bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural Processing of Gravito-Inertial Cues in Humans. I. Influence of the Semicircular Canals Following Post-Rotatory Tilt
Authors: Zupan L. H. , Peterka R. J. , Merfeld D. M.
Published: December 2017

Sensory systems often provide ambiguous information. Integration of various sensory cues is required for the CNS to resolve sensory ambiguity and elicit appropriate responses. The vestibular system includes two types of sensors: the semicircular canals, which measure head rotation, and the otolith organs, which measure gravito-inertial force (GIF), the sum of gravitational force and inertial force due to linear acceleration. According to Einstein's equivalence principle, gravitational force is indistinguishable from inertial force due to linear acceleration. As a consequence, otolith measurements must be supplemented with other sensory information for the CNS to distinguish tilt from translation. The GIF resolution hypothesis states that the CNS estimates gravity and linear acceleration, so that the difference between estimates of gravity and linear acceleration matches the measured GIF. Both otolith and semicircular canal cues influence this estimation of gravity and linear acceleration. The GIF resolution hypothesis predicts that inaccurate estimates of both gravity and linear acceleration can occur due to central interactions of sensory cues. The existence of specific patterns of vestibuloocular reflexes (VOR) related to these inaccurate estimates can be used to test the GIF resolution hypothesis. To investigate this hypothesis, we measured eye movements during two different protocols. In one experiment, eight subjects were rotated at a constant velocity about an earth-vertical axis and then tilted 90° in darkness to one of eight different evenly spaced final orientations, a so-called “dumping” protocol. Three speeds (200, 100, and 50°/s) and two directions, clockwise (CW) and counterclockwise (CCW), of rotation were tested. In another experiment, four subjects were rotated at a constant velocity (200°/s, CW and CCW) about an earth-horizontal axis and stopped in two different final orientations (nose-up and nose-down), a so-called “barbecue” protocol. The GIF resolution hypothesis predicts that post-rotatory horizontal VOR eye movements for both protocols should include an “induced” VOR component, compensatory to an interaural estimate of linear acceleration, even though no true interaural linear acceleration is present. The GIF resolution hypothesis accurately predicted VOR and induced VOR dependence on rotation direction, rotation speed, and head orientation. Alternative hypotheses stating that frequency segregation may discriminate tilt from translation or that the post-rotatory VOR time constant is dependent on head orientation with respect to the GIF direction did not predict the observed VOR for either experimental protocol.
Reorganization of Primary Motor Cortex in Adult Macaque Monkeys With Long-Standing Amputations
Authors: Qi Hui-Xin , Stepniewska Iwona , Kaas Jon H.
Published: December 2017

The organization of primary motor cortex (M1) of adult macaque monkeys was examined years after therapeutic amputation of part of a limb or digits. For each case, a large number of sites in M1 were electrically stimulated with a penetrating microelectrode, and the evoked movements and levels of current needed to evoke the movements were recorded. Results from four monkeys with the loss of a forelimb near or above the elbow show that extensive regions of cortex formerly devoted to the missing hand evoked movements of the stump and the adjoining shoulder. Threshold current levels for stump movements were comparable to those for normal arm movements. Few or no sites in the estimated former territory of the hand evoked face movements. Similar patterns of reorganization were observed in all four cases, which included two monkeys injured as adults, one as a juvenile, and one as an infant. In a single monkey with a hindlimb amputation at the knee as an infant, stimulation of cortex in the region normally devoted to the foot moved the leg stump, again at thresholds in the range for normal movements. Finally, in a monkey that had lost digit 5 and the distal phalanges of digits 2–4 at 2 yr of age, much of the hand portion of M1 was devoted to movements of the digit stumps.
Reward-Predicting and Reward-Detecting Neuronal Activity in the Primate Supplementary Eye Field
Authors: Amador Nelly , Schlag-Rey Madeleine , Schlag John
Published: December 2017

In addition to cells specifically active with visual stimuli, saccades, or fixation, the supplementary eye field contains cells that fire in precise temporal relationship with the occurrence of reward. We studied reward-related activity in two monkeys performing a prosaccade/antisaccade task and in one monkey trained in memory prosaccades only. Two types of neurons were distinguished by their reciprocal firing pattern: reward-predicting (RP) and reward-detecting (RD). RP neurons linearly increased their firing as early as 150 ms before saccade onset until the occurrence of reward, at which time they abruptly ceased firing. In contrast, RD neurons fired in phase with reward delivery, even when its duration was varied and when it was repeated at different frequencies. RD discharges were little affected or unaffected by the position of a visual cue that briefly anchored the goal at the onset of reward. The complementary firing patterns of the RP and RD neurons could provide a feedback mechanism necessary for learning and performing the task.
In Vivo Patch-Clamp Analysis of IPSCs Evoked in Rat Substantia Gelatinosa Neurons by Cutaneous Mechanical Stimulation
Authors: Narikawa Keita , Furue Hidemasa , Kumamoto Eiichi , Yoshimura Megumu
Published: December 2017

To know a functional role of inhibitory synaptic responses in transmitting noxious and innoxious information from the periphery to the rat spinal dorsal horn, we examined inhibitory postsynaptic currents (IPSCs) elicited in substantia gelatinosa (SG) neurons by mechanical stimuli applied to the skin using the newly developed in vivo patch-clamp technique. In the majority (80%) of SG neurons examined, a brush stimulus applied to the ipsilateral hind limb produced a barrage of IPSCs that persisted during the stimulus, while a pinch stimulus evoked IPSCs only at its beginning and end. The pinch-evoked IPSCs may have been caused by a touch that occurs at the on/off time of the pinch. The evoked IPSCs were blocked by either a glycine-receptor antagonist, strychnine (4 μM), or a GABAA-receptor antagonist, bicuculline (20 μM). All SG neurons examined received inhibitory inputs from a wide area throughout the thigh and lower leg. When IPSCs were examined together with excitatory postsynaptic currents (EPSCs) in the same neurons, a brush evoked a persistent activity of both IPSCs and EPSCs during the stimulus while a pinch evoked such an activity of EPSCs but not IPSCs. It is suggested that innoxious mechanical stimuli activate a GABAergic or glycinergic circuitry in the spinal dorsal horn. This inhibitory transmission may play an important role in the modulation of noxious information in the SG.
Congenitally Blind Individuals Rapidly Adapt to Coriolis Force Perturbations of Their Reaching Movements
Authors: DiZio Paul , Lackner James R.
Published: December 2017

Reaching movements made to visual targets in a rotating room are initially deviated in path and endpoint in the direction of transient Coriolis forces generated by the motion of the arm relative to the rotating environment. With additional reaches, movements become progressively straighter and more accurate. Such adaptation can occur even in the absence of visual feedback about movement progression or terminus. Here we examined whether congenitally blind and sighted subjects without visual feedback would demonstrate adaptation to Coriolis forces when they pointed to a haptically specified target location. Subjects were tested pre-, per-, and postrotation at 10 rpm counterclockwise. Reaching to straight ahead targets prerotation, both groups exhibited slightly curved paths. Per-rotation, both groups showed large initial deviations of movement path and curvature but within 12 reaches on average had returned to prerotation curvature levels and endpoints. Postrotation, both groups showed mirror image patterns of curvature and endpoint to the per-rotation pattern. The groups did not differ significantly on any of the performance measures. These results provide compelling evidence that motor adaptation to Coriolis perturbations can be achieved on the basis of proprioceptive, somatosensory, and motor information in the complete absence of visual experience.
Kinematic Coordinates In Which Motor Cortical Cells Encode Movement Direction
Authors: Ajemian Robert , Bullock Daniel , Grossberg Stephen
Published: December 2017

During goal-directed reaching in primates, a sensorimotor transformation generates a dynamical pattern of muscle activation. Within the context of this sensorimotor transformation, a fundamental question concerns the coordinate systems in which individual cells in the primary motor cortex (MI) encode movement direction. This article develops a mathematical framework that computes, as a function of the coordinate system in which an individual cell is hypothesized to operate, the spatial preferred direction (pd) of that cell as the arm configuration and hand location vary. Three coordinate systems are explicitly modeled: Cartesian spatial, shoulder-centered, and joint angle. The computed patterns of spatial pds are distinct for each of these three coordinate systems, and experimental approaches are described that can capitalize on these differences to compare the empirical adequacy of each coordinate hypothesis. One particular experiment involving curved motion was analyzed from this perspective. Out of the three coordinate systems tested, the assumption of joint angle coordinates best explained the observed cellular response properties. The mathematical framework developed in this paper can also be used to design new experiments that are capable of disambiguating between a given set of specified coordinate hypotheses.
Unique Properties of R-Type Calcium Currents in Neocortical and Neostriatal Neurons
Authors: Foehring Robert C. , Mermelstein Paul G. , Song Wen-Jie , Ulrich Sasha , Surmeier D. James
Published: December 2017

Whole cell recordings from acutely dissociated neocortical pyramidal neurons and striatal medium spiny neurons exhibited a calcium-channel current resistant to known blockers of L-, N-, and P/Q-type Ca2+channels. These R-type currents were characterized as high-voltage–activated (HVA) by their rapid deactivation kinetics, half-activation and half-inactivation voltages, and sensitivity to depolarized holding potentials. In both cell types, the R-type current activated at potentials relatively negative to other HVA currents in the same cell type and inactivated rapidly compared with the other HVA currents. The main difference between cell types was that R-type currents in neocortical pyramidal neurons inactivated at more negative potentials than R-type currents in medium spiny neurons. Ni2+sensitivity was not diagnostic for R-type currents in either cell type. Single-cell RT-PCR revealed that both cell types expressed the α1E mRNA, consistent with this subunit being associated with the R-type current.
Concentration Dependence of Bicarbonate-Induced Calcium Current Modulation
Authors: Bruehl C. , Wadman W. J. , Witte O. W.
Published: December 2017

High-voltage–activated calcium currents (HVA) of CA1 neurons are prominently attenuated following a switch from HEPES-buffered solution to one buffered with CO2/HCO3 −. In the present study we investigated whether bicarbonate ions or the dissolved CO2 induce this alteration in current characteristic. The study was carried out on freshly isolated CA1 neurons using the whole cell patch-clamp technique. Maximal calcium conductance and the mean peak amplitude of the currents showed a concentration-dependent decrease when cells were consecutively bathed in solutions containing increasing amounts of bicarbonate and CO2. This decrease is best described by the Hill equation, yielding a maximal attenuation of 69%, a half-maximal concentration (EC50) of 7.4 mM HCO3 −, and a Hill coefficient of 1.8. In parallel, the potentials of half-maximal activation ( V h,a) and inactivation ( V h,i) were linearly shifted in hyperpolarizing direction with a maximal shift, in the 10% CO2/37 mM HCO3 − containing solution of 10 ± 1 mV for V h,a( n = 23) and 17 ± 1.4 mV for V h,i ( n = 18). When currents were evoked in solutions containing equal concentrations of bicarbonate but different amounts of CO2, only nonsignificant changes were observed, while marked alterations of the currents were induced when bicarbonate was changed and CO2 held stable. The experiments suggest that bicarbonate is the modulating agent and not CO2. This bicarbonate-induced modulation may be of critical relevance for the excitation level of the CNS under pathological situation with altered concentration of this ion, such as hyperventilation and metabolic acidosis.
Role of Synaptic Inputs in Determining Input Resistance of Developing Brain Stem Motoneurons
Authors: Núñez-Abades Pedro A. , Pattillo John M. , Hodgson Tracy M. , Cameron William E.
Published: December 2017

The contribution of synaptic input to input resistance was examined in 208 developing genioglossal motoneurons in 3 postnatal age groups (5–7 day, 13–16 day, and 18–24 day) using sharp electrode recording in a slice preparation of the rat brain stem. High magnesium (Mg2+; 6 mM) media generated significant increases (21–38%) in both the input resistance ( R n) and the first time constant (τ0) that were reversible. A large percent of the conductance blocked by high Mg2+ was also sensitive to tetrodotoxin (TTX). Little increase in resistance was attained by adding blockers of specific amino acid (glutamate, glycine, and GABA) transmission over that obtained with the high Mg2+. Comparing across age groups, there was a significantly larger percent change in R n with the addition of high Mg2+ at postnatal days 13 to 15 ( P13–15; 36%) than that found at P5–6 (21%). Spontaneous postsynaptic potentials were sensitive to the combined application of glycine receptor antagonist, strychnine, and the GABAA receptor antagonist, bicuculline. Application of either 10 μM strychnine or bicuculline separately produced a reversible increase in both R n and τ0. Addition of 10 μM bicuculline to a strychnine perfusate failed to further increase either R n or τ0. The strychnine/bicuculline-sensitive component of the total synaptic conductance increased with age so that this form of neurotransmission constituted the majority (>60%) of the observed percent decrease in R n and τ0 in the oldest age group. The proportion of change in τ0 relative to R n following strychnine or high magnesium perfusate varied widely from cell to cell and from age to age without pattern. Based on a model from the literature, this pattern indicates a nonselective distribution of the blocked synaptic conductances over the cell body and dendrites. Taken together, the fast inhibitory synapses (glycine, GABAA) play a greater role in determining cell excitability in developing brain stem motoneurons as postnatal development progresses. These findings suggest that synaptically mediated conductances effect the membrane behavior of developing motoneurons.
Subclassified Acutely Dissociated Cells of Rat DRG: Histochemistry and Patterns of Capsaicin-, Proton-, and ATP-Activated Currents
Authors: Petruska Jeffrey C. , Napaporn Jintana , Johnson Richard D. , Gu Jianguo G. , Cooper Brian Y.
Published: December 2017

We used a “current signature” method to subclassify acutely dissociated dorsal root ganglion (DRG) cells into nine subgroups. Cells subclassified by current signature had uniform properties. The type 1 cell had moderate capsaicin sensitivity (25.9 pA/pF), powerful, slowly desensitizing (τ = 2,300 ms), ATP-activated current (13.3 pA/pF), and small nondesensitizing responses to acidic solutions (5.6 pA/pF). Type 1 cells expressed calcitonin gene–related peptide immunoreactivity (CGRP-IR), manifested a wide action potential (7.3 ms), long duration afterhyperpolarization (57.0 ms), and were IB4 positive. The type 2 cell exhibited large capsaicin activated currents (134.9 pA/pF) but weak nondesensitizing responses to protons (15.3 pA/pF). Currents activated by ATP and αβ-m-ATP (51.7 and 44.6 pA/pF, respectively) had fast desensitization kinetics (τ = 214 ms) that were distinct from all other cell types. Type 2 cells were IB4 positive but did not contain either substance P (SP) or CGRP-IR. Similar to capsaicin-sensitive nociceptors in vivo, the afterhyperpolarization of the type 2 cell was prolonged (54.7 ms). The type 3 cell expressed, amiloride-sensitive, rapidly desensitizing (τ = 683 ms) proton-activated currents (127.0 pA/pF), and was insensitive to ATP or capsaicin. The type 3 cell was IB4 negative and contained neither CGRP nor SP-IR. The afterhyperpolarization (17.5 ms) suggested nonnociceptive function. The type 4 cell had powerful ATP-activated currents (17.4 pA/pF) with slow desensitization kinetics (τ = 2,813 ms). The afterhyperpolarization was prolonged (46.5 ms), suggesting that this cell type might belong to a capsaicin-insensitive nociceptor population. The type 4 cell did not contain peptides. The type 7 cell manifested amiloride-sensitive, proton-activated currents (45.8 pA/pF) with very fast desensitization kinetics (τ = 255 ms) and was further distinct from the type 3 cell by virtue of a nondesensitizing amiloride-insensitive component (6.0 pA/pF). Capsaicin and ATP sensitivity were relatively weak (4.3 and 2.9 pA/pF, respectively). Type 7 cells were IB4 positive and contained both SP and CGRP-IR. They exhibited an exceptionally long afterhyperpolarization (110 ms) that was suggestive of a silent (mechanically insensitive) nociceptor. We concluded that presorting of DRG cells by current signatures separated them into internally homogenous subpopulations that were distinct from other subclassified cell types.
Resting and Active Properties of Pyramidal Neurons in Subiculum and CA1 of Rat Hippocampus
Authors: Staff Nathan P. , Jung Hae-Yoon , Thiagarajan Tara , Yao Michael , Spruston Nelson
Published: December 2017

Action potentials are the end product of synaptic integration, a process influenced by resting and active neuronal membrane properties. Diversity in these properties contributes to specialized mechanisms of synaptic integration and action potential firing, which are likely to be of functional significance within neural circuits. In the hippocampus, the majority of subicular pyramidal neurons fire high-frequency bursts of action potentials, whereas CA1 pyramidal neurons exhibit regular spiking behavior when subjected to direct somatic current injection. Using patch-clamp recordings from morphologically identified neurons in hippocampal slices, we analyzed and compared the resting and active membrane properties of pyramidal neurons in the subiculum and CA1 regions of the hippocampus. In response to direct somatic current injection, three subicular firing types were identified (regular spiking, weak bursting, and strong bursting), while all CA1 neurons were regular spiking. Within subiculum strong bursting neurons were found preferentially further away from the CA1 subregion. Input resistance ( R N), membrane time constant (τm), and depolarizing “sag” in response to hyperpolarizing current pulses were similar in all subicular neurons, while R N and τm were significantly larger in CA1 neurons. The first spike of all subicular neurons exhibited similar action potential properties; CA1 action potentials exhibited faster rising rates, greater amplitudes, and wider half-widths than subicular action potentials. Therefore both the resting and active properties of CA1 pyramidal neurons are distinct from those of subicular neurons, which form a related class of neurons, differing in their propensity to burst. We also found that both regular spiking subicular and CA1 neurons could be transformed into a burst firing mode by application of a low concentration of 4-aminopyridine, suggesting that in both hippocampal subfields, firing properties are regulated by a slowly inactivating, D-type potassium current. The ability of all subicular pyramidal neurons to burst strengthens the notion that they form a single neuronal class, sharing a burst generating mechanism that is stronger in some cells than others.
Parallels Between Timing of Onset Responses of Single Neurons in Cat and of Evoked Magnetic Fields in Human Auditory Cortex
Authors: Biermann Silke , Heil Peter
Published: December 2017

Sound onsets constitute particularly salient transients and evoke strong responses from neurons of the auditory system, but in the past, such onset responses have often been analyzed with respect to steady-state features of sounds, like the sound pressure level. Recent electrophysiological studies of single neurons from the auditory cortex of anesthetized cats have revealed that the timing and strength of onset responses are shaped by dynamic stimulus properties at their very onsets. Here we demonstrate with magnetoencephalography that stimulus-response relationships very similar to those of the single neurons are observed in two onset components, N100m and P50m, of auditory evoked magnetic fields (AEFs) from the auditory cortex of awake humans. In response to tones shaped with cosine-squared rise functions, N100m and P50m peak latencies vary systematically with tone level and rise time but form a rather invariant function of the acceleration of the envelope at tone onset. Hence N100m and P50m peak latencies, as well as peak amplitudes, are determined by dynamic properties of the stimuli within the first few milliseconds, though not necessarily by acceleration. The changes of N100m and P50m peak latencies with rise time and level are incompatible with a fixed-amplitude threshold model. The direct comparison of the neuromagnetic and single-neuron data shows that, on average, the variance of the neuromagnetic data is larger by one to two orders of magnitude but that favorable measurements can yield variances as low as those derived from neurons with mediocre precision of response timing. The striking parallels between the response timing of single cortical neurons and of AEFs provides a stronger link between single neuron and population activity.
Modulation of Spreading Depression by Changes in Extracellular pH
Authors: Tong C. K. , Chesler M.
Published: December 2017

Spreading depression (SD) and related phenomena have been implicated in hypoxic-ischemic injury. In such settings, SD occurs in the presence of marked extracellular acidosis. SD itself can also generate changes in extracellular pH (pHo), including a pronounced early alkaline shift. In a hippocampal slice model, we investigated the effect of interstitial acidosis on the generation and propagation of SD in the CA1 stratum radiatum. In addition, a carbonic anhydrase inhibitor (benzolamide) was used to decrease buffering of the alkaline shift to investigate its role in the modulation of SD. pHowas lowered by a decrease in saline HCO3−(from 26 to 13 to 6.5 mM at 5% CO2), or by an increase in the CO2content (from 5 to 15% in 26 mM HCO3−). Recordings with pH microelectrodes revealed respective pHo values of 7.23 ± 0.13, 6.95 ± 0.10, 6.67 ± 0.09, and 6.97 ± 0.12. The overall effect of acidosis was an increase in the threshold for SD induction, a decrease in velocity, and a shortened SD duration. This inhibition was most pronounced at the lowest pHo(in 6.5 mM HCO3−) where SD was often blocked. The effects of acidosis were reversible on return to control saline. Benzolamide (10 μM) caused an approximate doubling of the early alkaline shift to an amplitude of 0.3–0.4 U pH. The amplified alkalosis was associated with an increased duration and/or increased velocity of the wave. These effects were most pronounced in acidic media (13 mM HCO3−/5% CO2) where benzolamide increased the SD duration by 55 ± 32%. The initial velocity (including time for induction) and propagation velocity (measured between distal electrodes) were enhanced by 35 ± 25 and 26 ± 16%, respectively. Measurements of [Ca2+]odemonstrated an increase in duration of the Ca2+transient when the alkaline shift was amplified by benzolamide. The augmentation of SD caused by benzolamide was blocked in media containing the N-methyl-d-aspartate (NMDA) receptor antagonistdl−2-amino-5-phosphonovaleric acid. These data indicate that the induction and propagation of SD is inhibited by a fall in baseline pH characteristic of ischemic conditions and that the early alkaline shift can remove this inhibition by relieving the proton block on NMDA receptors. Under ischemic conditions, the intrinsic alkalosis may therefore enable SD and thereby contribute to NMDA receptor-mediated injury.
Differential Maintenance and Frequency-Dependent Tuning of LTP at Hippocampal Synapses of Specific Strains of Inbred Mice
Authors: Nguyen Peter V. , Duffy Steven N. , Young Jennie Z.
Published: December 2017

Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be “tuned” to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.
Postnatal Development of the Motor Representation in Primary Motor Cortex
Authors: Chakrabarty Samit , Martin John H.
Published: December 2017

The purpose of this study was to examine when the muscles and joints of the forelimb become represented in primary motor cortex (M1) during postnatal life and how local representation patterns change. We examined these questions in cats that were anesthetized (45–90 days, n = 14; adults, n = 3) and awake ( n = 4; 52–86 days). We used intracortical microstimulation (45 ms duration train, 330 Hz, 0.2-ms balanced biphasic pulses, with a leading cathodic pulse; up to 100 μA). In young animals (less than day 70), we also used stimulus trains and pulses that could produce greater temporal summation (up to 200-ms train duration, down to 143-Hz stimulus frequency, up to 0.8-ms pulse width). Anesthetized animals were areflexic, and muscle tone was similar to that of the awake cats (i.e., relaxed, not weight or load bearing, with minimal resistance to passive stretch). We monitored the kinematic effects of microstimulation and changes in electromyographic (EMG) activity in forelimb muscles. There was an age-dependent reduction in the number of sites where microstimulation did not produce a motor effect (i.e., ineffective sites), from 95% in animals younger than 60 days to 33% between 81 and 90 days. In adults, 24% of sites were ineffective. Median current thresholds for evoking movements dropped from 79 μA in animals younger than day 60 to 38 and 28 μA in day 81–90 animals and adults, respectively. There was a proximal-to-distal development of the somatotopic organization of the motor map. Stimulation at the majority of sites in animals younger than day 71 produced shoulder and elbow movement. Wrist sites were first present by day 71, and digit sites by day 81. Sites at which multiple responses were evoked, between 1.0 and 1.5 times threshold, were present after day 71, and increased with age. A higher percentage of distal joints were co-represented with other joints, rather than being represented alone. We found that effective sites initially were scattered and new sites representing proximal and distal joints filled in the gaps between effective sites. During most of the period examined, development of the caudal M1 subregion lagged that of the rostral subregion (percent of effective sites; threshold currents), although these differences were minimal or absent in adults. Our results show that the M1 motor representation is absent at day 45 and, during the subsequent month, the motor map is constructed by progressively representing more distal forelimb joints.
Representation of Temporal Features of Complex Sounds by the Discharge Patterns of Neurons in the Owl's Inferior Colliculus
Authors: Keller Clifford H. , Takahashi Terry T.
Published: December 2017

The spiking pattern evoked in cells of the owl's inferior colliculus by repeated presentation of the same broadband noise was found to be highly reproducible and synchronized with the temporal features of the noise stimulus. The pattern remained largely unchanged when the stimulus was presented from spatial loci that evoke similar average firing rates. To better understand this patterning, we computed the pre-event stimulus ensemble (PESE)—the average of the stimuli that preceded each spike. Computing the PESE by averaging the pressure waveforms produced a noisy, featureless trace, suggesting that the patterning was not synchronized to a particular waveform in the fine structure. By contrast, computing the PESE by averaging the stimulus envelope revealed an average envelope waveform, the “PESE envelope,” typically having a peak preceded by a trough. Increasing the overall stimulus level produced PESE envelopes with higher amplitudes, suggesting a decrease in the jitter of the cell's response. The effect of carrier frequency on the PESE envelope was investigated by obtaining a cell's response to broadband noise and either estimating the PESE envelope for each spectral band or by computing a spectrogram of the stimulus prior to each spike. Either method yielded the cell's PESE spectrogram, a plot of the average amplitude of each carrier-frequency component at various pre-spike times. PESE spectrograms revealed surfaces with peaks and troughs at certain frequencies and pre-spike times. These features are collectively called the spectrotemporal receptive field (STRF). The shape of the STRF showed that in many cases, the carrier frequency can affect the PESE envelope. The modulation transfer function (MTF), which describes a cell's ability to respond to time-varying amplitudes, was estimated with sinusoidally amplitude-modulated (SAM) noises. Comparison of the PESE envelope with the MTF in the time and frequency domains showed that the two were closely matched, suggesting that a cell's response to SAM stimuli is largely predictable from its response to a noise-modulated carrier. The STRF is considered to be a model of the linear component of a system's response to dynamic stimuli. Using the STRF, we estimated the degree to which we could predict a cell's response to an arbitrary broadband noise by comparing the convolution of the STRF and the envelope of the noise with the cell's post-stimulus time histogram to the same noise. The STRF explained 18–46% of the variance of a cell's response to broadband noise.
Selective Use of Perceptual Recalibration Versus Visuomotor Skill Acquisition
Authors: Clower Dottie M. , Boussaoud Driss
Published: December 2017

Exposure to laterally displacing prisms is characterized by systematic misreaching in the opposite direction after prisms are removed. Other learning tasks involving altered visuomotor mappings can often be mastered by the subject with minimal resulting aftereffects. One variable that may account for this difference is the nature of the feedback provided to the subject: during studies of prism exposure, subjects usually view the hand itself, whereas in many studies of visuomotor learning, subjects view a computer-generated representation of the hand position or movement. We compared the use of actual feedback of the hand with computer-generated representational feedback of its position during exposure to laterally displacing prisms. In the actual feedback condition (ACT), a light on the fingertip was illuminated immediately at the end of each reach. In the representational feedback condition (REP), a computer-generated spot of light was displayed to indicate the exact position of the fingertip at the end of each reach. Whereas the rate and magnitude of error correction were the same in both conditions, only the ACT condition produced the large adaptive aftereffect typically observed after prism exposure. These results suggest that the perception of a physical coincidence between the feedback source and the hand may be a key factor in determining whether adaptation is accomplished through perceptual recalibration or visuomotor skill acquisition.
Relative Contribution by GABA or Glycine to Cl−-Mediated Synaptic Transmission on Rat Hypoglossal Motoneurons In Vitro
Authors: Donato Roberta , Nistri Andrea
Published: December 2017

The relative contribution by GABA and glycine to synaptic transmission of motoneurons was investigated using an hypoglossus nucleus slice preparation from neonatal rats. Spontaneous, miniature, or electrically evoked postsynaptic currents (sPSCs, mPSCs, ePSCs, respectively) mediated by glycine or GABA were recorded under whole cell voltage clamp after blocking excitatory glutamatergic transmission with kynurenic acid. The overall majority of Cl−-mediated sPSCs was glycinergic, while only one-third was GABAergic; 70 ± 10% of mPSCs were glycinergic while 22 ± 8% were GABAergic. Tetrodotoxin (TTX) application dramatically reduced the frequency (and slightly the amplitude) of GABAergic events without changing frequency or amplitude of glycinergic sPSCs. These results indicate that, unlike spontaneous GABAergic transmission, glycine-mediated neurotransmission was essentially independent of network activity. There was a consistent difference in the kinetics of GABAergic and glycinergic responses as GABAergic events had significantly slower rise and decay times than glycinergic ones. Such a difference was always present whenever sPSCs, mPSCs, or ePSCs were measured. Finally, GABAergic and glycinergic mPSCs were differentially modulated by activation of glutamate metabotropic receptors (mGluRs), which are abundant in the hypoglossus nucleus. In fact, the broad-spectrum mGluR agonist (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid (50 μM), which in control solution increased the frequency of both GABAergic and glycinergic sPSCs, enhanced the frequency of glycinergic mPSCs only. These results indicate that on brain stem motoneurons, Cl−-mediated synaptic transmission is mainly due to glycine rather than GABA and that GABAergic and glycinergic events differ in terms of kinetics and pharmacological sensitivity to mGluR activation or TTX.
Genetic and Pharmacological Demonstration of Differential Recruitment of cAMP-Dependent Protein Kinases by Synaptic Activity
Authors: Woo Newton H. , Duffy Steven N. , Abel Ted , Nguyen Peter V.
Published: December 2017

cAMP-dependent protein kinase (PKA) is believed to play a critical role in the expression of long-lasting forms of hippocampal long-term potentiation (LTP). Can distinct patterns of synaptic activity induce forms of LTP that require different isoforms of PKA? To address this question, we used transgenic mice that have genetically reduced hippocampal PKA activity, and a specific pharmacological inhibitor of PKA, Rp-cAMPS. Transgenic mice [R(AB) mice] that express an inhibitory form of a particular type of regulatory subunit of PKA (type-Iα) showed significantly reduced LTP in area CA1 of hippocampal slices as compared with slices from wild-type mice. This impairment of LTP expression was evident when LTP was induced by applying repeated, temporally spaced stimulation (4 1-s bursts of 100-Hz applied once every 5 min). In contrast, LTP induced by applying just 60 pulses in a theta-burst pattern was normal in slices from R(AB) mice as compared with slices from wild-type mice. We found that Rp-cAMPS blocked the expression of LTP induced by both spaced tetra-burst and compressed theta-burst stimulation in hippocampal slices of wild-type and R(AB) mice, respectively. Since Rp-cAMPS is a PKA inhibitor that is not selective for any particular isoform of PKA and these R(AB) mice show reduced hippocampal PKA activity resulting from genetic manipulation of a single isoform of PKA regulatory subunit, our data support the idea that distinct patterns of synaptic activity can produce different forms of LTP that significantly engage different isoforms of PKA. In particular, theta-burst LTP significantly recruits isoforms of PKA containing regulatory subunits other than the mutant RIα subunit, whereas tetra-burst LTP requires PKA isoforms containing the mutant RIα subunit. Thus, altering both the total amount of imposed synaptic activity and the temporal spacing between bursts of imposed activity may subtly modulate the PKA dependence of hippocampal LTP by engaging distinct isoforms of PKA. In a broader context, our findings suggest that synaptic plasticity in the mammalian brain might be importantly regulated by activity-dependent recruitment of different isoforms of key signal transduction molecules.
Ryanodine-Sensitive Stores Regulate the Excitability of AH Neurons in the Myenteric Plexus of Guinea-Pig Ileum
Authors: Hillsley K. , Kenyon J. L. , Smith T. K.
Published: December 2017

Myenteric afterhyperpolarizing (AH) neurons are primary afferent neurons within the gastrointestinal tract. Stimulation of the intestinal mucosa evokes action potentials (AP) that are followed by a slow afterhyperpolarization (AHPslow) in the soma. The role of intracellular Ca2+ ([Ca2+]i) and ryanodine-sensitive Ca2+ stores in modulating the electrical activity of myenteric AH neurons was investigated by recording membrane potential and bis-fura-2 fluorescence from 34 AH neurons. Mean resting [Ca2+]i was ∼200 nM. Depolarizing current pulses that elicited APs evoked AHPslow and an increase in [Ca2+]i, with similar time courses. The amplitudes and durations of AHPslow and the Ca2+ transient were proportional to the number of evoked APs, with each AP increasing [Ca2+]i by ∼50 nM. Ryanodine (10 μM) significantly reduced both the amplitude and duration (by 60%) of the evoked Ca2+ transient and AHPslow over the range of APs tested (1–15). Calcium-induced calcium release (CICR) was graded and proportional to the number of APs, with each AP triggering a rise in [Ca2+]i of ∼30 nM Ca2+ via CICR. This indicates that CICR amplifies Ca2+ influx. Similar changes in [Ca2+]i and AHPslow were evoked by two APs in control and six APs in ryanodine. Thus, the magnitude of the change in bulk [Ca2+]i and not the source of the Ca2+ is the determinant of the magnitude of AHPslow. Furthermore, lowering of free [Ca2+]i, either by reducing extracellular Ca2+ or injecting high concentrations of Ca2+buffer, induced depolarization, increased excitability, and abolition of AHPslow. In addition, activation of synaptic input to AH neurons elicited a slow excitatory postsynaptic potential (sEPSP) that was completely blocked in ryanodine. These results demonstrate the importance of [Ca2+]i and CICR in sensory processing in AH neurons. Activity-dependent CICR may be a mechanism to grade the output of AH neurons according to the intensity of sensory input.
Processing of Kinetically Defined Boundaries in Areas V1 and V2 of the Macaque Monkey
Authors: Marcar V. L. , Raiguel S. E. , Xiao D. , Orban G. A.
Published: December 2017

We recorded responses in 107 cells in the primary visual area V1 and 113 cells in the extrastriate visual area V2 while presenting a kinetically defined edge or a luminance contrast edge. Cells meeting statistical criteria for responsiveness and orientation selectivity were classified as selective for the orientation of the kinetic edge if the preferred orientation for a kinetic boundary stimulus remained essentially the same even when the directions of the two motion components defining that boundary were changed by 90°. In area V2, 13 of the 113 cells met all three requirements, whereas in V1, only 4 cells met the criteria of 107 that were tested, and even these demonstrated relatively weak selectivity. Correlation analysis showed that V1 and V2 populations differed greatly ( P < 1.0 × 10−6, Student's t-test) in their selectively for specific orientations of kinetic edge stimuli. Neurons in V2 that were selective for the orientation of a kinetic boundary were further distinguished from their counterparts in V1 in displaying a strong, sharply tuned response to a luminance edge of the same orientation. We concluded that selectivity for the orientation of kinetically defined boundaries first emerges in area V2 rather than in primary visual cortex. An analysis of response onset latencies in V2 revealed that cells selective for the orientation of the motion-defined boundary responded about 40 ms more slowly, on average, to the kinetic edge stimulus than to a luminance edge. In nonselective cells, that is, those presumably responding only to the local motion in the stimulus, this difference was only about 20 ms. Response latencies for the luminance edge were indistinguishable in KE-selective and -nonselective neurons. We infer that while responses to luminance edges or local motion are indigenous to V2, KE-selective responses may involve feedback entering the ventral stream at a point downstream with respect to V2.
NMDA Receptor-Dependent Plasticity of Granule Cell Spiking in the Dentate Gyrus of Normal and Epileptic Rats
Authors: Lynch M. , Sayin Ü. , Golarai G. , Sutula T.
Published: December 2017

Because granule cells in the dentate gyrus provide a major synaptic input to pyramidal neurons in the CA3 region of the hippocampus, spike generation by granule cells is likely to have a significant role in hippocampal information processing. Granule cells normally fire in a single-spike mode even when inhibition is blocked and provide single-spike output to CA3 when afferent activity converging into the entorhinal cortex from neocortex, brainstem, and other limbic regions increases. The effects of enhancement of N-methyl-d-aspartate (NMDA) receptor-dependent excitatory synaptic transmission and reduction in γ-aminobutyric acid-A (GABAA) receptor-dependent inhibition on spike generation were examined in granule cells of the dentate gyrus. In contrast to the single-spike mode observed in normal bathing conditions, perforant path stimulation in Mg2+-free bathing conditions evoked graded burst discharges in granule cells which increased in duration, amplitude, and number of spikes as a function of stimulus intensity. After burst discharges were evoked during transient exposure to bathing conditions that relieve the Mg2+ block of the NMDA receptor, there was a marked increase in the NMDA receptor-dependent component of the EPSP, but no significant increase in the non-NMDA receptor-dependent component of the EPSP in normal bathing medium. Supramaximal perforant path stimulation still evoked only a single spike, but granule cell spike generation was immediately converted from a single-spike firing mode to a graded burst discharge mode when inhibition was then reduced. The induction of graded burst discharges in Mg2+-free conditions and the expression of burst discharges evoked in normal bathing medium with subsequent disinhibition were both blocked bydl-2-amino-4-phosphonovaleric acid (APV) and were therefore NMDA receptor dependent, in contrast to long-term potentiation (LTP) in the perforant path, which is induced by NMDA receptors and is also expressed by α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptors. The graded burst discharge mode was also observed in granule cells when inhibition was reduced after a single epileptic afterdischarge, which enhances the NMDA receptor-dependent component of evoked synaptic response, and in the dentate gyrus reorganized by mossy fiber sprouting in kindled and kainic acid-treated rats. NMDA receptor-dependent plasticity of granule cell spike generation, which can be distinguished from LTP and induces long-term susceptibility to epileptic burst discharge under conditions of reduced inhibition, could modify information processing in the hippocampus and promote epileptic synchronization by increasing excitatory input into CA3.
Voltage-Dependent Ion Channels in CAD Cells: A Catecholaminergic Neuronal Line That Exhibits Inducible Differentiation
Authors: Wang Haibin , Oxford Gerry S.
Published: December 2017

Cell lines derived from tumors engineered in the CNS offer promise as models of specific neuronal cell types. CAD cells are an unusual subclone of a murine cell line derived from tyrosine hydroxylase (TH) driven tumorigenesis, which undergoes reversible morphological differentiation on serum deprivation. Using single-cell electrophysiology we have examined the properties of ion channels expressed in CAD cells. Despite relatively low resting potentials, CAD cells can be induced to fire robust action potentials when mildly artificially hyperpolarized. Correspondingly, voltage-dependent sodium and potassium currents were elicited under voltage clamp. Sodium currents are TTX sensitive and exhibit conventional activation and inactivation properties. The potassium currents reflected two pharmacologically distinguishable populations of delayed rectifier type channels while no transient A-type channels were observed. Using barium as a charge carrier, we observed an inactivating current that was completely blocked by nimodipine and thus associated with L-type calcium channels. On differentiation, three changes in functional channel expression occurred; a 4-fold decrease in sodium current density, a 1.5-fold increase in potassium current density, and the induction of a small noninactivating barium current component. The neuronal morphology, excitability properties, and changes in channel function with differentiation make CAD cells an attractive model for study of catecholaminergic neurons.