes were cones, cylinders, and spindles, systematically varied in size to produce a large range of finger joint angle combinations. Three-dimensional reconstructions of 21 positions on the hand and wrist throughout the reach-to-grasp were obtained using a four-camera video system. Singular value decomposition on the temporal sequence of the marker positions was used to identify the common patterns (“eigenpostures”) across the 16 objects for each task and their weightings as a function of time. The first eigenposture explained an average of 97.3 ± 0.89% (mean ± SD) of the variance of the hand shape, and the second another 1.9 ± 0.85%. The first eigenposture was characterized by an open hand configuration that opens and closes during reach. The second eigenposture contributed to the control of the thumb and long fingers, particularly in the opening of the hand during the reach and the closing in preparation for object grasp. The eigenpostures and their temporal evolutions were similar across subjects and grasps. The higher order eigenpostures, although explaining only small amounts of the variance, contributed to the movements of the fingers and thumb. These findings suggest that much of reach-to-grasp is effected using a base posture with refinements in finger and thumb positions added in time to yield unique hand shapes.
Dopamine Inhibition of Evoked IPSCs in Rat Prefrontal Cortex
Authors: Gonzalez-Islas Carlos , Hablitz John J.
Published: December 2017

Rat prefrontal cortex (PFC) receives substantial dopamine (DA) input. This DA innervation appears critical for modulation of PFC cognitive functions. Clinical and experimental studies have also implicated DA in the pathogenesis of a number of neurological and psychiatric disorders including epilepsy and schizophrenia. However, the actions of DA at the cellular level are incompletely understood. Both inhibitory interneurons and pyramidal cells are targets of DA and may express different DA receptor types. Our recent findings suggest that DA can directly excite cortical interneurons and increase the frequency of spontaneous inhibitory postsynaptic currents (IPSCs). The present study was undertaken to determine the effect of specific DA receptor agonists on evoked (e) IPSCs. Visually identified pyramidal neurons were studied using whole cell voltage-clamp techniques. Bath application of DA 30 μM reduced IPSC amplitude to 80 ± 4% (mean ± SE) of control without any significant change in IPSC kinetics or passive membrane properties. The D1-like DA receptor agonist SKF 38393 reduced IPSC amplitude to 71.5 ± 8%, whereas the D2-like specific agonist quinpirole has no effect on amplitude (94.5 ± 5%). The D1-like receptor antagonist SCH 23390 prevented DA inhibition of IPSC amplitude (98.2 ± 4%), whereas IPSCs were still reduced in amplitude (79.7 ± 4%) by DA in the presence of the D2-like receptor antagonist sulpiride. DA increased significantly paired-pulse inhibition, whereas responses to puff applied GABA were unaffected. Addition of the PKA inhibitor H-8 blocked the effect of DA on IPSCs. These results suggest that DA can decrease IPSCs in layer II–III PFC neocortical pyramidal cells by activating presynaptic D1-like receptors.
Muscarine Reduces Calcium-Dependent Electrical Activity in Substantia Nigra Dopaminergic Neurons
Authors: Scroggs Reese S. , Cardenas Carla G. , Whittaker Joseph A. , Kitai Stephen T.
Published: December 2017

The effect of muscarine on Ca2+dependent electrical activity was studied in dopamine (DA) neurons located in the substantia nigra pars compacta (SNc) in brain slices from young rats, using sharp electrodes. In most DA neurons tested, muscarine (50 μM) reduced the amplitude of spontaneous oscillatory potentials and evoked Ca2+-dependent potentials recorded in the presence of TTX. Muscarine also reduced the amplitude of the slow afterhyperpolarization (sAHP) following action potentials in most DA neurons. These data suggest that muscarine reduces Ca2+entry in SNc DA neurons. The reduction of the amplitude of the sAHP by muscarine in DA neurons may facilitate bursting initiated by glutamatergic input by increasing the frequency at which DA neurons can fire. The reduction of the sAHP via activation of muscarinic receptors in vivo may provide a mechanism whereby cholinergic inputs to DA neurons from the tegmental peduncular pontine nucleus could modulate dopamine release at dopaminergic targets in the brain.
Interaction of Dopamine D1 and NMDA Receptors Mediates Acute Clozapine Potentiation of Glutamate EPSPs in Rat Prefrontal Cortex
Authors: Chen Long , Yang Charles R.
Published: December 2017

The atypical antipsychotic drug clozapine effectively alleviates both negative and positive symptoms of schizophrenia via unclear cellular mechanisms. Clozapine may modulate both glutamatergic and dopaminergic transmission in the prefrontal cortex (PFC) to achieve part of its therapeutic actions. Using whole cell patch-clamp techniques, current-clamp recordings in layers V–VI pyramidal neurons from rat PFC slices showed that stimulation of local afferents (in 2 μM bicuculline) evoked mixed [AMPA/kainate and N-methyl-d-aspartate (NMDA) receptors] glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs). Clozapine (1 μM) potentiated polysynaptically mediated evoked EPSPs ( V Hold = −65 mV), or reversed EPSPs (rEPSP, V Hold = +20 mV) for >30 min. The potentiated EPSPs or rEPSPs were attenuated by elevating [Ca2+]O(7 mM), by application of NMDA receptor antagonist 2-amino5-phosphonovaleric acid (50 μM), or by pretreatment with dopamine D1/D5 receptor antagonist SCH23390 (1 μM) but could be further enhanced by a dopamine reuptake inhibitor bupropion (1 μM). Clozapine had no significant effect on pharmacologically isolated evoked NMDA-rEPSP or AMPA-rEPSPs but increased spontaneous EPSPs without changing the steady-state resting membrane potential. Under voltage clamp, clozapine (1 μM) enhanced the frequency, and the number of low-amplitude (5–10 pA) AMPA receptor-mediated spontaneous EPSCs, while there was no such changes with the mini-EPSCs (in 1 μM TTX). Taken together these data suggest that acute clozapine can increase spike-dependent presynaptic release of glutamate and dopamine. The glutamate stimulates distal dendritic AMPA receptors to increase spontaneous EPSCs and enabled a voltage-dependent activation of neuronal NMDA receptors. The dopamine released stimulates postsynaptic D1 receptor to modulate a lasting potentiation of the NMDA receptor component of the glutamatergic synaptic responses in the PFC neuronal network. This sequence of early synaptic events induced by acute clozapine may comprise part of the activity that leads to later cognitive improvement in schizophrenia.
Quantification of Gastric Mill Network Effects on a Movement Related Parameter of Pyloric Network Output in the Lobster
Authors: Thuma Jeff B. , Hooper Scott L.
Published: December 2017

It has long been known that gastric mill network activity (cycle period 5–10 s) alters pyloric network output (cycle period approximately 1 s), but these effects have not been quantified. Many pyloric muscles extract gastric mill timed variations in pyloric motor neuron firing, and consequently produce gastric mill timed movements even though no gastric mill neurons innervate them. Determining pyloric behavior therefore requires detailed description of gastric mill effects on pyloric neural output. Pyloric muscle activity correlates well with motor neuron overall spike frequency (OSF, burst spike number divided by cycle period). We quantified OSF variation of all pyloric neurons as a function of time into the gastric mill cycle [as measured from the beginning of Gastric Mill (GM) neuron bursts] in the lobster, Panulirus interruptus. No repeating pattern within individual gastric mill cycles of Lateral Pyloric (LP) and Ventricular Dilator (VD) neuron OSF was visually apparent. Averaged data showed that VD and LP neuron OSF decreased (approximately 0.5 and 1.5 Hz, respectively) at the beginning of each gastric mill cycle. Visually apparent patterns of OSF waxing and waning within each gastric mill cycle were present for the Inferior Cardiac (IC), Pyloric Dilator (PD), and Pyloric (PY) neurons. However, when averaged as a function of phase or delay in the gastric mill cycle, the average changes were smaller than those in individual gastric mill cycles because when the OSF variations occurred varied considerably in different gastric mill cycles. We therefore used a “pattern-based” analysis in which an identifying characteristic of each neuron's repeating OSF variation pattern was defined as pattern pyloric cycle zero. The pyloric cycles in each repetition of the OSF variation pattern were numbered relative to the zero cycle, and averaged to create an average OSF variation profile. The zero cycle delays relative to GM neuron burst beginning were then averaged to determine when in the gastric mill cycle the profile occurred. This technique preserved the full extent of pyloric neuron OSF changes. Maximum PY neuron OSF occurred within the GM neuron burst, whereas maximum IC and PD neuron OSF occurred during the GM neuron interburst interval. Despite these changes, pyloric cycling did not phase lock with gastric mill activity, nor were an integer number of pyloric cycles present in each gastric mill cycle. In addition to providing data necessary to predict pyloric movement, this work shows how pattern-based analysis can successfully quantify interactions between nonphase-locked networks.
Layer I Ectopias and Increased Excitability in Murine Neocortex
Authors: Gabel Lisa A. , LoTurco Joseph J.
Published: December 2017

Cortical dysplasias are associated with both epilepsy and cognitive impairments in humans. Similarly, several animal models of cortical dysplasia show that dysplasia causes increased seizure susceptibility and behavioral deficits in vivo and increased levels of excitability in vitro. As most current animal models involve either global disruptions in cortical architecture or the induction of lesions, it is not yet clear whether small spontaneous neocortical malformations are also associated with increased excitability or seizure susceptibility. Small groups of displaced neurons in layer I of the neocortex, ectopias, have been identified in patients with cognitive impairments, and similar malformations occur sporadically in some inbred lines of mice where they are associated with behavioral and sensory-processing deficits. In a previous study, we characterized the physiology of cells within neocortical ectopias, in one of the inbred lines (NXSM-D/Ei) and showed that the presence of multiple ectopias is associated with the generation of spontaneous epileptiform activity in slices. In this study, we use extracellular recordings from brain slices to show that even single-layer I ectopias are associated with higher excitability. Specifically, slices that contain single ectopias display epileptiform activity at significantly lower concentrations of the GABAA receptor antagonist bicuculline than do slices without ectopias (either from opposite hemispheres or animals without ectopias). Moreover, because removal of ectopias from slices does not restore normal excitability, enhanced excitability is not generated within the ectopia. Finally, we show that in vivo, mice with ectopias are more sensitive to the convulsant pentylenetetrazole than are mice without ectopias. Together these results suggest that alterations in cortical hemispheres containing focal layer I malformations increase cortical excitability and that even moderately small spontaneous cortical dysplasias are associated with increased excitability in vitro and in vivo.