bluuebunny/crossref_metadata_2025 huggingface dataset:
Zinc and Flunitrazepam Modulation of GABA-Mediated Currents in Rat Suprachiasmatic Neurons
Authors: Strecker G. J. , Park W. K. , Dudek F. E.
Published: December 2017

Strecker, G. J., W. K. Park, and F. E. Dudek. Zinc and flunitrazepam modulation of GABA-mediated currents in rat suprachiasmatic neurons. J. Neurophysiol. 81: 184–191, 1999. The suprachiasmatic nucleus (SCN) of the hypothalamus is responsible for generating circadian rhythms in mammals, and GABA is the predominant neurotransmitter in the SCN. Properties of γ-aminobutyric acid-A (GABAA) responses in SCN neurons were examined in acutely prepared hypothalamic slices from 3- to 8-wk-old rats with the use of whole cell voltage-clamp techniques. Zn2+ reduced the amplitude of GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in a concentration-dependent manner ranging from a reduction of control amplitude to 88% at 10 μM to 27% at 1,000 μM. Zn2+ reduced IPSC amplitude to a similar degree in the presence of tetrodotoxin and also significantly reduced the amplitude of currents evoked by application of exogenous GABA (100 μM, pressure applied). Zn2+ increased the frequency of IPSCs at lower concentrations and decreased it at higher ones. Flunitrazepam (100 nM) usually failed to potentiate the amplitude of sIPSCs, but prolonged sIPSC kinetics. Two exponential components were normally resolved in the sIPSC decay constants, and flunitrazepam significantly increased those two components. Thus flunitrazepam increased the duration of sIPSCs and potentiated the amplitude of currents evoked by pressure application of GABA. Zn2+ and benzodiazepine each modulated the effect of GABA in nearly all cells, suggesting that most SCN neurons have a similar GABAA receptor subunit composition in this respect. Zn2+ also affected sIPSC frequency, which suggests that Zn2+ increased neuronal firing rate at lower concentrations. These results begin to define the cellular roles that these GABAA receptor modulators might play in circadian regulation.
Properties and Sex-Specific Differences of GABAA Receptors in Neurons Expressing γ1 Subunit mRNA in the Preoptic Area of the Rat
Authors: Nett Sholeen T. , Jorge-Rivera Juan Carlos , Myers Margaret , Clark Ann S. , Henderson Leslie P.
Published: December 2017

Nett, Sholeen T., Juan C. Jorge-Rivera, Margaret Myers, Ann S. Clark, and Leslie P. Henderson. Properties and sex-specific differences of GABAA receptors in neurons expressing γ1 subunit mRNA in the preoptic area of the rat. J. Neurophysiol. 81: 192–203, 1999. Gamma-aminobutyric acid type A (GABAA) receptors expressed within the medial preoptic area (mPOA) are known to play a critical role in regulating sexual and neuroendocrine functions. In the rat brain, high levels of expression of the γ1 subunit mRNA of the GABAA receptor are restricted to a limited number of regions that mediate sexual behaviors, including the mPOA. The biophysical and pharmacological profiles of native γ1-containing receptors in neurons are unknown. Here, we have characterized the properties of GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) and currents elicited by fast perfusion of GABA to isolated mPOA neurons of juvenile male and female rats. No significant sex-specific differences were evident in the mean peak amplitude, distribution of event amplitudes, kinetics of current decay, or the frequency of sIPSCs. The profile of modulation of sIPSCs by diazepam, β-CCM and zolpidem, allosteric modulators that act at the benzodiazepine (BZ) site of the GABAA receptor, support the assertion that mPOA neurons of both sexes express functional γ1-containing receptors. The ability of zolpidem to modulate both sIPSC amplitude and currents elicited by rapid perfusion of GABA to mPOA neurons differed significantly between the sexes. Zolpidem reversibly induced negative modulation of currents in mPOA neurons isolated from male rats, but had no effect in mPOA neurons from female rats. Concentration-response analysis of responses in neurons acutely isolated from male rats indicated an IC50 of 58 nM with maximal decreases of ∼50% of control peak current amplitude. In situ hybridization analysis demonstrated that levels of the γ1 subunit mRNA are significantly higher in mPOA neurons from male than female rats. No significant sex-specific differences were detected in the levels of α1, α2, or α5 mRNAs. These results suggest that native γ1-containing receptors are expressed in primary neurons of the mPOA and that sex-specific differences in the expression of this subunit may contribute to sexual dimorphism in GABAA receptor modulation by compounds acting at the BZ site.
A1Adenosine Receptors Modulate Respiratory Activity of the Neonatal Mouse Via the cAMP-Mediated Signaling Pathway
Authors: Mironov S. L. , Langohr K. , Richter D. W.
Published: December 2017

Mironov, S. L., K. Langohr, and D. W. Richter. A1adenosine receptors modulate respiratory activity of the neonatal mouse via the cAMP-mediated signaling pathway. J. Neurophysiol. 81: 247–255, 1999. The effects of adenosine and its analogs on the function of the respiratory center were studied in the spontaneously active rhythmic slice of neonatal and juvenile mice (4–14 days old). Whole cell, spontaneous postsynaptic currents (sPSCs) and single channel KATPcurrents were recorded in inspiratory neurons of the pre-Bötzinger complex. Adenosine (50–600 μM) inhibited the respiratory rhythm. This was accompanied by increase in the activity of KATPchannels in cell-attached patches. The A1adenosine receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA, 0.3–2 μM), inhibited the respiratory rhythm, sPSCs, and enhanced activity of KATPchannels. The A1adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1–3 μM), showed opposite effects and occluded the CCPA actions. Agents specific for A2adenosine receptors (CGS 21860 and NECA, both applied at 1–10 μM) were without effect. Elevation of intracellular cAMP concentration ([cAMP]i) by 8-Br-cAMP (200–500 μM), forskolin (0.5–2 μM), or isobutylmethylxantine (IBMX, 30–90 μM) reinforced the rhythm, whereas NaF (100–800 μM) depressed it. The open probability of single KATPchannels in cell-attached patches decreased after application of forskolin and increased in the presence of NaF. [cAMP]ielevation reversed the effects of A1receptors both on the respiratory rhythm and KATPchannels. A1receptors and [cAMP]imodified the hypoxic respiratory response. In the presence of A1agonists the duration of hypoxic augmentation shortened, and depression of the respiratory rhythm occurred earlier. Elevation of [cAMP]iprolonged augmentation and delayed the development of the depression. We conclude that A1adenosine receptors modulate the respiratory rhythm via inhibition of intracellular cAMP production and concomitant activation of KATPchannels.
Evidence for NMDA and mGlu Receptor-Dependent Long-Term Potentiation of Mossy Fiber–Granule Cell Transmission in Rat Cerebellum
Authors: D'Angelo Egidio , Rossi Paola , Armano Simona , Taglietti Vanni
Published: December 2017

D'Angelo, Egidio, Paola Rossi, Simona Armano, and Vanni Taglietti. Evidence for NMDA and mGlu receptor-dependent long-term potentiation of mossy fiber–granule cell transmission in rat cerebellum. J. Neurophysiol. 81: 277–287, 1999. Long-term potentiation (LTP) is a form of synaptic plasticity that can be revealed at numerous hippocampal and neocortical synapses following high-frequency activation of N-methyl-d-aspartate (NMDA) receptors. However, it was not known whether LTP could be induced at the mossy fiber–granule cell relay of cerebellum. This is a particularly interesting issue because theories of the cerebellum do not consider or even explicitly negate the existence of mossy fiber–granule cell synaptic plasticity. Here we show that high-frequency mossy fiber stimulation paired with granule cell membrane depolarization (−40 mV) leads to LTP of granule cell excitatory postsynaptic currents (EPSCs). Pairing with a relatively hyperpolarized potential (−60 mV) or in the presence of NMDA receptor blockers [5-amino-d-phosphonovaleric acid (APV) and 7-chloro-kynurenic acid (7-Cl-Kyn)] prevented LTP, suggesting that the induction process involves a voltage-dependent NMDA receptor activation. Metabotropic glutamate receptors were also involved because blocking them with (+)-α-methyl-4-carboxyphenyl-glycine (MCPG) prevented potentiation. At the cytoplasmic level, EPSC potentiation required a Ca2+ increase and protein kinase C (PKC) activation. Potentiation was expressed through an increase in both the NMDA and non-NMDA receptor-mediated current and by an NMDA current slowdown, suggesting that complex mechanisms control synaptic efficacy during LTP. LTP at the mossy fiber–granule cell synapse provides the cerebellar network with a large reservoir for memory storage, which may be needed to optimize pattern recognition and, ultimately, cerebellar learning and computation.
Ionic Mechanisms Underlying Depolarizing Responses of an Identified Insect Motor Neuron to Short Periods of Hypoxia
Authors: Le Corronc Hervé , Hue Bernard , Pitman Robert M.
Published: December 2017

Le Corronc, Hervé, Bernard Hue, and Robert M. Pitman. Ionic mechanisms underlying depolarizing responses of an identified insect motor neuron to short periods of hypoxia. J. Neurophysiol. 81: 307–318, 1999. Hypoxia can dramatically disrupt neural processing because energy-dependent homeostatic mechanisms are necessary to support normal neuronal function. In a human context, the long-term effects of such disruption may become all too apparent after a “stroke,” in which blood-flow to part of the brain is compromised. We used an insect preparation to investigate the effects of hypoxia on neuron membrane properties. The preparation is particularly suitable for such studies because insects respond rapidly to hypoxia, but can recover when they are restored to normoxic conditions, whereas many of their neurons are large, identifiable, and robust. Experiments were performed on the “fast” coxal depressor motoneuron (Df) of cockroach ( Periplaneta americana). Five-minute periods of hypoxia caused reversible multiphasic depolarizations (10–25 mV; n = 88), consisting of an initial transient depolarization followed by a partial repolarization and then a slower phase of further depolarization. During the initial depolarizing phase, spontaneous plateau potentials normally occurred, and inhibitory postsynaptic potential frequency increased considerably; 2–3 min after the onset of hypoxia all electrical activity ceased and membrane resistance was depressed. On reoxygenation, the membrane potential began to repolarize almost immediately, becoming briefly more negative than the normal resting potential. All phases of the hypoxia response declined with repeated periods of hypoxia. Blockade of ATP-dependent Na/K pump by 30 μM ouabain suppressed only the initial transient depolarization and the reoxygenation-induced hyperpolarization. Reduction of aerobic metabolism between hypoxic periods (produced by bubbling air through the chamber instead of oxygen) had a similar effect to that of ouabain. Although the depolarization seen during hypoxia was not reduced by tetrodotoxin (TTX; 2 μM), lowering extracellular Na+concentration or addition of 500 μM Cd2+greatly reduced all phases of the hypoxia-induced response, suggesting that Na influx occurs through a TTX-insensitive Cd2+-sensitive channel. Exposure to 20 mM tetraethylammonium and 1 mM 3,4-diaminopyridine increased the amplitude of the hypoxia-induced depolarization, suggesting that activation of K channels may normally limit the amplitude of the hypoxia response. In conclusion we suggest that the slow hypoxia-induced depolarization on motoneuron Dfis mainly carried by a TTX-resistant, Cd2+-sensitive sodium influx. Ca2+entry may also make a direct or indirect contribution to the hypoxia response. The fast transient depolarization appears to result from block of the Na/K pump, whereas the reoxygenation-induced hyperpolarization is largely caused by its subsequent reactivation.
Uninjured C-Fiber Nociceptors Develop Spontaneous Activity and α-Adrenergic Sensitivity Following L6 Spinal Nerve Ligation in Monkey
Authors: Ali Z. , Ringkamp M. , Hartke T. V. , Chien H. F. , Flavahan N. A. , Campbell J. N. , Meyer R. A.
Published: December 2017

Ali, Z., M. Ringkamp, T. V. Hartke, H. F. Chien, N. A. Flavahan, J. N. Campbell, and R. A. Meyer. Uninjured cutaneous C-fiber nociceptors develop spontaneous activity and α-adrenergic sensitivity following L6 spinal nerve ligation in the monkey. J. Neurophysiol. 81: 455–466, 1999. We investigated whether uninjured cutaneous C-fiber nociceptors in primates develop abnormal responses after partial denervation of the skin. Partial denervation was induced by tightly ligating spinal nerve L6 that innervates the dorsum of the foot. Using an in vitro skin-nerve preparation, we recorded from uninjured single afferent nerve fibers in the superficial peroneal nerve. Recordings were made from 32 C-fiber nociceptors 2–3 wk after ligation and from 29 C-fiber nociceptors in control animals. Phenylephrine, a selective α1-adrenergic agonist, and UK14304 (UK), a selective α2-adrenergic agonist, were applied to the receptive field for 5 min in increasing concentrations from 0.1 to 100 μM. Nociceptors from in vitro control experiments were not significantly different from nociceptors recorded by us previously in in vivo experiments. In comparison to in vitro control animals, the afferents found in lesioned animals had 1) a significantly higher incidence of spontaneous activity, 2) a significantly higher incidence of response to phenylephrine, and 3) a higher incidence of response to UK. In lesioned animals, the peak response to phenylephrine was significantly greater than to UK, and the mechanical threshold of phenylephrine-sensitive afferents was significantly lower than for phenylephrine-insensitive afferents. Staining with protein gene product 9.5 revealed an ∼55% reduction in the number of unmyelinated terminals in the epidermis of the lesioned limb compared with the contralateral limb. Thus uninjured cutaneous C-fiber nociceptors that innervate skin partially denervated by ligation of a spinal nerve acquire two abnormal properties: spontaneous activity and α-adrenergic sensitivity. These abnormalities in nociceptor function may contribute to neuropathic pain.
Actions of a Pair of Identified Cerebral-Buccal Interneurons (CBI-8/9) inAplysiaThat Contain the Peptide Myomodulin
Authors: Xin Yuanpei , Hurwitz Itay , Perrins Ray , Evans Colin G. , Alexeeva Vera , Weiss Klaudiusz R. , Kupfermann Irving
Published: December 2017

Actions of a pair of identified cerebral-buccal interneurons (CBI-8/9) in Aplysia that contain the peptide myomodulin. A combination of biocytin back-fills of the cerebral-buccal connectives and immunocytochemistry of the cerebral ganglion demonstrated that of the 13 bilateral pairs of cerebral-buccal interneurons in the cerebral ganglion, a subpopulation of 3 are immunopositive for the peptide myomodulin. The present paper describes the properties of two of these cells, which we have termed CBI-8 and CBI-9. CBI-8 and CBI-9 were found to be dye coupled and electrically coupled. The cells have virtually identical properties, and consequently we consider them to be “twin” pairs and refer to them as CBI-8/9. CBI-8/9 were identified by electrophysiological criteria and then labeled with dye. Labeled cells were found to be immunopositive for myomodulin, and, using high pressure liquid chromatography, the cells were shown to contain authentic myomodulin. CBI-8/9 were found to receive synaptic input after mechanical stimulation of the tentacles. They also received excitatory input from C-PR, a neuron involved in neck lengthening, and received a slow inhibitory input from CC5, a cell involved in neck shortening, suggesting that CBI-8/9 may be active during forward movements of the head or buccal mass. Firing of CBI-8 or CBI-9 resulted in the activation of a relatively small number of buccal neurons as evidenced by extracellular recordings from buccal nerves. Firing also produced local movements of the buccal mass, in particular a strong contraction of the I7 muscle, which mediates radula opening. CBI-8/9 were found to produce a slow depolarization and rhythmic activity of B48, the motor neuron for the I7 muscle. The data provide continuing evidence that the small population of cerebral buccal interneurons is composed of neurons that are highly diverse in their functional roles. CBI-8/9 may function as a type of premotor neuron, or perhaps as a peptidergic modulatory neuron, the functions of which are dependent on the coactivity of other neurons.
Voltage-Dependent Properties of Dendrites That Eliminate Location-Dependent Variability of Synaptic Input
Authors: Cook Erik P. , Johnston Daniel
Published: December 2017

Voltage-dependent properties of dendrites that eliminate location-dependent variability of synaptic input. We examined the hypothesis that voltage-dependent properties of dendrites allow for the accurate transfer of synaptic information to the soma independent of synapse location. This hypothesis is motivated by experimental evidence that dendrites contain a complex array of voltage-gated channels. How these channels affect synaptic integration is unknown. One hypothesized role for dendritic voltage-gated channels is to counteract passive cable properties, rendering all synapses electrotonically equidistant from the soma. With dendrites modeled as passive cables, the effect a synapse exerts at the soma depends on dendritic location (referred to as location-dependent variability of the synaptic input). In this theoretical study we used a simplified three-compartment model of a neuron to determine the dendritic voltage-dependent properties required for accurate transfer of synaptic information to the soma independent of synapse location. A dendrite that eliminates location-dependent variability requires three components: 1) a steady-state, voltage-dependent inward current that together with the passive leak current provides a net outward current and a zero slope conductance at depolarized potentials, 2) a fast, transient, inward current that compensates for dendritic membrane capacitance, and 3) both αamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid– and N-methyl-d-aspartate–like synaptic conductances that together permit synapses to behave as ideal current sources. These components are consistent with the known properties of dendrites. In addition, these results indicate that a dendrite designed to eliminate location-dependent variability also actively back-propagates somatic action potentials.
Simultaneous Measurement of Evoked Release and [Ca2+]iin a Crayfish Release Bouton Reveals High Affinity of Release to Ca2+
Authors: Ravin R. , Parnas H. , Spira M. E. , Volfovsky N. , Parnas I.
Published: December 2017

Simultaneous measurement of evoked release and [Ca2+]iin a crayfish release bouton reveals high affinity of release to Ca2+. The opener neuromuscular junction of crayfish was used to determine the affinity of the putative Ca2+receptor(s) responsible for evoked release. Evoked, asynchronous release, and steady-state intracellular Ca2+concentration, [Ca2+]ss, were measured concomitantly in single release boutons. It was found that, as expected, asynchronous release is highly correlated with [Ca2+]ss. Surprisingly, evoked release was also found to be highly correlated with [Ca2+]ss. The quantal content ( m) and the rate of asynchronous release ( S) showed sigmoidal dependence on [Ca2+]ss. The slope log m/log [Ca2+]ssvaried between 1.6 and 3.3; the higher slope observed at the lower [Ca2+]o. The slope log S/log [Ca2+]ssvaried between 3 and 4 and was independent of [Ca2+]o. These results are consistent with the assumption that evoked release is controlled by the sum of [Ca2+]ssand the local elevation of Ca2+concentration near the release sites resulting from Ca2+influx through voltage-gated Ca2+channels ( Y). On the basis of the above, we were able to estimate Y. We found Y to be significantly <10 μM even for [Ca2+]o= 13.5 mM. The dissociation constant ( Kd) of the Ca2+receptor(s) associated with evoked release was calculated to be in the range of 4–5 μM. This value of Kdis similar to that found previously for asynchronous release.
Optimality of Position Commands to Horizontal Eye Muscles: A Test of the Minimum-Norm Rule
Authors: Dean Paul , Porrill John , Warren Paul A.
Published: December 2017

Optimality of position commands to horizontal eye muscles: a test of the minimum-norm rule. Six muscles control the position of the eye, which has three degrees of freedom. Daunicht proposed an optimization rule for solving this redundancy problem, whereby small changes in eye position are maintained by the minimum possible change in motor commands to the eye (the minimum-norm rule). The present study sought to test this proposal for the simplified one-dimensional case of small changes in conjugate eye position in the horizontal plane. Assuming such changes involve only the horizontal recti, Daunicht’s hypothesis predicts reciprocal innervation with the size of the change in command matched to the strength of the recipient muscle at every starting position of the eye. If the motor command to a muscle is interpreted as the summed firing rate of its oculomotor neuron (OMN) pool, the minimum-norm prediction can be tested by comparing OMN firing rates with forces in the horizontal recti. The comparison showed 1) for the OMN firing rates given by Van Gisbergen and Van Opstal and the muscle forces given by Robinson, there was good agreement between the minimum-norm prediction and experimental observation over about a ±30° range of eye positions. This fit was robust with respect to variations in muscle stiffness and in methods of calculating muscle innervation. 2) Other data sets gave different estimates for the range of eye-positions within which the minimum-norm prediction held. The main sources of variation appeared to be disagreement about the proportion of OMNs with very low firing-rate thresholds (i.e., less than ∼35° in the off direction) and uncertainty about eye-muscle behavior for extreme (>30°) positions of the eye. 3) For all data sets, the range of eye positions over which the minimum-norm rule applied was determined by the pattern of motor-unit recruitment inferred for those data. It corresponded to the range of eye positions over which the size principle of recruitment was obeyed by both agonist and antagonist muscles. It is argued that the current best estimate of the oculomotor range over which minimum-norm control could be used for conjugate horizontal eye position is approximately ±30°. The uncertainty associated with this estimate would be reduced by obtaining unbiased samples of OMN firing rates. Minimum-norm control may result from reduction of the image movement produced by noise in OMN firing rates.
Long-Term Effects of Prior Heat Shock on Neuronal Potassium Currents Recorded in a Novel Insect Ganglion Slice Preparation
Authors: Ramirez J. M. , Elsen F. P. , Robertson R. M.
Published: December 2017

Long-term effects of prior heat shock on neuronal potassium currents recorded in a novel insect ganglion slice preparation. Brief exposure to high temperatures (heat shock) induces long-lasting adaptive changes in the molecular biology of protein interactions and behavior of poikilotherms. However, little is known about heat shock effects on neuronal properties. To investigate how heat shock affects neuronal properties we developed an insect ganglion slice from locusts. The functional integrity of neuronal circuits in slices was demonstrated by recordings from rhythmically active respiratory neurons and by the ability to induce rhythmic population activity with octopamine. Under these “functional” in vitro conditions we recorded outward potassium currents from neurons of the ventral midline of the A1 metathoracic neuromere. In control neurons, voltage steps to 40 mV from a holding potential of −60 mV evoked in control neurons potassium currents with a peak current of 10.0 ± 2.5 nA and a large steady state current of 8.5 ± 2.6 nA, which was still activated from a holding potential of −40 mV. After heat shock most of the outward current inactivated rapidly (peak amplitude: 8.4 ± 2.4 nA; steady state: 3.6 ± 2.0 nA). This current was inactivated at a holding potential of −40 mV. The response to temperature changes was also significantly different. After changing the temperature from 38 to 42°C the amplitude of the peak and steady-state current was significantly lower in neurons obtained from heat-shocked animals than those obtained from controls. Our study indicates that not only heat shock can alter neuronal properties, but also that it is possible to investigate ion currents in insect ganglion slices.
Neuronal Activity in Somatosensory Cortex of Monkeys Using a Precision Grip. I. Receptive Fields and Discharge Patterns
Authors: Salimi Iran , Brochier Thomas , Smith Allan M.
Published: December 2017

Neuronal activity in somatosensory cortex of monkeys using a precision grip. I. Receptive fields and discharge patterns. Three adolescent Macaca fascicularis monkeys weighing between 3.5 and 4 kg were trained to use a precision grip to grasp a metal tab mounted on a low friction vertical track and to lift and hold it in a 12- to 25-mm position window for 1 s. The surface texture of the metal tab in contact with the fingers and the weight of the object could be varied. The activity of 386 single cells with cutaneous receptive fields contacting the metal tab were recorded in Brodmann’s areas 3b, 1, 2, 5, and 7 of the somatosensory cortex. In this first of a series of papers, we describe three types of discharge pattern, the receptive-field properties, and the anatomic distribution of the neurons. The majority of the receptive fields were cutaneous and covered less than one digit, and a χ2 test did not reveal any significant differences in the Brodmann’s areas representing the thumb and index finger. Two broad categories of discharge pattern cells were identified. The first category, dynamic cells, showed a brief increase in activity beginning near grip onset, which quickly subsided despite continued pressure applied to the receptive field. Some of the dynamic neurons responded to both skin indentation and release. The second category, static cells, had higher activity during the stationary holding phase of the task. These static neurons demonstrated varying degrees of sensitivity to rates of pressure change on the skin. The percentage of dynamic versus static cells was about equal for areas 3b, 2, 5, and 7. Only area 1 had a higher proportion of dynamic cells (76%). A third category was identified that contained cells with significant pregrip activity and included cortical cells with both dynamic or static discharge patterns. Cells in this category showed activity increases before movement in the absence of receptive-field stimulation, suggesting that, in addition to peripheral cutaneous input, these cells also receive strong excitation from movement-related regions of the brain.
Frontal Cognitive Impairments and Saccadic Deficits in Low-Dose MPTP-Treated Monkeys
Authors: Slovin Hamutal , Abeles Moshe , Vaadia Eilon , Haalman Iris , Prut Yifat , Bergman Hagai
Published: December 2017

Frontal cognitive impairments and saccadic deficits in low-dose MPTP-treated monkeys. There is considerable overlap between the cognitive deficits observed in humans with frontal lobe damage and those described in patients with Parkinson’s disease. Similar frontal impairments have been found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinsonism. Here we provide quantitative documentation of the cognitive, oculomotor, and skeletomotor dysfunctions of monkeys trained on a frontal task and treated with low-doses (LD) of MPTP. Two rhesus monkeys were trained to perform a spatial delayed-response task with frequent alternations between two behavioral modes (go andno-go). After control recordings, the monkeys were treated with one placebo and successive LD MPTP courses. Monkey Cdeveloped motor Parkinsonian signs after a fourth course of medium-dose (MD) MPTP and later was treated with combined dopaminergic therapy (CDoT). There were no gross motor changes after the LD MPTP courses, and the average movement time (MT) did not increase. However, reaction time (RT) increased significantly. Both RT and MT were further increased in the symptomatic state, under CDoT. Self-initiated saccades became hypometric after LD MPTP treatments and their frequency decreased. Visually triggered saccades were affected to a lesser extent by the LD MPTP treatments. All saccadic parameters declined further in the symptomatic state and improved partially during CDoT. The number ofgo mode (no-response, location, and early release) errors increased after MPTP treatment. The monkeys made more perseverative errors while switching from the go to the no-gomode. Saccadic eye movement patterns suggest that frontal deficits were involved in most observed errors. CDoT had a differential effect on the behavioral errors. It decreased omission errors but did not improve location errors or perseverative errors. Tyrosine hydroxylase immunohistochemistry showed moderate (∼70–80%) reduction in the number of dopaminergic neurons in the substantia nigra pars compacta after MPTP treatment. These results show that cognitive and motor disorders can be dissociated in the LD MPTP model and that cognitive and oculomotor impairments develop before the onset of skeletal motor symptoms. The behavioral and saccadic deficits probably result from the marked reduction of dopaminergic neurons in the midbrain. We suggest that these behavioral changes result from modified neuronal activity in the frontal cortex.
Retinal Input Induces Three Firing Patterns in Neurons of the Superficial Superior Colliculus of Neonatal Rats
Authors: Lo Fu-Sun , Mize R. Ranney
Published: December 2017

Retinal input induces three firing patterns in neurons of the superficial superior colliculus of neonatal rats. By using an in vitro isolated brain stem preparation, we recorded extracellular responses to electrical stimulation of the optic tract (OT) from 71 neurons in the superficial superior colliculus (SC) of neonatal rats (P1–13). At postnatal day 1 (P1), all tested neurons ( n = 10) already received excitatory input from the retina. Sixty-nine (97%) superficial SC neurons of neonatal rats showed three response patterns to OT stimulation, which depended on stimulus intensity. A weak stimulus evoked only one spike that was caused by activation of non– N-methyl-d-aspartate (NMDA) glutamate receptors. A moderate stimulus elicited a short train (<250 ms) of spikes, which was induced by activation of both NMDA and non-NMDA receptors. A strong stimulus gave rise to a long train (>300 ms) of spikes, which was associated with additional activation of L-type high-threshold calcium channels. The long train firing pattern could also be induced either by temporal summation of retinal inputs or by blocking γ-aminobutyric acid-A receptors. Because retinal ganglion cells show synchronous bursting activity before eye opening at P14, the retinotectal inputs appear to be sufficient to activate L-type calcium channels in the absence of pattern vision. Therefore activation of L-type calcium channels is likely to be an important source for calcium influx into SC neurons in neonatal rats.
Epinephrine Produces a β-Adrenergic Receptor-Mediated Mechanical Hyperalgesia and In Vitro Sensitization of Rat Nociceptors
Authors: Khasar Sachia G. , McCarter Gordon , Levine Jon D.
Published: December 2017

Epinephrine produces a β-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of nociceptor-like neurons in the rat. Hyperalgesic and nociceptor sensitizing effects mediated by the β-adrenergic receptor were evaluated in the rat. Intradermal injection of epinephrine, the major endogenous ligand for the β-adrenergic receptor, into the dorsum of the hindpaw of the rat produced a dose-dependent mechanical hyperalgesia, quantified by the Randall-Selitto paw-withdrawal test. Epinephrine-induced hyperalgesia was attenuated significantly by intradermal pretreatment with propranolol, a β-adrenergic receptor antagonist, but not by phentolamine, an α-adrenergic receptor antagonist. Epinephrine-induced hyperalgesia developed rapidly; it was statistically significant by 2 min after injection, reached a maximum effect within 5 min, and lasted 2 h. Injection of a more β-adrenergic receptor-selective agonist, isoproterenol, also produced dose-dependent hyperalgesia, which was attenuated by propranolol but not phentolamine. Epinephrine-induced hyperalgesia was not affected by indomethacin, an inhibitor of cyclo-oxygenase, or by surgical sympathectomy. It was attenuated significantly by inhibitors of the adenosine 3′,5′-cyclic monophosphate signaling pathway (the adenylyl cyclase inhibitor, SQ 22536, and the protein kinase A inhibitors, Rp-adenosine 3′,5′-cyclic monophosphate and WIPTIDE), inhibitors of the protein kinase C signaling pathway (chelerythrine and bisindolylmaleimide) and a μ-opioid receptor agonist DAMGO ([d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin). Consistent with the hypothesis that epinephrine produces hyperalgesia by a direct action on primary afferent nociceptors, it was found to sensitize small-diameter dorsal root ganglion neurons in culture, i.e., to produce an increase in number of spikes and a decrease in latency to firing during a ramped depolarizing stimulus. These effects were blocked by propranolol. Furthermore epinephrine, like several other direct-acting hyperalgesic agents, caused a potentiation of tetrodotoxin-resistant sodium current, an effect that was abolished by Rp-adenosine 3′,5′-cyclic monophosphate and significantly attenuated by bisindolylmaleimide. Isoproterenol also potentiated tetrodotoxin-resistant sodium current. In conclusion, epinephrine produces cutaneous mechanical hyperalgesia and sensitizes cultured dorsal root ganglion neurons in the absence of nerve injury via an action at a β-adrenergic receptor. These effects of epinephrine are mediated by both the protein kinase A and protein kinase C second-messenger pathways.
Tonic Activation of Presynaptic GABAB Receptors in the Opener Neuromuscular Junction of Crayfish
Authors: Parnas Itzchak , Rashkovan Grigory , Ong Jennifer , Kerr David I. B.
Published: December 2017

Tonic activation of presynaptic GABAB receptors in the opener neuromuscular junction of crayfish. 1184–1191 Release of excitatory transmitter from boutons on crayfish nerve terminals was inhibited by (R,S)-baclofen, an agonist at GABAB receptors. Baclofen had no postsynaptic actions as it reduced quantal content without affecting quantal amplitude. The effect of baclofen increased with concentration producing 18% inhibition at 10 μM; EC50, 50% inhibition at 30 μM; maximal inhibition, 85% at 100 μM and higher. There was no desensitization, even with 200 or 320 μM baclofen. Phaclofen, an antagonist at GABABreceptors, competitively antagonized the inhibitory action of baclofen ( K D = 50 μM, equivalent to a pA2 = 4.3 ± 0.1). Phaclofen on its own at concentrations below 200 μM had no effect on release, whereas at 200 μM phaclofen itself increased the control level of release by 60%, as did 2-hydroxy-saclofen (200 μM), another antagonist at GABAB receptors. This increase was evidently due to antagonism of a persistent level of GABA in the synaptic cleft, since the effect was abolished by destruction of the presynaptic inhibitory fiber, using intra-axonal pronase. We conclude that presynaptic GABAB receptors, with a pharmacological profile similar to that of mammalian GABAB receptors, are involved in the control of transmitter release at the crayfish neuromuscular junction.
Inhibitory Nature of Tiagabine-Augmented GABAAReceptor–Mediated Depolarizing Responses in Hippocampal Pyramidal Cells
Authors: Jackson Michael F. , Esplin Barbara , C̆apek Radan
Published: December 2017

Inhibitory nature of tiagabine-augmented GABAA receptor–mediated depolarizing responses in hippocampal pyramidal cells. Tiagabine is a potent GABA uptake inhibitor with demonstrated anticonvulsant activity. GABA uptake inhibitors are believed to produce their anticonvulsant effects by prolonging the postsynaptic actions of GABA, released during episodes of neuronal hyperexcitability. However, tiagabine has recently been reported to facilitate the depolarizing actions of GABA in the CNS of adult rats following the stimulation of inhibitory pathways at a frequency (100 Hz) intended to mimic interneuronal activation during epileptiform activity. In the present study, we performed extracellular and whole cell recordings from CA1 pyramidal neurons in rat hippocampal slices to examine the functional consequences of tiagabine-augmented GABA-mediated depolarizing responses. Orthodromic population spikes (PSs), elicited from the stratum radiatum, were inhibited following the activation of recurrent inhibitory pathways by antidromic conditioning stimulation of the alveus, which consisted of either a single stimulus or a train of stimuli delivered at high-frequency (100 Hz, 200 ms). The inhibition of orthodromic PSs produced by high-frequency conditioning stimulation (HFS), which was always of much greater strength and duration than that produced by a single conditioning stimulus, was greatly enhanced following the bath application of tiagabine (2–100 μM). Thus, in the presence of tiagabine (20 μM), orthodromic PSs, evoked 200 and 800 ms following HFS, were inhibited to 7.8 ± 2.6% (mean ± SE) and 34.4 ± 18.5% of their unconditioned amplitudes compared with only 35.4 ± 12.7% and 98.8 ± 12.4% in control. Whole cell recordings revealed that the bath application of tiagabine (20 μM) either caused the appearance or greatly enhanced the amplitude of GABA-mediated depolarizing responses (DR). Excitatory postsynaptic potentials (EPSPs) evoked from stratum radiatum at time points that coincided with the DR were inhibited to below the threshold for action-potential firing. Independently of the stimulus intensity with which they were evoked, the charge transferred to the soma by excitatory postsynaptic currents (EPSCs), elicited in the presence of tiagabine (20 μM) during the large (1,428 ± 331 pA) inward currents that underlie the DRs, was decreased on the average by 90.8 ± 1.7%. Such inhibition occurred despite the presence of the GABAB receptor antagonist, CGP 52 432 (10 μM), indicating that GABAB heteroreceptors, located on glutamatergic terminals, do not mediate the observed reduction in the amplitude of excitatory postsynaptic responses. The present results suggest that despite facilitating the induction of GABA-mediated depolarizations, tiagabine application may nevertheless increase the effectiveness of synaptic inhibition during the synchronous high-frequency activation of inhibitory interneurons by enhanced shunting.
Projections and Firing Properties of Down Eye-Movement Neurons in the Interstitial Nucleus of Cajal in the Cat
Authors: Chimoto Sohei , Iwamoto Yoshiki , Yoshida Kaoru
Published: December 2017

Projections and firing properties of down eye-movement neurons in the interstitial nucleus of Cajal in the cat. To clarify the role of the interstitial nucleus of Cajal (INC) in the control of vertical eye movements, projections of burst-tonic and tonic neurons in and around the INC were studied. This paper describes neurons with downwardon directions. We examined, by antidromic activation, whether these down INC (d-INC) neurons contribute to two pathways: a commissural pathway to the contralateral (c-) INC and a descending pathway to the ipsilateral vestibular nucleus (i-VN). Stimulation of the two pathways showed that as many as 74% of neurons were activated antidromically from one of the pathways. Of 113 d-INC neurons tested, 44 were activated from the commissural pathway and 40 from the descending pathway. No neurons were activated from both pathways. We concluded that commissural and descending pathways from the INC originate from two separate groups of neurons. Tracking of antidromic microstimulation in the two nuclei revealed multiple low-threshold sites and varied latencies; this was interpreted as a sign of existence of axonal arborization. Neurons with commissural projections tended to be located more dorsally than those with descending projections. Neurons with descending projections had significantly greater eye-position sensitivity and smaller saccadic sensitivity than neurons with commissural projections. The two groups of INC neurons increased their firing rate in nose-up head rotations and responded best to the rotation in the plane of contralateral posterior/ipsilateral anterior canal pair. Neurons with commissural projections showed a larger phase lag of response to sinusoidal rotation (54.6 ± 7.6°) than neurons with descending projections (45.0 ± 5.5°). Most neurons with descending projections received disynaptic excitation from the contralateral vestibular nerve. Neurons with commissural projections rarely received such disynaptic input. We suggest that downward-position-vestibular (DPV) neurons in the VN and VN-projecting d-INC neurons form a loop, together with possible commissural loops linking the bilateral VNs and the bilateral INCs. By comparing the quantitative measures of d-INC neurons with those of DPV neurons, we further suggest that integration of head velocity signals proceeds from DPV neurons to d-INC neurons with descending projections and then to d-INC neurons with commissural projections, whereas saccadic velocity signals are processed in the reverse order.
Role of Presynaptic L-Type Ca2+ Channels in GABAergic Synaptic Transmission in Cultured Hippocampal Neurons
Authors: Jensen Kimmo , Jensen Morten Skovgaard , Lambert John D. C.
Published: December 2017

Role of presynaptic L-type Ca2+ channels in GABAergic synaptic transmission in cultured hippocampal neurons. Using dual whole cell patch-clamp recordings of monosynaptic GABAergic inhibitory postsynaptic currents (IPSCs) in cultured rat hippocampal neurons, we have previously demonstrated posttetanic potentiation (PTP) of IPSCs. Tetanic stimulation of the GABAergic neuron leads to accumulation of Ca2+ in the presynaptic terminals. This enhances the probability of GABA-vesicle release for up to 1 min, which underlies PTP. In the present study, we have examined the effect of altering the probability of release on PTP of IPSCs. Baclofen (10 μM), which depresses presynaptic Ca2+ entry through N- and P/Q-type voltage-dependent Ca2+ channels (VDCCs), caused a threefold greater enhancement of PTP than did reducing [Ca2+]o to 1.2 mM, which causes a nonspecific reduction in Ca2+ entry. This finding prompted us to investigate whether presynaptic L-type VDCCs contribute to the Ca2+ accumulation in the boutons during spike activity. The L-type VDCC antagonist, nifedipine (10 μM), had no effect on single IPSCs evoked at 0.2 Hz but reduced the PTP evoked by a train of 40 Hz for 2 s by 60%. Another L-type VDCC antagonist, isradipine (5 μM), similarly inhibited PTP by 65%. Both L-type VDCC blockers also depressed IPSCs during the stimulation (i.e., they increased tetanic depression). The L-type VDCC “agonist” (−)BayK 8644 (4 μM) had no effect on PTP evoked by a train of 40 Hz for 2 s, which probably saturated the PTP process, but enhanced PTP evoked by a train of 1 s by 91%. In conclusion, the results indicate that L-type VDCCs do not participate in low-frequency synchronous transmitter release, but contribute to presynaptic Ca2+ accumulation during high-frequency activity. This helps maintain vesicle release during tetanic stimulation and also enhances the probability of transmitter release during the posttetanic period, which is manifest as PTP. Involvement of L-type channels in these processes represents a novel presynaptic regulatory mechanism at fast CNS synapses.
Electrophysiological and Behavioral Analysis of Lip Touch as a Component of the Food Stimulus in the SnailLymnaea
Authors: Staras Kevin , Kemenes György , Benjamin Paul R.
Published: December 2017

Electrophysiological and behavioral analysis of lip touch as a component of the food stimulus in the snail Lymnaea. Electrophysiological and video recording methods were used to investigate the function of lip touch in feeding ingestion behavior of the pond snail Lymnaea stagnalis. Although this stimulus was used successfully as a conditioning stimulus (CS) in appetitive learning experiments, the detailed role of lip touch as a component of the sensory stimulus provided by food in unconditioned feeding behavior was never ascertained. Synaptic responses to lip touch in identified feeding motoneurons, central pattern generator interneurons, and modulatory interneurons were recorded by intracellular electrodes in a semi-intact preparation. We showed that touch evoked a complex but characteristic sequence of synaptic inputs on each neuron type. Touch never simply activated feeding cycles but provided different types of synaptic input, determined by the feeding phase in which the neuron was normally active in the rhythmic feeding cycle. The tactile stimulus evoked mainly inhibitory synaptic inputs in protraction-phase neurons and excitation in rasp-phase neurons. Swallow-phase neurons were also excited after some delay, suggesting that touch first reinforces the rasp then swallow phase. Video analysis of freely feeding animals demonstrated that during normal ingestion of a solid food flake the food is drawn across the lips throughout the rasp phase and swallow phase and therefore provides a tactile stimulus during both these retraction phases of the feeding cycle. The tactile component of the food stimulus is strongest during the rasp phase when the lips are actively pressed onto the substrate that is being moved across them by the radula. By using a semi-intact preparation we demonstrated that application of touch to the lips during the rasp phase of a sucrose-driven fictive feeding rhythm increases both the regularity and frequency of rasp-phase motoneuron firing compared with sucrose applied alone.
Action of the Brain Stem Saccade Generator During Horizontal Gaze Shifts. I. Discharge Patterns of Omnidirectional Pause Neurons
Authors: Phillips James O. , Ling Leo , Fuchs Albert F.
Published: December 2017

Action of the brain stem saccade generator during horizontal gaze shifts. I. Discharge patterns of omnidirectional pause neurons. Omnidirectional pause neurons (OPNs) pause for the duration of a saccade in all directions because they are part of the neural mechanism that controls saccade duration. In the natural situation, however, large saccades are accompanied by head movements to produce rapid gaze shifts. To determine whether OPNs are part of the mechanism that controls the whole gaze shift rather than the eye saccade alone, we monitored the activity of 44 OPNs that paused for rightward and leftward gaze shifts but otherwise discharged at relatively constant average rates. Pause duration was well correlated with the duration of either eye or gaze movement but poorly correlated with the duration of head movement. The time of pause onset was aligned tightly with the onset of either eye or gaze movement but only loosely aligned with the onset of head movement. These data suggest that the OPN pause does not encode the duration of head movement. Further, the end of the OPN pause was often better aligned with the end of the eye movement than with the end of the gaze movement for individual gaze shifts. For most gaze shifts, the eye component ended with an immediate counterrotation owing to the vestibuloocular reflex (VOR), and gaze ended at variable times thereafter. In those gaze shifts where eye counterrotation was delayed, the end of the pause also was delayed. Taken together, these data suggest that the end of the pause influences the onset of eye counterrotation, not the end of the gaze shift. We suggest that OPN neurons act to control only that portion of the gaze movement that is commanded by the eye burst generator. This command is expressed by driving the saccadic eye movement directly and also by suppressing VOR eye counterrotation. Because gaze end is less well correlated with pause end and often occurs well after counterrotation onset, we conclude that elements of the burst generator typically are not active till gaze end, and that gaze end is determined by another mechanism independent of the OPNs.