bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting Neuronal Activity in the Dorsal and Ventral Premotor Areas During Preparation to Reach
Authors: Hoshi Eiji , Tanji Jun
Published: May 2017

We compared neuronal activity in the dorsal and ventral premotor areas (PMd and PMv, respectively) when monkeys were preparing to perform arm-reaching movements in a motor-set period before their actual execution. They were required to select one of four possible movements (reaching to a target on the left or right, using either the left or right arm) in accordance with two sets of instruction cues, followed by a delay period, and a subsequent motor-set period. During the motor-set period, the monkeys were required to get ready for a movement-trigger signal to start the arm-reach promptly. We analyzed the activity of 211 PMd and 109 PMv neurons that showed selectivity for the combination of the two instruction cues during the motor-set period. A majority (53%) of PMd neurons exhibited activity significantly tuned to both target location and arm use, and an approximately equal number of PMd neurons showed selectivity to either forthcoming arm use or target location. In contrast, 60% of PMv neurons showed selectivity for target location only and not for arm use. These findings point to preference in the use of neuronal activity in the two areas: preparation for action in the PMd and preparation for target acquisition in the PMv.
Myocardial Ischemia Recruits Mechanically Insensitive Cardiac Sympathetic Afferents in Cats
Authors: Pan Hui-Lin , Chen Shao-Rui
Published: May 2017

Chest pain caused by myocardial ischemia is mediated by cardiac sympathetic afferents. Although silent nociceptors exist in somatic structures and some visceral organs, their presence in the heart remains uncertain. The present study examined the presence and the functional characteristics of mechanically insensitive cardiac sympathetic afferents using an electrical search technique. Single-unit activity of afferents innervating the left ventricle was recorded from the sympathetic chain in anesthetized cats. Cardiac afferents were identified initially with a stimulating electrode placed on the surface of the heart. Responses of cardiac afferents to mechanical stimuli, 5 min of myocardial ischemia, and topical application of bradykinin (1–10 μg/ml) and lactic acid (10–50 μg/ml) were then determined. Ischemia activated all 38 mechanically insensitive afferents and 17 of 25 mechanically sensitive afferents. The mechanically sensitive afferents typically were spontaneously active and had a smaller receptive field and a slightly faster conduction velocity. On the other hand, the mechanically insensitive afferents were slow conducting C fibers and had a large electrical receptive field on the epicardium. The response of 38 mechanically insensitive afferents to ischemia [2.83 ± 0.14 (SD) imp/s] was significantly greater than that of 17 mechanically sensitive afferents (from 0.41 ± 0.05 to 0.74 ± 0.15 imp/s). The mechanically insensitive afferents also exhibited a greater response to topical application of bradykinin or lactic acid in a concentration-dependent manner. This study provides important new evidence that the heart is innervated by silent sympathetic afferents, which are activated profoundly by myocardial ischemia. These data also suggest that the mechanically insensitive sympathetic afferents may function as cardiac nociceptors.
Functional Independence of Layer IV Barrels
Authors: Laaris Nora , Keller Asaf
Published: May 2017

Our aim was to investigate the patterns of functional inputs and outputs from individual barrels in the mouse somatosensory cortex, and to test the hypothesis that individual barrels in layer IV are functionally independent of direct inputs from neighboring barrels. In a mouse in vitro slice preparation of the barrel cortex, we recorded voltage-sensitive dye signals evoked in response to microstimulation of a single barrel. Activity propagated from the stimulated barrel to the supragranular layers, where it spread to activate several barrel columns. However, in no instance did activity propagate directly from the stimulated barrel to neighboring barrels. Neither suppression of GABAergic inhibition, nor activation of N-methyl-d-aspartate receptors, revealed direct interbarrel interactions. By contrast, microstimulation in the supra- or infragranular layers resulted in direct propagation of activity to neighboring barrel columns. We conclude that the neurons within individual barrels are functionally independent of direct inputs from neighboring barrels. This suggests that the response properties of layer IV barrel neurons are shaped primarily by their presynaptic thalamic afferents and by intrabarrel interactions, and that these responses are independent of direct inputs from neighboring barrels.
Cerebellar Nodulectomy Impairs Spatial Memory of Vestibular and Optokinetic Stimulation in Rabbits
Authors: Barmack N. H. , Errico P. , Ferraresi A. , Fushiki H. , Pettorossi V. E. , Yakhnitsa V.
Published: May 2017

Natural vestibular and optokinetic stimulation were used to investigate the possible role of the cerebellar nodulus in the regulation and modification of reflexive eye movements in rabbits. The nodulus and folium 9d of the uvula were destroyed by surgical aspiration. Before and after nodulectomy the vertical and horizontal vestibuloocular reflexes (VVOR, HVOR) were measured during sinusoidal vestibular stimulation about the longitudinal (roll) and vertical (yaw) axes. Although the gain of the HVOR (GHVOR = peak eye movement velocity/peak head velocity) was not affected by the nodulectomy, the gain of the VVOR (GVVOR) was reduced. The gains of the vertical and horizontal optokinetic reflexes (GVOKR, GHOKR) were measured during monocular, sinusoidal optokinetic stimulation (OKS) about the longitudinal and vertical axes. Following nodulectomy, there was no reduction in GVOKR or GHOKR. Long-term binocular OKS was used to generate optokinetic afternystagmus, OKAN II, that lasts for hours. After OKAN II was induced, rabbits were subjected to static pitch and roll, to determine how the plane and velocity of OKAN II is influenced by a changing vestibular environment. During static pitch, OKAN II slow phase remained aligned with earth-horizontal. This was true for normal and nodulectomized rabbits. During static roll, OKAN II remained aligned with earth-horizontal in normal rabbits. During static roll in nodulectomized rabbits, OKAN II slow phase developed a centripetal vertical drift. We examined the suppression and recovery of GVVOR following exposure to conflicting vertical OKS for 10–30 min. This vestibular-optokinetic conflict reduced GVVOR in both normal and nodulectomized rabbits. The time course of recovery of GVVOR after conflicting OKS was the same before and after nodulectomy. In normal rabbits, the head pitch angle, at which peak OKAN II velocity occurred, corresponded to the head pitch angle maintained during long-term OKS. If the head was maintained in a “pitched-up” or “pitched-down” orientation during long-term OKS, the subsequently measured OKAN II peak velocity occurred at the same orientation. This was not true for nodulectomized rabbits, who had OKAN II peak velocities at head pitch angles independent of those maintained during long-term OKS. We conclude that the nodulus participates in the regulation of compensatory reflexive movements. The nodulus also influences “remembered” head position in space derived from previous optokinetic and vestibular stimulation.
Changes in Gene Expression and Neuronal Phenotype in Brain Stem Pain Modulatory Circuitry After Inflammation
Authors: Miki Kenji , Zhou Q.-Q. , Guo W. , Guan Y. , Terayama R. , Dubner R. , Ren K.
Published: May 2017

Recent studies indicate that descending pain modulatory pathways undergo time-dependent changes in excitability following inflammation involving both facilitation and inhibition. The cellular and molecular mechanisms of these phenomena are unclear. In the present study, we examined N-methyl-d-aspartate (NMDA) receptor gene expression and neuronal activity in the rostral ventromedial medulla (RVM), a pivotal structure in pain modulatory circuitry, after complete Freund's adjuvant (CFA)-induced hindpaw inflammation. The reverse transcription polymerase chain reaction analysis indicated that there was an upregulation of mRNAs encoding NMDA receptor subunits in the RVM after inflammation. The increase in the NR1, NR2A, and NR2B receptor mRNAs started at 5 h, maintained for 1–7 days ( P< 0.05–0.001) and returned to the control level at 14 days after inflammation. Western blot analysis indicated that the protein translation products of the NR2A subunit were also increased ( P < 0.01). In single-unit extracellular recordings, we correlated RVM neuronal activity with the paw withdrawal response in rats with inflammation. We describe these RVM cells as on-, off-, and neutral-like cells because of their similarity to previous studies in which neuronal responses were correlated with tail-flick nocifensive behavior in the absence of inflammation. In contrast to previous studies in the absence of inflammation, using tail flick as a behavioral correlate, fewer off-like cells in naı̈ve animals exhibited a complete pause before the paw withdrawal to a noxious thermal stimulus. The percentage of cells showing a pause of activity after noxious stimulation was further reduced after inflammation (χ2 P < 0.0001 vs. naı̈ve rats). Continuous neuronal recordings (3–6.5 h) revealed a phenotypic switch of RVM neurons during the development of inflammation: 11/15 neutral-like cells initially unresponsive to noxious stimuli exhibited and maintained response profiles characteristic of pain modulatory neurons (became off-like: n = 5; became on-like: n = 6). Neutral-like cells recorded in noninflamed animals did not show response profile changes during continuous recordings (5–5.5 h, n = 7). A population study ( n = 165) confirmed an increase in on- and off-like cells and a decrease in neutral-like cells at 24 h after inflammation as compared with naı̈ve rats ( P < 0.001). These results suggest that enhanced NMDA receptor activation mediates time-dependent changes in excitability of RVM pain modulatory circuitry. The functional phenotypic switch of RVM neurons provides a novel mechanism underlying activity-dependent plasticity and enhanced net descending inhibition after inflammation.
Distance-Dependent Ni2+-Sensitivity of Synaptic Plasticity in Apical Dendrites of Hippocampal CA1 Pyramidal Cells
Authors: Isomura Yoshikazu , Fujiwara-Tsukamoto Yoko , Imanishi Michiko , Nambu Atsushi , Takada Masahiko
Published: May 2017

Low concentration of Ni2+, a T- and R-type voltage-dependent calcium channel (VDCC) blocker, is known to inhibit the induction of long-term potentiation (LTP) in the hippocampal CA1 pyramidal cells. These VDCCs are distributed more abundantly at the distal area of the apical dendrite than at the proximal dendritic area or soma. Therefore we investigated the relationship between the Ni2+-sensitivity of LTP induction and the synaptic location along the apical dendrite. Field potential recordings revealed that 25 μM Ni2+ hardly influenced LTP at the proximal dendritic area (50 μm distant from the somata). In contrast, the same concentration of Ni2+ inhibited the LTP induction mildly at the middle dendritic area (150 μm) and strongly at the distal dendritic area (250 μm). Ni2+ did not significantly affect either the synaptic transmission at the distal dendrite or the burst-firing ability at the soma. However, synaptically evoked population spikes recorded near the somata were slightly reduced by Ni2+ application, probably owing to occlusion of dendritic excitatory postsynaptic potential (EPSP) amplification. Even when the stimulating intensity was strengthened sufficiently to overcome such a reduction in spike generation during LTP induction, the magnitude of distal LTP was not significantly recovered from the Ni2+-dependent inhibition. These results suggest that Ni2+ may inhibit the induction of distal LTP directly by blocking calcium influx through T- and/or R-type VDCCs. The differentially distributed calcium channels may play a critical role in the induction of LTP at dendritic synapses of the hippocampal pyramidal cells.
Auditory Thalamocortical Synaptic Transmission In Vitro
Authors: Cruikshank Scott J. , Rose Heather J. , Metherate Raju
Published: May 2017

To facilitate an understanding of auditory thalamocortical mechanisms, we have developed a mouse brain-slice preparation with a functional connection between the ventral division of the medial geniculate (MGv) and the primary auditory cortex (ACx). Here we present the basic characteristics of the slice in terms of physiology (intracellular and extracellular recordings, including current source density analysis), pharmacology (including glutamate receptor involvement), and anatomy (gross anatomy, Nissl, parvalbumin immunocytochemistry, and tract tracing with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate). Thalamocortical transmission in this preparation (the “primary” slice) involves both α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid/kainate and N-methyl-d-aspartate-type glutamate receptors that appear to mediate monosynaptic inputs to layers 3-4 of ACx. MGv stimulation also initiates disynaptic inhibitory postsynaptic potentials and longer-duration intracortical, polysynaptic activity. Important differences between responses elicited by MGv versus conventional columnar (“on-beam”) stimulation emphasize the necessity of thalamic activation to infer thalamocortical mechanisms. We also introduce a second slice preparation, the “shell” slice, obtained from the brain region immediately ventral to the primary slice, that may contain a nonprimary thalamocortical pathway to temporal cortex. In the shell slice, stimulation of the thalamus or the region immediately ventral to it appears to produce fast activation of synapses in cortical layer 1 followed by robust intracortical polysynaptic activity. The layer 1 responses may result from orthodromic activation of nonprimary thalamocortical pathways; however, a plausible alternative could involve antidromic activation of corticotectal neurons and their layer 1 collaterals. The primary and shell slices will provide useful tools to investigate mechanisms of information processing in the ACx.
Neural Correlates of the Precedence Effect in the Inferior Colliculus: Effect of Localization Cues
Authors: Litovsky R. Y. , Delgutte B.
Published: May 2017

The precedence effect (PE) is an auditory phenomenon involved in suppressing the perception of echoes in reverberant environments, and is thought to facilitate accurate localization of sound sources. We investigated physiological correlates of the PE in the inferior colliculus (IC) of anesthetized cats, with a focus on directional mechanisms for this phenomenon. We used a virtual space (VS) technique, where two clicks (a “lead” and a “lag”) separated by a brief time delay were each filtered through head-related transfer functions (HRTFs). For nearly all neurons, the response to the lag was suppressed for short delays and recovered at long delays. In general, both the time course and the directional patterns of suppression resembled those reported in free-field studies in many respects, suggesting that our VS simulation contained the essential cues for studying PE phenomena. The relationship between the directionality of the response to the lead and that of its suppressive effect on the lag varied a great deal among IC neurons. For a majority of units, both excitation produced by the lead and suppression of the lag response were highly directional, and the two were similar to one another. For these neurons, the long-lasting inhibitory inputs thought to be responsible for suppression seem to have similar spatial tuning as the inputs that determine the excitatory response to the lead. Further, the behavior of these neurons is consistent with psychophysical observations that the PE is strongest when the lead and the lag originate from neighboring spatial locations. For other neurons, either there was no obvious relationship between the directionality of the excitatory lead response and the directionality of suppression, or the suppression was highly directional whereas the excitation was not, or vice versa. For these neurons, the excitation and the suppression produced by the lead seem to depend on different mechanisms. Manipulation of the directional cues (such as interaural time and level differences) contained in the lead revealed further dissociations between excitation and suppression. Specifically, for about one-third of the neurons, suppression depended on different directional cues than did the response to the lead, even though the directionality of suppression was similar to that of the lead response when all cues were present. This finding suggests that the inhibitory inputs causing suppression may originate in part from subcollicular auditory nuclei processing different directional cues than the inputs that determine the excitatory response to the lead. Neurons showing such dissociations may play an important role in the PE when the lead and the lag originate from very different directions.
Differential Roles for mGluR1 and mGluR5 in the Persistent Prolongation of Epileptiform Bursts
Authors: Merlin Lisa R.
Published: May 2017

Transient activation of group I metabotropic glutamate receptors (mGluRs) with the selective agonist ( S)-3,5-dihydroxyphenylglycine (DHPG) produces persistent prolongation of epileptiform bursts in guinea pig hippocampal slices, the maintenance of which can be reversibly suppressed with group I mGluR antagonists. To determine the relative roles of mGluR1 and mGluR5 in these group I mGluR-dependent induction and maintenance processes, subtype-selective antagonists were utilized. In the presence of picrotoxin, DHPG (50 μM, 20–45 min) converted interictal bursts into 1- to 3-s discharges that persisted for hours following washout of the mGluR agonist. 2-methyl-6-(phenylethynyl)-pyridine (MPEP, an mGluR5 antagonist; 25 μM) and (+)-2-methyl-4-carboxyphenylglycine (LY367385, an mGluR1 antagonist; 20–25 μM) each significantly suppressed the ongoing expression of the mGluR-induced prolonged bursts. However, LY367385 was more effective, reducing the burst prolongation by nearly 90%; MPEP only produced a 64% reduction in burst prolongation. Nevertheless, MPEP was more effective at preventing the induction of the burst prolongation; all 10 slices tested failed to express prolonged bursts both during and after co-application of DHPG with MPEP. Co-application of DHPG with LY367385, in contrast, resulted in significant burst prolongation (in 68% of slices tested) that was revealed on washout of the two agents. These results suggest that while both receptor subtypes participate in both the induction and maintenance of mGluR-mediated burst prolongation, mGluR1 activation plays a greater role in sustaining the expression of prolonged bursts, whereas mGluR5 activation may be a more critical contributor to the induction process underlying this type of epileptogenesis.
Transfer of Podokinetic Adaptation From Stepping to Hopping
Authors: Earhart Gammon M. , Melvill Jones G. , Horak F. B. , Block E. W. , Weber K. D. , Fletcher W. A.
Published: May 2017

Following stepping in-place on the surface of a rotating circular treadmill, a subject attempting to step in-place or walk in a straight line across the floor without vision will rotate relative to space. This adaptation, termed podokinetic after-rotation (PKAR), transfers to backward walking following forward walking on the rotating disk. We asked whether adaptation obtained during stepping in-place on the rotating disk would transfer to hopping on both feet. We hypothesized that subjects would demonstrate PKAR during both hopping and stepping, adding support to the hypothesis that PKAR is a centrally mediated adaptation of general locomotor trajectory that is not specific to the form of locomotion used while on the rotating disk. Subjects demonstrated PKAR during both hopping and stepping after stepping in-place on the rotating disk. The time courses of PKAR during hopping and stepping were similar, although the angular velocity amplitude of PKAR was lower in hopping than in stepping. This difference in amplitude suggests an incomplete transfer of PKAR.
Morphological and Electrophysiological Evidence for an Ionotropic GABA Receptor of Novel Pharmacology
Authors: Shen D.-W. , Higgs M. H. , Salvay D. , Olney J. W. , Lukasiewicz P. D. , Romano C.
Published: May 2017

Evidence from toxicological studies suggested that an ionotropic GABA receptor of novel pharmacology (picrotoxin-insensitive, bicuculline-sensitive) exists in the chick embryo retina. In this report, we provide direct morphological and electrophysiological evidence for the existence of such an iGABA receptor. Chick embryo retinas (14–16 days old) incubated in the presence of kainic acid showed pronounced histopathology in all retinal layers. Maximal protection from this toxicity required a combination of bicuculline and picrotoxin. Individual application of the antagonists indicated that a picrotoxin-insensitive, bicuculline-sensitive GABA receptor is likely to be present on ganglion and amacrine, but not bipolar, cells. GABA currents in embryonic and mature chicken retinal neurons were measured by whole cell patch clamp. GABA was puffed at the dendritic processes in the IPL. Picrotoxin (500 μM, in the bath) eliminated all (>95%) the GABA current in the majority of ganglion and amacrine cells tested, but many cells possessed a substantial picrotoxin-insensitive component. This current was eliminated by bicuculline (200 μM). This current was not a transporter-associated current, since it was not altered by GABA transport blockers or sodium removal. The current–voltage relation was linear and reversed near E Cl, as expected for a ligand-gated chloride current. Both pentobarbital and lorazepam enhanced the picrotoxin-insensitive current. We conclude that chicken retinal ganglion and amacrine cells express a GABA receptor that is GABA-A–like, in that it can be blocked by bicuculline, and positively modulated by barbiturates and benzodiazepines, but is insensitive to the noncompetitive blocker picrotoxin. Understanding the molecular properties of this receptor will be important for understanding both physiological GABA neurotransmission and the pathology of GABA receptor overactivation.
Modulation of Somatodendritic Dopamine Release by Endogenous H2O2: Susceptibility in Substantia Nigra But Resistance in VTA
Authors: Chen Billy T. , Avshalumov Marat V. , Rice Margaret E.
Published: May 2017

We showed previously that dopamine (DA) release in dorsal striatum is inhibited by endogenously generated hydrogen peroxide (H2O2). Here, we examined whether endogenous H2O2 can also modulate somatodendritic DA release in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), with companion measurements in DA terminal regions. Evoked DA release was monitored in brain slices using carbon-fiber microelectrodes with fast-scan cyclic voltammetry. Exogenous H2O2decreased DA release by 50–60% in SNc and VTA but only by 35% in nucleus accumbens. Whether endogenous H2O2 also modulated somatodendritic release was examined using the glutathione peroxidase inhibitor, mercaptosuccinate (MCS), which should increase stimulation-evoked H2O2levels. In the presence of MCS, DA release was suppressed by 30–40% in SNc as well as in dorsal striatum and nucleus accumbens. In striking contrast, DA release in the VTA was unaffected by MCS. These data are consistent with stronger H2O2 regulation or lower H2O2 generation in VTA than in the other regions. Importantly, oxidative stress has been linked causally to Parkinson's disease, in which DA cells in SNc degenerate, but VTA cells are spared. The present data suggest that differences in oxidant regulation or generation between SNc and VTA could contribute to this.
A Cortical Network Sensitive to Stimulus Salience in a Neutral Behavioral Context Across Multiple Sensory Modalities
Authors: Downar Jonathan , Crawley Adrian P. , Mikulis David J. , Davis Karen D.
Published: May 2017

Stimulus salience depends both on behavioral context and on other factors such as novelty and frequency of occurrence. The temporo-parietal junction (TPJ) responds preferentially to behaviorally relevant stimuli and is thought to play a general role in detecting salient stimuli. If so, it should respond preferentially to novel or infrequent events, even in a neutral behavioral context. To test this hypothesis, we used event-related functional magnetic resonance imaging (fMRI) to identify brain regions sensitive to the novelty of visual, auditory, and tactile stimuli during passive observation. Cortical regions with a greater response to novel than familiar stimuli across all modalities were identified at two sites in the TPJ region: the supramarginal gyrus (SMG) and superior temporal gyrus. The right inferior frontal gyrus (IFG), right anterior insula, left anterior cingulate cortex (ACC), and left inferior temporal gyrus also showed sensitivity to novelty. The novelty-sensitive TPJ activation in SMG overlaps a region previously identified as sensitive behavioral context. This region may play a general role in identifying salient stimuli, whether the salience is due to the current behavioral context or not. The IFG activation overlaps regions previously identified as responsive to nonnovel sensory events regardless of behavioral context. The IFG may therefore play a general role in stimulus evaluation rather than a specific role in identifying novel stimuli. The ACC activation lies in a region active during complex response-selection tasks, suggesting a general role in detecting and/or planning responses to salient events. A frontal-parietal-cingulate network may serve to identify and evaluate salient sensory stimuli in general.
Effects of K+ Channel Blockers on Developing Rat Myelinated CNS Axons: Identification of Four Types of K+Channels
Authors: Devaux Jerome , Gola Maurice , Jacquet Guy , Crest Marcel
Published: May 2017

Four blockers of voltage-gated potassium channels (Kv channels) were tested on the compound action potentials (CAPs) of rat optic nerves in an attempt to determine the regulation of Kv channel expression during the process of myelination. Before myelination occurred, 4-aminopyridine (4-AP) increased the amplitude, duration, and refractory period of the CAPs. On the basis of their pharmacological sensitivity, 4-AP-sensitive channels were divided in two groups, the one sensitive to kaliotoxin (KTX), dendrotoxin-I (DTX-I), and 4-AP, and the other sensitive only to 4-AP. In addition, tetraethylammonium chloride (TEA) applied alone broadened the CAPs. At the onset of myelination, DTX-I induced a more pronounced effect than KTX; this indicates that a fourth group of channels sensitive to 4-AP and DTX-I but insensitive to KTX had developed. The effects of KTX and DTX-I gradually disappeared during the period of myelination. Electron microscope findings showed that the disappearance of these effects was correlated with the ongoing process of myelination. This was confirmed by the fact that DTX-I and KTX enlarged the CAPs of demyelinated adult optic nerves. These results show that KTX- and DTX-sensitive channels are sequestrated in paranodal regions. During the process of myelination, KTX had less pronounced effects than DTX-I on demyelinated nerves, which suggests that the density of the KTX-sensitive channels decreased during this process. By contrast, 4-AP increased the amplitude, duration, and refractory period of the CAPs at all the ages tested and to a greater extent than KTX and DTX-I. The effects of TEA alone also gradually disappeared during this period. However, effects of TEA on CAPs were observed when this substance was applied after 4-AP to the adult optic nerve; this shows that TEA-sensitive channels are not masked by the myelin sheath. In conclusion, the process of myelination seems to play an important part in the regulation and setting of Kv channels in optic nerve axons.
Calcium Signaling at Single Mossy Fiber Presynaptic Terminals in the Rat Hippocampus
Authors: Liang Yong , Yuan Li-Lian , Johnston Daniel , Gray Richard
Published: May 2017

We investigated internal Ca2+release at mossy fiber synapses on CA3 pyramidal neurons (mossy fiber terminals, MFTs) in the hippocampus. Presynaptic Ca2+influx was induced by giving a brief train of 20 stimuli at 100 Hz to the mossy fiber pathway. Using Ca2+imaging techniques, we recorded the Ca2+response as Δ F/ F,which increased rapidly with stimulation, but was often accompanied by a delayed peak that occurred after the train. The rise in presynaptic [Ca2+] could be completely blocked by application of 400 μM Cd2+. Furthermore, the evoked Ca2+signals were reduced by group II mGluR agonists. Under the same experimental conditions, we investigated the effects of several agents on MFTs that disrupt regulation of intracellular Ca2+stores resulting in depletion of internal Ca2+. We found that ryanodine, cyclopiazonic acid, thapsigargin, and ruthenium red all decreased both the early and the delayed increase in the Ca2+signals. We applied d,l-2-amino-5-phosphonovaleric acid (d,l-APV; 50 μM) and 6,7-Dinitroquinoxaline-2,3-dione (DNQX; 20 μM) to exclude the action of N-methyl-d-aspartate (NMDA) and non-NMDA receptors. Experiments with alternative lower affinity indicators for Ca2+(fura-2FF and calcium green-2) and the transient K+channel blocker, 4-aminopyridine were performed to control for the possible saturation of fura-2. Taken together, these results strongly support the hypothesis that the recorded terminals were from the mossy fibers of the dentate gyrus and suggest that a portion of the presynaptic Ca2+signal in response to brief trains of stimuli is due to release of Ca2+from internal stores.
Partial Ablations of the Flocculus and Ventral Paraflocculus in Monkeys Cause Linked Deficits in Smooth Pursuit Eye Movements and Adaptive Modification of the VOR
Authors: Rambold H. , Churchland A. , Selig Y. , Jasmin L. , Lisberger S. G.
Published: May 2017

The vestibuloocular reflex (VOR) generates compensatory eye movements to stabilize visual images on the retina during head movements. The amplitude of the reflex is calibrated continuously throughout life and undergoes adaptation, also called motor learning, when head movements are persistently associated with image motion. Although the floccular-complex of the cerebellum is necessary for VOR adaptation, it is not known whether this function is localized in its anterior or posterior portions, which comprise the ventral paraflocculus and flocculus, respectively. The present paper reports the effects of partial lesions of the floccular-complex in five macaque monkeys, made either surgically or with stereotaxic injection of 3-nitropropionic acid (3-NP). Before and after the lesions, smooth pursuit eye movements were tested during sinusoidal and step-ramp target motion. Cancellation of the VOR was tested by moving a target exactly with the monkey during sinusoidal head rotation. The control VOR was tested during sinusoidal head rotation in the dark and during 30°/s pulses of head velocity. VOR adaptation was studied by having the monkeys wear ×2 or ×0.25 optics for 4–7 days. In two monkeys, bilateral lesions removed all of the flocculus except for parts of folia 1 and 2 but did not produce any deficits in smooth pursuit, VOR adaptation, or VOR cancellation. We conclude that the flocculus alone probably is not necessary for either pursuit or VOR learning. In two monkeys, unilateral lesions including a large fraction of the ventral paraflocculus produced small deficits in horizontal and vertical smooth pursuit, and mild impairments of VOR adaptation and VOR cancellation. We conclude that the ventral paraflocculus contributes to both behaviors. In one monkey, a bilateral lesion of the flocculus and ventral paraflocculus produced severe deficits smooth pursuit and VOR cancellation, and a complete loss of VOR adaptation. Considering all five cases together, there was a strong correlation between the size of the deficits in VOR learning and pursuit. We found the strongest correlation between the behavior deficits and the size of the lesion of the ventral paraflocculus, a weaker but significant correlation for the full floccular complex, and no correlation with the size of the lesion of the flocculus. We conclude that 1) lesions of the floccular complex cause linked deficits in smooth pursuit and VOR adaptation, and 2) the relevant portions of the structure are primarily in the ventral paraflocculus, although the flocculus may participate.
Motor Facilitation While Observing Hand Actions: Specificity of the Effect and Role of Observer's Orientation
Authors: Maeda Fumiko , Kleiner-Fisman Galit , Pascual-Leone Alvaro
Published: May 2017

Action observation enhances cortico-spinal excitability. Here we tested the specificity of this effect and the role played by the orientation of the observer. Ten normal subjects observed video clips of right hand performing three different finger movements ( thumb ab-/adduction, index ab-/adduction, index extens-/flexion) in two different orientations ( Away, i.e., natural hand-orientation facing out from the observer; or Toward, i.e., unnatural hand-orientation facing toward the observer). Motor-evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS) were recorded from the abductor pollicis brevis (APB) and the first dorsal interosseus (FDI) muscles. Movement direction of the index finger was recorded using force transducers. Facilitation of MEP size was significantly greater for APB during observation of thumb movements and for FDI during observation of index finger movements. Facilitation of MEP size was significantly greater when the hand presented on screen was facing out from and corresponding to that of the observer (Away orientation). The direction of the index finger movement evoked by TMS shifted toward extension/flexion versus ab-/adduction matching the observed movement. Our results give further evidence that observation of a movement enhances motor output to the muscles involved in the movement and facilitates the observed action. In addition, we provide novel evidence about the high degree of specificity of this observation-induced motor cortical modulation. The degree of modulation depends on hand orientation. The modulation is maximal when the observed action corresponds to the orientation of the observer.
On the Interaction Between Voltage-Gated Conductances and Ca2+Regulation Mechanisms in Retinal Horizontal Cells
Authors: Hayashida Yuki , Yagi Tetsuya
Published: May 2017

The horizontal cell is a second-order retinal neuron that is depolarized in the dark and responds to light with graded potential changes. In such a nonspiking neuron, not only the voltage-gated ionic conductances but also Ca2+regulation mechanisms, e.g., the Na+/Ca2+exchange and the Ca2+pump, are considered to play important roles in generating the voltage responses. To elucidate how these physiological mechanisms interact and contribute to generating the responses of the horizontal cell, physiological experiments and computer simulations were made. Fura-2 fluorescence measurements made on dissociated carp horizontal cells showed that intracellular Ca2+concentration ([Ca2+]i) was maintained <100 nM in the resting state and increased with an initial transient to settle at a steady level of ≃600 nM during prolonged applications of l-glutamate (l-glu, 100 μM). A preapplication of caffeine (10 mM) partially suppressed the initial transient of [Ca2+]iinduced by l-glu but did not affect thel-glu-induced steady [Ca2+]i. This suggests that a part of the initial transient can be explained by the Ca2+-induced Ca2+release from the caffeine-sensitive Ca2+store. The Ca2+regulation mechanisms and the ionic conductances found in the horizontal cell were described by model equations and incorporated into a hemi-spherical cable model to simulate the isolated horizontal cell. The physiological ranges of parameters of the model equations describing the voltage-gated conductances, the glutamate-gated conductance and the Na+/Ca2+exchange were estimated by referring to previous experiments. The parameters of the model equation describing the Ca2+pump were estimated to reproduce the steady levels of [Ca2+]imeasured by Fura-2 fluorescence measurements. Using the cable model with these parameters, we have repeated simulations so that the voltage response and [Ca2+]ichange induced by l-glu applications were reproduced. The simulation study supports the following conclusions. 1) The Ca2+-dependent inactivation of the voltage-gated Ca2+conductance has a time constant of ∼2.86 s. 2) The falling phase of the [Ca2+]itransient induced by l-glu is partially due to the inactivation of the voltage-gated Ca2+conductance. 3) Intracellular Ca2+is extruded mainly by the Na+/Ca2+exchange when [Ca2+]iis more than ∼2 μM and by the Ca2+pump when [Ca2+]iis less than ∼1 μM. 4) In the resting state, the Na+/Ca2+exchange may operate in the reverse mode to induce Ca2+influx and the Ca2+pump extrudes intracellular Ca2+to counteract the influx. The model equations of physiological mechanisms developed in the present study can be used to elucidate the underlying mechanisms of the light-induced response of the horizontal cell in situ.
Calcium Waves and Closure of Potassium Channels in Response to GABA Stimulation in Hermissenda Type B Photoreceptors
Authors: Blackwell K. T.
Published: May 2017

Classical conditioning of Hermissenda crassicornisrequires the paired presentation of a conditioned stimulus (light) and an unconditioned stimulus (turbulence). Light stimulation of photoreceptors leads to production of diacylglycerol, an activator of protein kinase C, and inositol triphosphate (IP3), which releases calcium from intracellular stores. Turbulence causes hair cells to release GABA onto the terminal branches of the type B photoreceptor. One prior study has shown that GABA stimulation produces a wave of calcium that propagates from the terminal branches to the soma and raises the possibility that two sources of calcium are required for memory storage. GABA stimulation also causes an inhibitory postsynaptic potential (IPSP) followed by a late depolarization and increase in input resistance, whose cause has not been identified. A model was developed of the effect of GABA stimulation on the Hermissenda type B photoreceptor to evaluate the currents underlying the late depolarization and to evaluate whether a calcium wave could propagate from the terminal branches to the soma. The model included GABAA, GABAB, and calcium-sensitive potassium leak channels; calcium dynamics including release of calcium from intracellular stores; and the biochemical reactions leading from GABAB receptor activation to IP3 production. Simulations show that it is possible for a wave of calcium to propagate from the terminal branches to the soma. The wave is initiated by IP3-induced calcium release but propagation requires release through the ryanodine receptor channel where IP3 concentration is small. Wave speed is proportional to peak calcium concentration at the crest of the wave, with a minimum speed of 9 μm/s in the absence of IP3. Propagation ceases when peak concentration drops below 1.2 μM; this occurs if the rate of calcium pumping into the endoplasmic reticulum is too large. Simulations also show that both a late depolarization and an increase in input resistance occur after GABA stimulation. The duration of the late depolarization corresponds to the duration of potassium leak channel closure. Neither the late depolarization nor the increase in input resistance are observed when a transient calcium current and a hyperpolarization-activated current are added to the model as replacement for closure of potassium leak channels. Thus the late depolarization and input resistance elevation can be explained by a closure of calcium-sensitive leak potassium currents but cannot be explained by a transient calcium current and a hyperpolarization-activated current.
Evidence That the Superior Colliculus Participates in the Feedback Control of Saccadic Eye Movements
Authors: Soetedjo Robijanto , Kaneko Chris R. S. , Fuchs Albert F.
Published: May 2017

There is general agreement that saccades are guided to their targets by means of a motor error signal, which is produced by a local feedback circuit that calculates the difference between desired saccadic amplitude and an internal copy of actual saccadic amplitude. Although the superior colliculus (SC) is thought to provide the desired saccadic amplitude signal, it is unclear whether the SC resides in the feedback loop. To test this possibility, we injected muscimol into the brain stem region containing omnipause neurons (OPNs) to slow saccades and then determined whether the firing of neurons at different sites in the SC was altered. In 14 experiments, we produced saccadic slowing while simultaneously recording the activity of a single SC neuron. Eleven of the 14 neurons were saccade-related burst neurons (SRBNs), which discharged their most vigorous burst for saccades with an optimal amplitude and direction (optimal vector). The optimal directions for the 11 SRBNs ranged from nearly horizontal to nearly vertical, with optimal amplitudes between 4 and 17°. Although muscimol injections into the OPN region produced little change in the optimal vector, they did increase mean saccade duration by 25 to 192.8% and decrease mean saccade peak velocity by 20.5 to 69.8%. For optimal vector saccades, both the acceleration and deceleration phases increased in duration. However, during 10 of 14 experiments, the duration of deceleration increased as fast as or faster than that of acceleration as saccade duration increased, indicating that most of the increase in duration occurred during the deceleration phase. SRBNs in the SC changed their burst duration and firing rate concomitantly with changes in saccadic duration and velocity, respectively. All SRBNs showed a robust increase in burst duration as saccadic duration increased. Five of 11 SRBNs also exhibited a decrease in burst peak firing rate as saccadic velocity decreased. On average across the neurons, the number of spikes in the burst was constant. There was no consistent change in the discharge of the three SC neurons that did not exhibit bursts with saccades. Our data show that the SC receives feedback from downstream saccade-related neurons about the ongoing saccades. However, the changes in SC firing produced in our study do not suggest that the feedback is involved with producing motor error. Instead, the feedback seems to be involved with regulating the duration of the discharge of SRBNs so that the desired saccadic amplitude signal remains present throughout the saccade.
Response of MSTd Neurons to Simulated 3D Orientation of Rotating Planes
Authors: Sugihara Hiroki , Murakami Ikuya , Shenoy Krishna V. , Andersen Richard A. , Komatsu Hidehiko
Published: May 2017

We studied whether the dorsal division of the medial superior temporal area (MSTd) in the macaque has activity related to structure-from-motion (SFM) processing. As the simplest form of three-dimensional (3D) structure, we chose a planar stimulus and examined the relation between the neural responses and the simulated 3D orientation of the plane defined by motion cues. We recorded from 114 MSTd neurons while monkeys were performing a visual fixation task. These neurons responded to a basic set of optic flow patterns such as translation, expansion/contraction, and rotation. Reponses of these neurons to rotating plane stimuli were examined to see whether the MSTd neurons exhibited selectivity to the tilt and slant that characterize the 3D orientation of the plane. We found that most MSTd neurons tested (97 of 114) responded to the plane stimuli, and many neurons (65 of 97) exhibited selectivity to tilt and/or slant. Of 97 neurons, 18% (17/97) were selective only to tilt, 24% (23/97) only to slant, and 26% (25/97) to both. Control experiments rejected the possibility that the selectivity could be explained solely by the sensitivity to local stimulus components such as local translation, local speed, and local speed gradients. These results suggest that MSTd neurons are sensitive to stimulus features specific to the perceived 3D orientation of the rotating plane stimuli and suggest that area MSTd is involved in SFM processing.
Functional Specialization Within the Cat Red Nucleus
Authors: Horn K. M. , Pong M. , Batni S. R. , Levy S. M. , Gibson A. R.
Published: May 2017

Magnocellular (RNm) and parvicellular (RNp) divisions of the cat red nucleus (RN) project to the cervical spinal cord. RNp projects more heavily to upper cervical levels and RNm projects more heavily to lower levels. The cells in RN are active during reaching and grasping, and the differences in termination suggest that the divisions influence different musculature during this behavior. However, the spinal termination may not reflect function because most rubrospinal terminations are to interneuronal regions, which can influence motor neurons at other spinal levels. To test for functional differences between RNm and RNp, we selectively stimulated RNm and RNp as well as the efferent fibers from each region. Electromyographic activity was recorded from seven muscles of the cat forelimb during reaching. The activity from each muscle was averaged over several thousand stimuli to detect influences of stimulation on muscle activity. Stimulation within the RN produced a characteristic pattern of poststimulus effects. The digit dorsiflexor, extensor digitorum communis (edc), was most likely to show facilitation, and several other muscles showed suppression. The pattern of activation did not differ between RNm and RNp. In contrast, stimulation of RNp fibers favored facilitation of shoulder muscles (spinodeltoideus and supraspinatus), and stimulation of RNm fibers favored facilitation of digit and wrist muscles (edc, palmaris longus, and extensor carpi ulnaris). Fiber stimulation produced few instances of poststimulus suppression. The results from fiber stimulation indicate that the physiological actions of RNm and RNp match their levels of spinal termination. The complex pattern of facilitation and suppression seen with RN stimulation may reflect synaptic actions within the nucleus.
MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma
Authors: Lu Xinyuan , Peled Nir , Greer John , Wu Wei , Choi Peter , Berger Alice H. , Wong Sergio , Jen Kuang-Yu , Seo Youngho , Hann Byron , Brooks Angela , Meyerson Matthew , Collisson Eric A.
Published: May 2017

Targeting somatically activated oncogenes has revolutionized the treatment of non–small cell lung cancer (NSCLC). Mutations in the gene mesenchymal–epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor–dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host. Cancer Res; 77(16); 4498–505. ©2017 AACR.