bluuebunny/crossref_metadata_2025 huggingface dataset:
Context Compensation in the Vestibuloocular Reflex During Active Head Rotations
Authors: Medendorp W. P. , Van Gisbergen J.A.M. , Van Pelt S. , Gielen C.C.A.M.
Published: December 2017

The vestibuloocular reflex (VOR) needs to modulate its gain depending on target distance to prevent retinal slip during head movements. We investigated gain modulation (context compensation) for binocular gaze stabilization in human subjects during voluntary yaw and pitch head rotations. Movements of each eye were recorded, both when attempting to maintain gaze on a small visual target at straight-ahead in a darkened room and after its disappearance (remembered target). In the analysis, we relied on a binocular coordinate system yielding a version and a vergence component. We examined how frequency and target distance, approached here by using vergence angle, affected the gain and phase of the version component of the VOR and compared the results to the requirements for ideal performance. Linear regression analysis on the version gain-vergence relationship yielded a slope representing the influence of target proximity and an intercept corresponding to the response at zero vergence (“default gain”). The slope of the fitted relationship, divided by the geometrically required slope, provided a measure for the quality of version context compensation (“context gain”). In both yaw and pitch experiments, we found default version gains close to one even for the remembered target condition, indicating that the active VOR for far targets is already close to ideal without visual support. In near target experiments, the presence of visual feedback yielded near unity context gains, indicating close to optimal performance (retinal slip <0.4°/s). For remembered targets, the context gain deteriorated but was still superior to performance in corresponding passive studies reported in the literature. In general, context compensation in the remembered target paradigm was better for vertical than for horizontal head rotations. The phase delay of version eye velocity relative to head velocity was small (∼2°) for both horizontal and vertical head movements. Analysis of the vergence data from the near target experiments showed that context compensation took into account that the two eyes require slightly different VORs. In thediscussion, comparison of the present default VOR gains and context gains with data from earlier passive studies has led us to propose a limited role for efference copies during self-generated movements. We also discuss how our analysis can provide a framework for evaluating two different hypotheses for the generation of binocular VOR eye movements.
Synaptic Connections From Multiple Subfields Contribute to Granule Cell Hyperexcitability in Hippocampal Slice Cultures
Authors: Bausch Suzanne B. , McNamara James O.
Published: December 2017

Limbic status epilepticus and preparation of hippocampal slice cultures both produce cell loss and denervation. This commonality led us to hypothesize that morphological and physiological alterations in hippocampal slice cultures may be similar to those observed in human limbic epilepsy and animal models. To test this hypothesis, we performed electrophysiological and morphological analyses in long-term ( postnatal day 11; 40–60 days in vitro) organotypic hippocampal slice cultures. Electrophysiological analyses of dentate granule cell excitability revealed that granule cells in slice cultures were hyperexcitable compared with acute slices from normal rats. In physiological buffer, spontaneous electrographic granule cell seizures were seen in 22% of cultures; in the presence of a GABAA receptor antagonist, seizures were documented in 75% of cultures. Hilar stimulation evoked postsynaptic potentials (PSPs) and multiple population spikes in the granule cell layer, which were eliminated by glutamate receptor antagonists, demonstrating the requirement for excitatory synaptic transmission. By contrast, under identical recording conditions, acute hippocampal slices isolated from normal rats exhibited a lack of seizures, and hilar stimulation evoked an isolated population spike without PSPs. To examine the possibility that newly formed excitatory synaptic connections to the dentate gyrus contribute to granule cell hyperexcitability in slice cultures, anatomical labeling and electrophysiological recordings following knife cuts were performed. Anatomical labeling of individual dentate granule, CA3 and CA1 pyramidal cells with neurobiotin illustrated the presence of axonal projections that may provide reciprocal excitatory synaptic connections among these regions and contribute to granule cell hyperexcitability. Knife cuts severing connections between CA1 and the dentate gyrus/CA3c region reduced but did not abolish hilar-evoked excitatory PSPs, suggesting the presence of newly formed, functional synaptic connections to the granule cells from CA1 and CA3 as well as from neurons intrinsic to the dentate gyrus. Many of the electrophysiological and morphological abnormalities reported here for long-term hippocampal slice cultures bear striking similarities to both human and in vivo models, making this in vitro model a simple, powerful system to begin to elucidate the molecular and cellular mechanisms underlying synaptic rearrangements and epileptogenesis.
Regeneration of Cerebral-Buccal Interneurons and Recovery of Ingestion Buccal Motor Programs in Aplysia After CNS Lesions
Authors: Sánchez José Antonio D. , Li Yongsheng , Kirk Mark D.
Published: December 2017

In the sea slug Aplysia, rhythmic biting is eliminated after bilateral cerebral-buccal connective (CBC) crushes and recovers within 14 days postlesion (dpl). The ability of cerebral-buccal interneuron-2 (CBI-2) to elicit ingestion buccal motor programs (iBMPs; i.e., fictive rhythmic ingestion) and to regenerate synaptic connections with target buccal neurons was assessed with intracellular recordings and dye injections. Isolated central ganglia were obtained from control animals and from lesioned animals at selected times after bilateral CBC crushes. Within 3 wk postlesion, transected CBI-2 axons sprouted at least 10 fine neurites confined to the core of the CBC that projected across the crush site toward the buccal ganglia. When fired with depolarizing current steps, CBI-2 was not observed to elicit iBMPs in preparations until 14 dpl. Thereafter a progressive enhancement in CBI-2's ability to elicit iBMPs was observed with time postlesion. By 40 dpl, CBI-2-elicited iBMPs were indistinguishable from those of controls. CBI-2 regenerated monosynaptic connections with appropriate buccal premotor- and motorneurons by 14 dpl, and the strength of these connections increased with time postlesion. Dramatic frequency facilitation was exhibited by the regenerating CBI-2 buccal synapses; for instance, at early postlesion times, no observable excitatory postsynaptic potentials (EPSPs) were obtained with 1- Hz stimulation of CBI-2, while at 7 Hz, a dramatic increase in EPSP amplitude was obtained with successive spikes. The present study shows that the time course of axonal and synaptic regeneration by command-like interneuron CBI-2 is correlated with the recovery of ingestion buccal motor programs elicited by CBI-2. These results parallel our previous findings of functional neural regeneration in the feeding system and suggest that functional neural regeneration is at least in part mediated by regeneration of specific synaptic pathways.
Synaptic Efficacy and the Transmission of Complex Firing Patterns Between Neurons
Authors: Faure Philippe , Kaplan Daniel , Korn Henri
Published: December 2017

In central neurons, the summation of inputs from presynaptic cells combined with the unreliability of synaptic transmission produces incessant variations of the membrane potential termed synaptic noise (SN). These fluctuations, which depend on both the unpredictable timing of afferent activities and quantal variations of postsynaptic potentials, have defied conventional analysis. We show here that, when applied to SN recorded from the Mauthner (M) cell of teleosts, a simple method of nonlinear analysis reveals previously undetected features of this signal including hidden periodic components. The phase relationship between these components is compatible with the notion that the temporal organization of events comprising this noise is deterministic rather than random and that it is generated by presynaptic interneurons behaving as coupled periodic oscillators. Furthermore a model of the presynaptic network shows how SN is shaped both by activities in incoming inputs and by the distribution of their synaptic weights expressed as mean quantal contents of the activated synapses. In confirmation we found experimentally that long-term tetanic potentiation (LTP), which selectively increases some of these synaptic weights, permits oscillating temporal patterns to be transmitted more effectively to the postsynaptic cell. Thus the probabilistic nature of transmitter release, which governs the strength of synapses, may be critical for the transfer of complex timing information within neuronal assemblies.
Learning- and Expectation-Related Changes in the Human Brain During Motor Learning
Authors: Ramnani N. , Toni I. , Josephs O. , Ashburner J. , Passingham R. E.
Published: December 2017

We have studied a simple form of motor learning in the human brain so as to isolate activity related to motor learning and the prediction of sensory events. Whole-brain, event-related functional magnetic resonance imaging (fMRI) was used to record activity during classical discriminative delay eyeblink conditioning. Auditory conditioned stimulus (CS+) trials were presented either with a corneal airpuff unconditioned stimulus (US, paired), or without a US (unpaired). Auditory CS− trials were never reinforced with a US. Trials were presented pseudorandomly, 66 times each. The subjects gradually produced conditioned responses to CS+ trials, while increasingly differentiating between CS+ and CS− trials. The increasing difference between hemodynamic responses for unpaired CS+ and for CS− trials evolved slowly during conditioning in the ipsilateral cerebellar cortex (Crus I/Lobule HVI), contralateral motor cortex and hippocampus. To localize changes that were related to sensory prediction, we compared trials on which the expected airpuff US failed to occur (Unpaired CS+) with trials on which it occurred as expected (Paired CS+). Error-related signals in the contralateral cerebellum and somatosensory cortex were seen to increase during learning as the sensory prediction became stronger. The changes seen in the ipsilateral cerebellar cortex may be due either to the violations of sensory predictions, or to learning-related increases in the excitability of cerebellar neurons to presentations of the CS+.
Peptide-Induced Ca2+Movements in a Tonic Insect Muscle: Effects of Proctolin and Periviscerokinin-2
Authors: Wegener Christian , Nässel Dick R.
Published: December 2017

Although most of the characterized insect neuropeptides have been detected by their actions on muscle contractions, not much is known about the mechanisms underlying excitation-contraction coupling. Thus we initiated a pharmacological study on the myotropic action of the peptides periviscerokinin-2 (PVK-2) and proctolin on the hyperneural muscle of the cockroach Periplaneta americana. Both peptides required extracellular Ca2+to induce muscle contraction, and a blockage of sarcolemmal Ca2+channels by Mn2+or La3+inhibited myotropic effects. The peptides were able to induce contractions in dependence on the extracellular Ca2+concentration in muscles depolarized with high K+saline. A reduction of extracellular Na+, K+, or Cl−did not effect peptide action. Nifedipine, an L-type Ca2+-channel blocker, partially blocked the response to both peptides but to a much lesser extent than contractions evoked by elevated K+. Using calcium imaging with fluo-3, we show that proctolin induces an increase of the intracellular Ca2+concentration. In calcium-free saline, no increase of the intracellular Ca2+concentration could be detected. The inhibiting effect of ryanodine, thapsigargin, and TMB-8 on peptide-induced contractions suggests that Ca2+release from the sarcoplasmic reticulum plays a major role during peptide-induced contractions. Preliminary experiments suggest that the peptides do not employ cyclic nucleotides as second messengers, but may activate protein kinase C. Our results indicate that the peptides induce Ca2+influx by an activation or modulation of dihydropyridine-sensitive and voltage-independent sarcolemmal Ca2+channels. Ca2+-induced Ca2+release from intracellular stores, but not inositol trisphosphate-induced Ca2+release, seems to account for most of the observed increase in intracellular Ca2+. Additionally, both peptides were able to potentiate glutamate-induced contractions at threshold concentrations.
Short- and Long-Term Changes in CA1 Network Excitability After Kainate Treatment in Rats
Authors: Smith Bret N. , Dudek F. Edward
Published: December 2017

Neuron loss, axon sprouting, and the formation of new synaptic circuits have been hypothesized to contribute to seizures in temporal lobe epilepsy (TLE). Using the kainate-treated rat, we examined how alterations in the density of CA1 pyramidal cells and interneurons, and subsequent sprouting of CA1 pyramidal cell axons, were temporally associated with functional changes in the network properties of the CA1 area. Control rats were compared with animals during the first week after kainate treatment versus several weeks after treatment. The density of CA1 pyramidal cells and putative inhibitory neurons in stratum oriens was reduced within 8 days after kainate treatment. Axon branching of CA1 pyramidal cells was similar between controls and animals examined in the first week after kainate treatment but was increased several weeks after kainate treatment. Stimulation of afferent fibers in brain slices containing the isolated CA1 region produced graded responses in slices from controls and kainate-treated rats tested <8 days after treatment. In contrast, synchronous all-or-none bursts of spikes at low stimulus intensity (i.e., “network bursts”) were only observed in the CA1 several weeks after kainate treatment. In the presence of bicuculline, the duration of evoked bursts was significantly longer in CA1 pyramidal cells weeks after kainate treatment than from controls or those examined in the first week posttreatment. Spontaneous network bursts were also observed in the isolated CA1 several weeks after kainate treatment in bicuculline-treated slices. The data suggest that the early loss of neurons directly associated with kainate-induced status epilepticus is followed by increased axon sprouting and new recurrent excitatory circuits in CA1 pyramidal cells. These changes characterize the transition from the initial acute effects of the kainate-induced insult to the eventual development of all-or-none epileptiform discharges in the CA1 area.
Feedback Connections Act on the Early Part of the Responses in Monkey Visual Cortex
Authors: Hupé Jean-Michel , James Andrew C. , Girard Pascal , Lomber Stephen G. , Payne Bertram R. , Bullier Jean
Published: December 2017

We previously showed that feedback connections from MT play a role in figure/ground segmentation. Figure/ground coding has been described at the V1 level in the late part of the neuronal responses to visual stimuli, and it has been suggested that these late modulations depend on feedback connections. In the present work we tested whether it actually takes time for this information to be fed back to lower order areas. We analyzed the extracellular responses of 169 V1, V2, and V3 neurons that we recorded in two anesthetized macaque monkeys. MT was inactivated by cooling. We studied the time course of the responses of the neurons that were significantly affected by the inactivation of MT to see whether the effects were delayed relative to the onset of the response. We first measured the time course of the feedback influences from MT on V1, V2, and V3 neurons tested with moving stimuli. For the large majority of the 51 neurons for which the response decreased, the effect was present from the beginning of the response. In the responses averaged after normalization, the decrease of response was significant in the first 10-ms bin of response. A similar result was found for six neurons for which the response significantly increased when MT was inactivated. We then looked at the time course of the responses to flashed stimuli (95 neurons). We observed 15 significant decreases of response and 14 significant increases. In both populations, the effects were significant within the first 10 ms of response. For some neurons with increased responses we even observed a shorter latency when MT was inactivated. We measured the latency of the response to the flashed stimuli. We found that even the earliest responding neurons were affected early by the feedback from MT. This was true for the response to flashed and to moving stimuli. These results show that feedback connections are recruited very early for the treatment of visual information. It further indicates that the presence or absence of feedback effects cannot be deduced from the time course of the response modulations.
Response Modulations by Static Texture Surround in Area V1 of the Macaque Monkey Do Not Depend on Feedback Connections From V2
Authors: Hupé Jean-Michel , James Andrew C. , Girard Pascal , Bullier Jean
Published: December 2017

We analyzed the extracellular responses of 70 V1 neurons (recorded in 3 anesthetized macaque monkeys) to a single oriented line segment (or bar) placed within the cell classical receptive field (RF), or center of the RF. These responses could be modulated when rings of bars were placed entirely outside, but around the RF (the “near” surround region), as described in previous studies. Suppression was the main effect. The response was enhanced for 12 neurons when orthogonal bars in the surround were presented instead of bars having the same orientation as the center bar. This orientation contrast property is possibly involved in the mediation of perceptual pop-out. The enhancement was delayed compared with the onset of the response by about 40 ms. We also observed a suppression originating specifically from the flanks of the surround. This “side-inhibition,” significant for nine neurons, was delayed by about 20 ms. We tested whether these center/surround interactions in V1 depend on feedback connections from area V2. V2 was inactivated by GABA injections. We used devices made of six micropipettes to inactivate the convergent zone from V2 to V1. We could reliably inactivate a 2- to 4-mm-wide region of V2. Inactivation of V2 had no effect on the center/surround interactions of V1 neurons, even those that were delayed. Therefore the center/surround interactions of V1 neurons that might be involved in pop-out do not appear to depend on feedback connections from V2, at least in the anesthetized monkey. We conclude that these properties are probably shaped by long-range connections within V1 or depend on other feedback connections. The main effect of V2 inactivation was a decrease of the response to the single bar for about 10% of V1 neurons. The decrease was delayed by <20 ms after the response onset. Even the earliest neurons to respond could be affected by the feedback from V2. Together with the results on feedback connections from MT (previous paper), these findings show that feedback connections potentiate the responses to stimulation of the RF center and are recruited very early for the treatment of visual information.
Tufted Cell Dendrodendritic Inhibition in the Olfactory Bulb Is Dependent on NMDA Receptor Activity
Authors: Christie J. M. , Schoppa N. E. , Westbrook G. L.
Published: December 2017

Mitral and tufted cells constitute the primary output cells of the olfactory bulb. While tufted cells are often considered as “displaced” mitral cells, their actual role in olfactory bulb processing has been little explored. We examined dendrodendritic inhibition between tufted cells and interneurons using whole cell voltage-clamp recording. Dendrodendritic inhibitory postsynaptic currents (IPSCs) generated by depolarizing voltage steps in tufted cells were completely blocked by the N-methyl-d-aspartate (NMDA) receptor antagonistd,l-2amino-5-phosphonopentanoic acid (d,l-AP5), whereas the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2-3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f] quinoxaline-7-sulfonamide (NBQX) had no effect. Tufted cells in the external plexiform layer (EPL) and in the periglomerular region (PGR) showed similar behavior. These results indicate that NMDA receptor–mediated excitation of interneurons drives inhibition of tufted cells at dendrodendritic synapses as it does in mitral cells. However, the spatial extent of lateral inhibition in tufted cells was much more limited than in mitral cells. We suggest that the sphere of influence of tufted cells, while qualitatively similar to mitral cells, is centered on only one or a few glomeruli.
Theta Rhythm of Hippocampal CA1 Neuron Activity: Gating by GABAergic Synaptic Depolarization
Authors: Sun Miao-Kun , Zhao Wei-Qin , Nelson Thomas J. , Alkon Daniel L.
Published: December 2017

Information processing and memory consolidation during exploratory behavior require synchronized activity known as hippocampal theta (θ) rhythm. While it is well established that the θ activity depends on cholinergic inputs from the medial septum/vertical limb of the diagonal band nucleus (MS/DBv) and θ discharges of GABAergic interneurons, and can be induced with cholinergic receptor agonists, it is not clear how the increased excitation of pyramidal cells could occur with increased discharges of GABAergic interneurons during θ waves. Here, we show that the characteristic θ activity in adult rat hippocampal CA1 pyramidal cells is associated with GABAergic postsynaptic depolarization and a shift of the reversal potential from Cl−toward HCO3−(whose ionic gradient is regulated by carbonic anhydrase). The θ activity was abolished by GABAAreceptor antagonists and carbonic anhydrase inhibitors, but largely unaffected by blocking glutamate receptors. Carbonic anhydrase inhibition also impaired spatial learning in a watermaze without affecting other sensory/locomotor behaviors. Thus HCO3−-mediated signaling, as regulated by carbonic anhydrase, through reversed polarity of GABAergic postsynaptic responses is implicated in both θ and memory consolidation in rat spatial maze learning. We suggest that this mechanism may be important for the phase forward shift of the place cell discharges for each θ cycle during the animal's traversal of the place field for that cell.
Metrifonate Decreases sI AHP in CA1 Pyramidal Neurons In Vitro
Authors: Power John M. , Oh M. Mathew , Disterhoft John F.
Published: December 2017

Metrifonate, a cholinesterase inhibitor, has been shown to enhance learning in aging rabbits and rats, and to alleviate the cognitive deficits observed in Alzheimer's disease patients. We have previously determined that bath application of metrifonate reduces the spike frequency adaptation and postburst afterhyperpolarization (AHP) in rabbit CA1 pyramidal neurons in vitro using sharp electrode current-clamp recording. The postburst AHP and accommodation observed in current clamp are the result of four slow outward potassium currents (s I AHP, I AHP, I M, and I C) and the hyperpolarization activated mixed cation current, I h. We recorded from visually identified CA1 hippocampal pyramidal neurons in vitro using whole cell voltage-clamp technique to better isolate and characterize which component currents of the AHP are affected by metrifonate. We observed an age-related enhancement of the slow component of the AHP tail current (s I AHP), but not of the fast decaying component of the AHP tail current ( I AHP, I M, and I C). Bath perfusion of metrifonate reduced s I AHP at concentrations that cause a reduction of the AHP and accommodation in current-clamp recordings, with no apparent reduction of I AHP, I M, and I C. The functional consequences of metrifonate administration are apparently mediated solely through modulation of the s I AHP.
Bidirectional Synaptic Plasticity Correlated With the Magnitude of Dendritic Calcium Transients Above a Threshold
Authors: Cormier R. J. , Greenwood A. C. , Connor J. A.
Published: December 2017

The magnitude of postsynaptic Ca2+transients is thought to affect activity-dependent synaptic plasticity associated with learning and memory. Large Ca2+transients have been implicated in the induction of long-term potentiation (LTP), while smaller Ca2+transients have been associated with long-term depression (LTD). However, a direct relationship has not been demonstrated between Ca2+measurements and direction of synaptic plasticity in the same cells, using one induction protocol. Here, we used glutamate iontophoresis to induce Ca2+transients in hippocampal CA1 neurons injected with the Ca2+-indicator fura-2. Test stimulation of one or two synaptic pathways before and after iontophoresis showed that the direction of synaptic plasticity correlated with glutamate-induced Ca2+levels above a threshold, below which no plasticity occurred (∼180 nM). Relatively low Ca2+levels (180–500 nM) typically led to LTD of synaptic transmission and higher levels (>500 nM) often led to LTP. Failure to show plasticity correlated with Ca2+levels in two distinct ranges: <180 nM and ∼450–600 nM, while only LTD occurred between these ranges. Our data support a class of models in which failure of Ca2+transients to affect transmission may arise either from insufficient Ca2+to affect Ca2+-sensitive proteins regulating synaptic strength through opposing activities or from higher Ca2+levels that reset activities of such proteins without affecting the net balance of activities. Our estimates of the threshold Ca2+level for LTD (∼180 nM) and for the transition from LTD to LTP (∼540 nM) may assist in constraining the molecular details of such models.
Essential Role of a Fast Persistent Inward Current in Action Potential Initiation and Control of Rhythmic Firing
Authors: Lee R. H. , Heckman C. J.
Published: December 2017

In spinal motoneurons in an in vivo preparation, we investigated the relationship between a fast persistent inward current located in or near the soma and the capacity of these cells to fire rhythmically. The fast persistent current could be markedly reduced by prolonged depolarization. Modest reductions resulted in profound changes in the slope of the frequency-current relationship. At greater reduction levels, rhythmic firing failed and could not be restored by increasing injected current. However, fully formed spikes still occurred in a slow, uncoordinated fashion, suggesting that the fast inactivating Na+ currents that generate the spike itself remained unchanged. Consequently, the fast persistent inward current, which may be primarily generated by persistent Na+ channels, appears to be essential for initiation of spikes during rhythmic firing. Additionally, it appears that the fast persistent current plays a major role in setting the frequency-current gain.
Mu Opiates Inhibit Long-Term Potentiation Induction in the Spinal Cord Slice
Authors: Terman Gregory W. , Eastman Clifford L. , Chavkin Charles
Published: December 2017

Long-term potentiation (LTP) involves a prolonged increase in neuronal excitability following repeated afferent input. This phenomenon has been extensively studied in the hippocampus as a model of learning and memory. Similar long-term increases in neuronal responses have been reported in the dorsal horn of the spinal cord following intense primary afferent stimulation. In these studies, we utilized the spinal cord slice preparation to examine effects of the potently antinociceptive mu opioids in modulating primary afferent/dorsal horn neurotransmission as well as LTP of such transmission. Transverse slices were made from the lumbar spinal cord of 10- to 17-day-old rats, placed in a recording chamber, and perfused with artificial cerebrospinal fluid also containing bicuculline (10 μM) and strychnine (1 μM). Primary afferent activation was achieved in the spinal slice by electrical stimulation of the dorsal root (DR) or the tract of Lissauer (LT) which is known to contain a high percentage of small diameter fibers likely to transmit nociception. Consistent with this anatomy, response latencies of LT-evoked field potentials in the dorsal horn were considerably slower than the response latencies of DR-evoked potentials. Only LT-evoked field potentials were found to be reliably inhibited by the mu opioid receptor agonist [d-Ala2, N-Me-Phe4, Gly5] enkephalin-ol (DAMGO, 1 μM), although evoked potentials from both DR and LT were blocked by the AMPA/kainate glutamate receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione. Moreover repeated stimulation of LT produced LTP of LT- but not DR-evoked potentials. In contrast, repeated stimulation of DR showed no reliable LTP. LTP of LT-evoked potentials depended on N-methyl-d-aspartate (NMDA) receptor activity, in that it was attenuated by the NMDA antagonist APV. Moreover, such LTP was inhibited by DAMGO interfering with LTP induction mechanisms. Finally, in whole cell voltage-clamp studies of Lamina I neurons, DAMGO inhibited excitatory postsynaptic current (EPSC) response amplitudes from LT stimulation-evoked excitatory amino acid release but not from glutamate puffed onto the cell and increased paired-pulse facilitation of EPSCs evoked by LT stimulation. These studies suggest that mu opioids exert their inhibitory effects presynaptically, likely through the inhibition of glutamate release from primary afferent terminals, and thereby inhibit the induction of LTP in the spinal dorsal horn.
Electrophysiological and Morphological Characterization of Neurons Within Neocortical Ectopias
Authors: Gabel Lisa A. , LoTurco Joseph J.
Published: December 2017

Focal developmental abnormalities in neocortex, including ectopic collections of neurons in layer I (ectopias), have been associated with behavioral and neurological deficits. In this study, we used infrared differential interference contrast microscopy and whole cell patch-clamp to complete the first characterization of neurons within and surrounding neocortical ectopias. Current-clamp recordings revealed that neurons within ectopias display multiple types of action potential firing patterns, and biocytin labeling indicated that ∼20% of the cells in neocortical ectopias can be classified as nonpyramidal cells and the rest as atypically oriented pyramidal cells. All cells had spontaneous excitatory (glutamatergic) and inhibitory (GABAergic) postsynaptic currents. Exhibitory postsynaptic currents consisted of both N-methyl-d-aspartate (NMDA) receptor-mediated and AMPA/kainate (A/K) receptor-mediated currents. The NMDA receptor-mediated component had decay time constants of 15.35 ± 2.2 (SE) ms, while the A/K component had faster decay kinetics of 7.6 ± 1.7 ms at −20 mV. GABAAreceptor-mediated synaptic currents in ectopic cells reversed at potentials near the Cl−equilibrium potential and had decay kinetics of 16.65 ± 1.3 ms at 0 mV. Furthermore we show that cells within ectopias receive direct excitatory and inhibitory input from adjacent normatopic cortex and can display a form of epileptiform activity.
Differential Actions of PKA and PKC in the Regulation of Glutamate Release by Group III mGluRs in the Entorhinal Cortex
Authors: Evans D. Ieuan , Jones Roland S. G. , Woodhall Gavin
Published: December 2017

In a previous study we showed that activation of a presynaptically located metabotropic glutamate receptor (mGluR) with pharmacological properties of mGluR4a causes a facilitation of glutamate release in layer V of the rat entorhinal cortex (EC) in vitro. In the present study we have begun to investigate the intracellular coupling linking the receptor to transmitter release. We recorded spontaneous α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–mediated excitatory postsynaptic currents (EPSCs) in the whole cell configuration of the patch-clamp technique, from visually identified neurons in layer V. Bath application of the protein kinase A (PKA) activator, forskolin, resulted in a marked facilitation of EPSC frequency, similar to that seen with the mGluR4a specific agonist, ACPT-1. Preincubation of slices with the PKA inhibitor H-89 abolished the effect of ACPT-1, as did preincubation with the adenylate cyclase inhibitor, SQ22536. Activation of protein kinase C (PKC) using phorbol 12 myristate 13-acetate (PMA) did not affect sEPSC frequency; however, it did abolish the facilitatory effect of ACPT-1 on glutamate release. A robust enhancement of EPSC frequency was seen in response to bath application of the specific PKC inhibitor, GF 109203X. Both H-89 and the group III mGluR antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG) abolished the effects of GF 109203X. These data suggest that in layer V of the EC, presynaptic group III mGluRs facilitate release via a positive coupling to adenylate cyclase and subsequent activation of PKA. We have also demonstrated that the PKC system tonically depresses transmitter release onto layer V cells of the EC and that an interaction between mGluR4a, PKA, and PKC may exist at these synapses.
5-HT Modulation of Multiple Inward Rectifiers in Motoneurons in Intact Preparations of the Neonatal Rat Spinal Cord
Authors: Kjaerulff Ole , Kiehn Ole
Published: December 2017

This study introduces novel aspects of inward rectification in neonatal rat spinal motoneurons (MNs) and its modulation by serotonin (5-HT). Whole cell tight-seal recordings were made from MNs in an isolated lumbar spinal cord preparation from rats 1–2 days of age. In voltage clamp, hyperpolarizing step commands were generated from holding potentials of −50 to −40 mV. Discordant with previous reports involving slice preparations, fast inward rectification was commonly expressed and in 44% of the MNs co-existed with a slow inward rectification related to activation of I h. The fast inward rectification is likely caused by an I Kir. Thus it appeared around E K and was sensitive to low concentrations (100–300 μM) of Ba2+ but not to ZD 7288, which blocked I h. Both I Kir and I h were inhibited by Cs2+ (0.3–1.5 mM). Extracellular addition of 5-HT (10 μM) reduced the instantaneous conductance, most strongly at membrane potentials above E K. Low [Ba2+] prevented the 5-HT–induced instantaneous conductance reduction below, but not that above, E K. This suggests that 5-HT inhibits I Kir, but also other instantaneous conductances. The biophysical parameters of I h were evaluated before and under 5-HT. The maximal I h conductance, G max, was 12 nS, much higher than observed in slice preparations. G maxwas unaffected by 5-HT. In contrast, 5-HT caused a 7-mV depolarizing shift in the activation curve of I h. Double-exponential fits were generally needed to describe I h activation. The fast and slow time constants obtained by these fits differed by an order of magnitude. Both time constants were accelerated by 5-HT, the slow time constant to the largest extent. We conclude that spinal neonatal MNs possess multiple forms of inward rectification. I h may be carried by two spatially segregated channel populations, which differ in kinetics and sensitivity to 5-HT. 5-HT increases MN excitability in several ways, including inhibition of a barium-insensitive leak conductance, inhibition of I Kir, and enhancement of I h. The quantitative characterization of these effects should be useful for further studies seeking to understand how neuromodulation prepares vertebrate MNs for concerted behaviors such as locomotor activity.
Axotomy- and Autotomy-Induced Changes in Ca2+and K+ Channel Currents of Rat Dorsal Root Ganglion Neurons
Authors: Abdulla Fuad A. , Smith Peter A.
Published: December 2017

Sciatic nerve section (axotomy) increases the excitability of rat dorsal root ganglion (DRG) neurons. The changes in Ca2+ currents, K+ currents, Ca2+-sensitive K+ current, and hyperpolarization-activated cation current ( I H) that may be associated with this effect were examined by whole cell recording. Axotomy affected the same conductances in all types of DRG neuron. In general, the largest changes were seen in “small” cells and the smallest changes were seen in “large” cells. High-voltage–activated Ca2+-channel current (HVA- I Ba) was reduced by axotomy. Although currents recorded in axotomized neurons exhibited increased inactivation, this did not account for all of the reduction in HVA- I Ba. Activation kinetics were unchanged, and experiments with nifedipine and/or ω-conotoxin GVIA showed that there was no change in the percentage contribution of L-type, N-type, or “other” HVA- I Bato the total current after axotomy. T-type (low-voltage–activated) I Ba was not affected by axotomy. Ca2+-sensitive K+conductance ( g K,Ca) appeared to be reduced, but when voltage protocols were adjusted to elicit similar amounts of Ca2+ influx into control and axotomized cells, I K,Ca(s) were unchanged. After axotomy, Cd2+-insensitive, steady-state K+ channel current, which primarily comprised delayed rectifier K+ current ( I K), was reduced by about 60% in small, medium, and large cells. These data suggest that axotomy-induced increases in excitability are associated with decreases in I K and/or decreases in g K,Ca that are secondary to decreased Ca2+-influx. Because I H was reduced by axotomy, changes in this current do not contribute to increased excitability. The amplitude and inactivation of I Ba in all cell types was changed more profoundly in animals that exhibited self-mutilatory behavior (autotomy). The onset of this behavior corresponded with significant reduction in I Ba of large neurons. This finding supports the hypothesis that autotomy, that may be related to human neuropathic pain, is associated with changes in the properties of large myelinated sensory neurons.
Facilitated Glutamatergic Transmission in the Striatum of D2 Dopamine Receptor-Deficient Mice
Authors: Cepeda C. , Hurst R. S. , Altemus K. L. , Flores-Hernández J. , Calvert C. R. , Jokel E. S. , Grandy D. K. , Low M. J. , Rubinstein M. , Ariano M. A. , Levine M. S.
Published: December 2017

Dopamine (DA) receptors play an important role in the modulation of excitability and the responsiveness of neurons to activation of excitatory amino acid receptors in the striatum. In the present study, we utilized mice with genetic deletion of D2 or D4 DA receptors and their wild-type (WT) controls to examine if the absence of either receptor subtype affects striatal excitatory synaptic activity. Immunocytochemical analysis verified the absence of D2 or D4 protein expression in the striatum of receptor-deficient mutant animals. Sharp electrode current- and whole cell patch voltage-clamp recordings were obtained from slices of receptor-deficient and WT mice. Basic membrane properties were similar in D2 and D4 receptor-deficient mutants and their respective WT controls. In current-clamp recordings in WT animals, very little low-amplitude spontaneous synaptic activity was observed. The frequency of these spontaneous events was increased slightly in D2 receptor-deficient mice. In addition, large-amplitude depolarizations were observed in a subset of neurons from only the D2 receptor-deficient mutants. Bath application of the K+ channel blocker 4-aminopyridine (100 μM) and bicuculline methiodide (10 μM, to block synaptic activity due to activation of GABAA receptors) markedly increased spontaneous synaptic activity in receptor-deficient mutants and WTs. Under these conditions, D2 receptor-deficient mice displayed significantly more excitatory synaptic activity than their WT controls, while there was no difference between D4receptor-deficient mice and their controls. In voltage-clamp recordings, there was an increase in frequency of spontaneous glutamate receptor-mediated inward currents without a change in mean amplitude in D2 receptor-deficient mutants. In WT mice, activation of D2 family receptors with quinpirole decreased spontaneous excitatory events and conversely sulpiride, a D2 receptor antagonist, increased activity. In D2 receptor-deficient mice, sulpiride had very little net effect. Morphologically, a subpopulation of medium-sized spiny neurons from D2 receptor-deficient mice displayed decreased dendritic spines compared with cells from WT mice. These results provide evidence that D2 receptors play an important role in the regulation of glutamate receptor-mediated activity in the corticostriatal or thalamostriatal pathway. These receptors may function as gatekeepers of glutamate release or of its subsequent effects and thus may protect striatal neurons from excessive excitation.
Blockade of Long-Term Potentiation by β-Amyloid Peptides in the CA1 Region of the Rat Hippocampus In Vivo
Authors: Freir Darragh B. , Holscher Christian , Herron Caroline E.
Published: December 2017

The effect of intracerebroventricular (icv) injections of β-amyloid peptide fragments Aβ[15–25], Aβ[25–35], and Aβ[35–25] were examined on synaptic transmission and long-term potentiation (LTP) in the hippocampal CA1 region in vivo. Rats were anesthetized using urethan, and changes in synaptic efficacy were determined from the slope of the excitatory postsynaptic potential (EPSP). Baseline synaptic responses were monitored for 30 min prior to icv injection of Aβ peptides or vehicle. High-frequency stimulation (HFS) to induce LTP was applied to the Schaffer-collateral pathway 5 min or 1 h following the icv injection. HFS comprised 3 episodes of 10 stimuli at 200 Hz, 10 times, applied at 30-s intervals. Normal LTP measured 30 min following HFS, was produced following icv injection of vehicle (191 ± 17%, mean ± SE, n = 6) or Aβ[15–25; 100 nmol] (177 ± 6%, n = 6) 1 h prior to HFS. LTP was, however, markedly reduced by Aβ[25–35; 10 nmol] (129 ± 9%, n = 6, P < 0.001) and blocked by Aβ[25–35; 100 nmol] (99 ± 6%, n = 6, P < 0.001). Injection of the reverse peptide, Aβ[35–25], also impaired LTP at concentrations of 10 nmol (136 ± 3%, n = 6, P < 0.01) and 100 nmol (144 ± 7, n = 8, P < 0.05). Using a different protocol, HFS was delivered 5 min following Aβ injections, and LTP was measured 1 h post HFS. Stable LTP was produced in the control group (188 ± 15%, n = 7) and blocked by Aβ[25–35, 100 nmol] (108 ± 15%, n = 6, P < 0.001). A lower dose of Aβ[25–35; 10 nmol] did not significantly impair LTP (176 ± 30%, n = 4). The Aβ-peptides tested were also shown to have no significant effect on paired pulse facilitation (interstimulus interval of 50 ms), suggesting that neither presynaptic transmitter release or activity of interneurons in vivo are affected. The effects of Aβ on LTP are therefore likely to be mediated via a postsynaptic mechanism. This in vivo model of LTP is extremely sensitive to Aβ-peptides that can impair LTP in a time- ([25–35]) and concentration-dependent manner ([25–35] and [35–25]). These effects of Aβ-peptides may then contribute to the cognitive deficits associated with Alzheimer's disease.
Capsaicin Inhibits Activation of Voltage-Gated Sodium Currents in Capsaicin-Sensitive Trigeminal Ganglion Neurons
Authors: Liu L. , Oortgiesen M. , Li L. , Simon S. A.
Published: December 2017

Capsaicin, the pungent ingredient in hot pepper, activates nociceptors to produce pain and inflammation. However, repeated exposures of capsaicin will cause desensitization to nociceptive stimuli. In cultured trigeminal ganglion (TG) neurons, we investigated mechanisms underlying capsaicin-mediated inhibition of action potentials (APs) and modulation of voltage-gated sodium channels (VGSCs). Capsaicin (1 μM) inhibited APs and VGSCs only in capsaicin-sensitive neurons. Repeated applications of capsaicin produced depolarizing potentials but failed to evoke APs. The capsaicin-induced inhibition of VGSCs was prevented by preexposing the capsaicin receptor antagonist, capsazepine (CPZ). The magnitude of the capsaicin-induced inhibition of VGSCs was dose dependent, having a K 1/2 = 0.45 μM. The magnitude of the inhibition of VGSCs was proportional to the capsaicin induced current (for – I CAP < 0.2 nA). Capsaicin inhibited activation of VGSCs without changing the voltage dependence of activation or markedly changing channel inactivation and use-dependent block. To explore the changes leading to this inhibition, it was found that capsaicin increased cAMP with a K 1/2 = 0.18 μM. At 1 μM capsaicin, this cAMP generation was inhibited 64% by10 μM CPZ, suggesting that activation of capsaicin receptors increased cAMP. The addition of 100 μM CPT-cAMP increased the capsaicin-activated currents but inhibited the VGSCs in both capsaicin-sensitive and -insensitive neurons. In summary, the inhibitory effects of capsaicin on VGSCs and the generation of APs are mediated by activation of capsaicin receptors. The capsaicin-induced activation of second messengers, such as cAMP, play a part in this modulation. These data distinguish two pathways by which neuronal sensitivity can be diminished by capsaicin: by modulation of the capsaicin receptor sensitivity, since the block of VGSCs is proportional to the magnitude of the capsaicin-evoked currents, and by modulation of VGSCs through second messengers elevated by capsaicin receptor activation. These mechanisms are likely to be important in understanding the analgesic effects of capsaicin.
Interaction of the Frontal Eye Field and Superior Colliculus for Saccade Generation
Authors: Hanes Doug P. , Wurtz Robert H.
Published: December 2017

Both the frontal eye field (FEF) in the prefrontal cortex and the superior colliculus (SC) on the roof of the midbrain participate in the generation of rapid or saccadic eye movements and both have projections to the premotor circuits of the brain stem where saccades are ultimately generated. In the present experiments, we tested the contributions of the pathway from the FEF to the premotor circuitry in the brain stem that bypasses the SC. We assayed the contribution of the FEF to saccade generation by evoking saccades with direct electrical stimulation of the FEF. To test the role of the SC in conveying information to the brain stem, we inactivated the SC, thereby removing the circuit through the SC to the brain stem, and leaving only the direct FEF–brain stem pathway. If the contributions of the direct pathway were substantial, removal of the SC should have minimal effect on the FEF stimulation, whereas if the FEF stimulation were dependent on the SC, removal of the SC should alter the effect of FEF stimulation. By acutely inactivating the SC, instead of ablating it, we were able to test the efficiency of the direct FEF–brain stem pathway before substantial compensatory mechanisms could mask the effect of removing the SC. We found two striking effects of SC inactivation. In the first, we stimulated the FEF at a site that evoked saccades with vectors that were very close to those evoked at the site of the SC inactivation, and with such optimal alignment, we found that SC inactivation eliminated the saccades evoked by FEF stimulation. The second effect was evident when the FEF evoked saccades were disparate from those evoked in the SC, and in this case we observed a shift in the direction of the evoked saccade that was consistent with the SC inactivation removing a component of a vector average. Together these observations lead to the conclusion that in the nonablated monkey the direct FEF–brain stem pathway is not functionally sufficient to generate accurate saccades in the absence of the indirect pathway that courses from the FEF through the SC to the brain stem circuitry. We suggest that the recovery of function following SC ablation that has been seen in previous studies must result not from the use of an already functioning parallel pathway but from neural plasticity within the saccadic system.