bluuebunny/crossref_metadata_2025 huggingface dataset:
Fast NMDA Receptor–Mediated Synaptic Currents in Neurons From Mice Lacking the ε2 (NR2B) Subunit
Authors: Tovar Kenneth R. , Sprouffske Kathleen , Westbrook Gary L.
Published: December 2017

The N-methyl-d-aspartate (NMDA) receptor has been implicated in the formation of synaptic connections. To investigate the role of the ε2 (NR2B) NMDA receptor subunit, which is prominently expressed during early development, we used neurons from mice lacking this subunit. Although ε2−/− mice die soon after birth, we examined whether NMDA receptor targeting to the postsynaptic membrane was dependent on the ε2 subunit by rescuing hippocampal neurons from these mice and studying them in autaptic cultures. In voltage-clamp recordings, excitatory postsynaptic currents (EPSCs) from ε2−/− neurons expressed an NMDA receptor–mediated EPSC that was apparent as soon as synaptic activity developed. However, compared with wild-type neurons, NMDA receptor–mediated EPSC deactivation kinetics were much faster and were less sensitive to glycine, but were blocked by Mg2+ or AP5. Whole cell currents from ε2−/− neurons were also more sensitive to block by low concentrations of Zn2+ and much less sensitive to the ε2-specific antagonist ifenprodil than wild-type currents. The rapid NMDA receptor–mediated EPSC deactivation kinetics and the pharmacological profile from ε2−/−neurons are consistent with the expression of ζ1/ε1 diheteromeric receptors in excitatory hippocampal neurons from mice lacking the ε2 subunit. Thus ε1 can substitute for the ε2 subunit at synapses and ε2 is not required for targeting of NMDA receptors to the postsynaptic membrane.
Damping Actions of the Neuromuscular System With Inertial Loads: Soleus Muscle of the Decerebrate Cat
Authors: Lin David C. , Rymer W. Zev
Published: December 2017

A transient perturbation applied to a limb held in a given posture can induce oscillations. To restore the initial posture, the neuromuscular system must provide damping, which is the dissipation of the mechanical energy imparted by such a perturbation. Despite their importance, damping properties of the neuromuscular system have been poorly characterized. Accordingly, this paper describes the damping characteristics of the neuromuscular system interacting with inertial loads. To quantitatively examine damping, we coupled simulated inertial loads to surgically isolated, reflexively active soleus muscles in decerebrate cats. A simulated force impulse was applied to the load, causing a muscle stretch, which elicited a reflex response. The resulting deviation from the initial position gave rise to oscillations, which decayed progressively. Damping provided by the neuromuscular system was then calculated from the load kinetics. To help interpret our experimental results, we compared our kinetic measurements with those of an analogous linear viscoelastic system and found that the experimental damping properties differed in two respects. First, the amount of damping was greater for large oscillation amplitudes than for small (damping is independent of amplitude in a linear system). Second, plots of force against length during the induced movements showed that damping was greater for shortening than lengthening movements, reflecting greater effective viscosity during shortening. This again is different from the behavior of a linear system, in which damping effects would be symmetrical. This asymmetric and nonlinear damping behavior appears to be related to both the intrinsic nonlinear mechanical properties of the soleus muscle and to stretch reflex properties. The muscle nonlinearities include a change in muscle force-generating capacity induced by forced lengthening, akin to muscle yield, and the nonlinear force-velocity property of muscle, which is different for lengthening versus shortening. Stretch reflex responses are also known to be asymmetric and amplitude dependent. The finding that damping is greater for larger amplitude motion represents a form of automatic gain adjustment to a larger perturbation. In contrast, because of reduced damping at small amplitudes, smaller oscillations would tend to persist, perhaps contributing to normal or “physiological” tremor. This lack of damping for small amplitudes may represent an acceptable compromise for postural regulation in that there is substantial damping for larger movements, where energy dissipation is more critical. Finally, the directional asymmetry in energy dissipation provided by muscle and reflex properties must be reflected in the neural mechanisms for a stable posture.
Vasopressin Increases GABAergic Inhibition of Rat Hypothalamic Paraventricular Nucleus Neurons In Vitro
Authors: Hermes M.L.H.J. , Ruijter J. M. , Klop A. , Buijs R. M. , Renaud L. P.
Published: December 2017

This investigation used an in vitro hypothalamic brain slice preparation and whole cell and perforated-patch recording to examine the response of magnocellular neurons in hypothalamic paraventricular nucleus (PVN) to bath applications of vasopressin (VP; 100–500 nM). In 22/38 cells, responses were characterized by an increase in the frequency of bicuculline-sensitive inhibitory postsynaptic potentials or currents with no detectable influence on excitatory postsynaptic events. Perforated-patch recordings confirmed that VP did not have an effect on intrinsic membrane properties of magnocellular PVN neurons ( n = 17). Analysis of intrinsic membrane properties obtained with perforated-patch recording ( n = 23) demonstrated that all of nine VP-sensitive neurons showed a rebound depolarization after transient membrane hyperpolarization from rest. By contrast, 12/14 nonresponding neurons displayed a delayed return to resting membrane potentials. Recordings of reversed inhibitory postsynaptic currents with chloride-loaded electrodes showed that responses to VP persisted in media containing glutamate receptor antagonists but were abolished in the presence of tetrodotoxin. In addition, responses were mimicked by vasotocin [Phe2, Orn8], a selective V1a receptor agonist, and blocked by [β-Mercapto-β,β-cyclopentamethylenepropionyl1,O-Me-Tyr2, Arg8]-VP (Manning compound), a V1a/OT receptor antagonist. Neither [deamino-Cys1,Val4,d-Arg8]-VP, a selective V2 receptor agonist, nor oxytocin were effective. Collectively, the results imply that VP acts at V1a receptors to excite GABAergic neurons that are presynaptic to a population of magnocellular PVN neurons the identity of which features a unique rebound depolarization. Endogenous sources of VP may be VP-synthesizing neurons in suprachiasmatic nucleus, known to project toward the perinuclear regions of PVN, and/or the magnocellular neurons within PVN.
Modifications of Seizure Susceptibility inDrosophila
Authors: Kuebler Daniel , Tanouye Mark A.
Published: December 2017

In a given population, certain individuals are much more likely to have seizures than others. This increase in seizure susceptibility can lead to spontaneous seizures, such as seen in idiopathic epilepsy, or to symptomatic seizures that occur after insults to the nervous system. Despite the frequency of these seizure disorders in the human population, the genetic and physiological basis for these defects remains unclear. The present study makes use of Drosophila as a potentially powerful model for understanding seizure susceptibility in humans. In addition to the genetic and molecular advantages of using Drosophila, it has been found that seizures in Drosophila share much in common with seizures seen in humans. However, the most powerful aspect of this model lies in the ability to accurately measure seizure susceptibility across genotypes and over time. In the current study seizure susceptibility was quantified in a variety of mutant and wild-type strains, and it was found that genetic mutations can modulate susceptibility over an extremely wide range. This genetic modulation of seizure susceptibility apparently occurs without affecting the threshold of individual neurons. Seizure susceptibility also varied depending on the experience of the fly, decreasing immediately after a seizure and then gradually increasing over time. A novel phenomenon was also identified in which seizures are suppressed after certain high-intensity stimuli. These results demonstrate the utility of Drosophila as a model system for studying human seizure disorders and provide insights into the possible mechanisms by which seizure susceptibility is modified.
Modification of Synaptic Transmission and Sodium Channel Inactivation by the Insect-Selective Scorpion Toxin LqhαIT
Authors: Lee Daewoo , Gurevitz Michael , Adams Michael E.
Published: December 2017

The peptide LqhαIT is an α-scorpion toxin that shows significant selectivity for insect sodium channels over mammalian channels. We examined the symptoms of LqhαIT-induced paralysis and its neurophysiological correlates in the house fly ( Musca domestica). Injection of LqhαIT into fly larvae produced hyperactivity characterized by continuous, irregular muscle twitching throughout the body. These symptoms were correlated with elevated excitability in motor units caused by two physiological effects of the toxin: 1) increased transmitter release and 2) repetitive action potentials in motor nerves. Increased transmitter release was evident as augmentation of neurally evoked synaptic current, and this was correlated with an increased duration of action potential–associated current (APAC) in loose patch recordings from nerve terminals. Repetitive APACs were observed to invade nerve endings. The toxin produced marked inhibition of sodium current inactivation in fly central neurons, which can account for increased duration of the APAC and elevated neurotransmitter release at the neuromuscular junction. Steady-state inactivation was shifted significantly to more positive potentials, whereas voltage-dependent activation of the channels was not affected. The shift in steady-state inactivation provides a mechanism for inducing repetitive activity in motoneurons. The effects of LqhαIT on sodium channel inactivation in motor nerve endings can account both for increased transmitter release and repetitive activity leading to hyperactivity in affected insects.
Ratio of Inhibited-to-Activated Pallidal Neurons Decreases Dramatically During Passive Limb Movement in the MPTP-Treated Monkey
Authors: Boraud T. , Bezard E. , Bioulac B. , Gross C. E.
Published: December 2017

Mink advanced the hypothesis in 1996 that the role of the basal ganglia (BG) is primarily one of focused selection; the encouragement of motor mechanisms inducing a desired movement and the inhibition of competing mechanisms. This would imply, in normal subjects, a ratio of inhibited-to-activated (I/A) movement-related globus pallidus pars internalis (GPi) neurons <1 and a drastic decrease of this ratio in the parkinsonian state. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication should therefore decrease the specificity of the response of this neuronal population. To test this working hypothesis we studied the activity of GPi neurons in response to passive limb movement in the normal and the parkinsonian monkey. Extracellular unit recordings monitored any correlation between passive limb movements and eventual modifications of the neuronal activity of the GPi in two calm, awake, and drug naive monkeys ( Macaca fascicularis) before and after MPTP intoxication. In the normal animal, arm- and leg-related neurons were located in clusters in the medial part of the GPi. The I/A ratio was 0.22. Most GPi cells were linked to a single joint. In the MPTP-treated monkey, the number of movement-related neurons increased, the I/A ratio dropped significantly to 0.03, and most responding cells were linked to several joints. These data, which cannot be explained by the classic “box” model, endorse Mink's hypothesis.
Electrical Cochlear Stimulation in the Deaf Cat: Comparisons Between Psychophysical and Central Auditory Neuronal Thresholds
Authors: Beitel Ralph E. , Snyder Russell L. , Schreiner Christoph E. , Raggio Marcia W. , Leake Patricia A.
Published: December 2017

Cochlear prostheses for electrical stimulation of the auditory nerve (“electrical hearing”) can provide auditory capacity for profoundly deaf adults and children, including in many cases a restored ability to perceive speech without visual cues. A fundamental challenge in auditory neuroscience is to understand the neural and perceptual mechanisms that make rehabilitation of hearing possible in these deaf humans. We have developed a feline behavioral model that allows us to study behavioral and physiological variables in the same deaf animals. Cats deafened by injection of ototoxic antibiotics were implanted with either a monopolar round window electrode or a multichannel scala tympani electrode array. To evaluate the effects of perceptually significant electrical stimulation of the auditory nerve on the central auditory system, an animal was trained to avoid a mild electrocutaneous shock when biphasic current pulses (0.2 ms/phase) were delivered to its implanted cochlea. Psychophysical detection thresholds and electrical auditory brain stem response (EABR) thresholds were estimated in each cat. At the conclusion of behavioral testing, acute physiological experiments were conducted, and threshold responses were recorded for single neurons and multineuronal clusters in the central nucleus of the inferior colliculus (ICC) and the primary auditory cortex (A1). Behavioral and neurophysiological thresholds were evaluated with reference to cochlear histopathology in the same deaf cats. The results of the present study include: 1) in the cats implanted with a scala tympani electrode array, the lowest ICC and A1 neural thresholds were virtually identical to the behavioral thresholds for intracochlear bipolar stimulation; 2) behavioral thresholds were lower than ICC and A1 neural thresholds in each of the cats implanted with a monopolar round window electrode; 3) EABR thresholds were higher than behavioral thresholds in all of the cats (mean difference = 6.5 dB); and 4) the cumulative number of action potentials for a sample of ICC neurons increased monotonically as a function of the amplitude and the number of stimulating biphasic pulses. This physiological result suggests that the output from the ICC may be integrated spatially across neurons and temporally integrated across pulses when the auditory nerve array is stimulated with a train of biphasic current pulses. Because behavioral thresholds were lower and reaction times were faster at a pulse rate of 30 pps compared with a pulse rate of 2 pps, spatial-temporal integration in the central auditory system was presumably reflected in psychophysical performance.
Serotonin-Induced Spike Narrowing in a Locomotor Pattern Generator Permits Increases in Cycle Frequency During Accelerations
Authors: Satterlie Richard A. , Norekian Tigran P. , Pirtle Thomas J.
Published: December 2017

During serotonin-induced swim acceleration in the pteropod mollusk Clione limacina, interneurons of the central pattern generator (CPG) exhibit significant action potential narrowing. Spike narrowing is apparently necessary for increases in cycle frequency during swim acceleration because, in the absence of narrowing, the combined duration of the spike and the inhibitory postsynaptic potential (IPSP) of a single cycle is greater than the available cycle duration. Spike narrowing could negatively influence synaptic efficacy in all interneuron connections, including reciprocal inhibitory connections between the two groups of antagonistic CPG interneurons as well as the interneuron-to-motoneuron connections. Thus compensatory mechanisms must exist to produce the overall excitatory behavioral change of swim acceleration. Such mechanisms include 1) a baseline depolarization of interneurons, which brings them closer to spike threshold, 2) enhancement of their postinhibitory rebound, and 3) direct modulation of swim motoneurons and muscles, all through inputs from serotonergic modulatory neurons.
Response of Cutaneous A- and C-Fiber Nociceptors in the Monkey to Controlled-Force Stimuli
Authors: Slugg R. M. , Meyer R. A. , Campbell J. N.
Published: December 2017

The goal of this study was to determine the capacity of primary afferent nociceptive fibers (nociceptors) to encode information about noxious mechanical stimuli in primates. Teased-fiber techniques were used to record from 14 A-fiber nociceptors and 18 C-fiber nociceptors that innervated the hairy skin. Stimulus-response functions were examined with an ascending series of force-controlled stimuli. Stimulus-interaction effects were examined with use of a series of paired stimuli in which the interval between the stimulus pairs was varied systematically. Both A-fiber and C-fiber nociceptors exhibited a slowly adapting response to the stepped force stimuli. The response of the A fibers increased monotonically with increasing force, whereas the response of the C fibers reached a plateau at low force levels. The slope of the stimulus-response function for the A fibers was significantly steeper than that for the C fibers, and the total response was greater. The A fibers also provided more discriminative information regarding stimulus intensity. The C fibers demonstrated a significant fatigue in response when the interstimulus interval between the paired stimuli was ≤150 s, whereas the A fibers did not demonstrate a significant fatigue until the interstimulus interval was ≤30 s. This fatigue in response was not due to changes in tissue compliance. These results suggest that A- and C-fiber nociceptors have different mechanical transduction mechanisms. A-fiber nociceptors exhibit steeper stimulus-response functions and less fatigue than C-fiber nociceptors.
Robust Changes of Afferent-Induced Excitation in the Rat Spinal Dorsal Horn After Conditioning High-Frequency Stimulation
Authors: Ikeda Hiroshi , Asai Tatsuya , Murase Kazuyuki
Published: December 2017

We investigated the neuronal plasticity in the spinal dorsal horn and its relationship with spinal inhibitory networks using an optical-imaging method that detects neuronal excitation. High-intensity single-pulse stimulation of the dorsal root activating both A and C fibers evoked an optical response in the lamina II (the substantia gelatinosa) of the dorsal horn in transverse slices of 12- to 25-day-old rat spinal cords stained with a voltage-sensitive dye, RH-482. The optical response, reflecting the net neuronal excitation along the slice-depth, was depressed by 28% for more than 1 h after a high-frequency conditioning stimulation of A fibers in the dorsal root (3 tetani of 100 Hz for 1 s with an interval of 10 s). The depression was not induced in a perfusion solution containing an NMDA antagonist,dl-2-amino-5-phosphonovaleric acid (AP5; 30 μM). In a solution containing the inhibitory amino acid antagonists bicuculline (1 μM) and strychnine (3 μM), and also in a low Cl−solution, the excitation evoked by the single-pulse stimulation was enhanced after the high-frequency stimulation by 31 and 18%, respectively. The enhanced response after conditioning was depotentiated by a low-frequency stimulation of A fibers (0.2–1 Hz for 10 min). Furthermore, once the low-frequency stimulation was applied, the high-frequency conditioning could not potentiate the excitation. Inhibitory transmissions thus regulate the mode of synaptic plasticity in the lamina II most likely at afferent terminals. The high-frequency conditioning elicits a long-term depression (LTD) of synaptic efficacy under a greater activity of inhibitory amino acids, but it results in a long-term potentiation (LTP) when inhibition is reduced. The low-frequency preconditioning inhibits the potentiation induction and maintenance by the high-frequency conditioning. These mechanisms might underlie robust changes of nociception, such as hypersensitivity after injury or inflammation and pain relief after electrical or cutaneous stimulation.
Citrate Enhances Olfactory Receptor Responses and Triggers Oscillatory Receptor Activity in the Channel Catfish
Authors: Parker James M. , Chang Qinhui , Caprio John
Published: December 2017

Citrate, a normal constituent of cellular metabolism, in a binary mixture with an amino acid enhanced asynchronous olfactory receptor responses in the channel catfish, Ictalurus punctatus. In addition, high concentrations of either citrate (≥3 mM) alone or an amino acid (≥0.1 mM) in a binary mixture with citrate (≥1 mM) triggered synchronized voltage oscillations of olfactory receptor neurons (ORNs) known as “peripheral waves” (PWs). Binary mixtures containing lower concentrations of an amino acid also triggered PW activity if the concentration of citrate in the mixture was increased. Both the enhancement of asynchronous activity and the generation of PW activity were the result of citrate chelating calcium, which lowers the surface potential of ORNs making them hyperexcitable. These effects of citrate are replicated by EGTA. Inactivation of the chelating ability of citrate and EGTA with 1 mM calcium chloride, barium chloride, or strontium chloride abolished both the enhancement of asynchronous olfactory responses and PW activity, while not affecting olfactory receptor responses to the amino acids alone.
Effects on Peroneal Motoneurons of Cutaneous Afferents Activated by Mechanical or Electrical Stimulations
Authors: Perrier Jean-François , D'Incamps Boris Lamotte , Kouchtir-Devanne Nezha , Jami Léna , Zytnicki Daniel
Published: December 2017

The postsynaptic potentials elicited in peroneal motoneurons by either mechanical stimulation of cutaneous areas innervated by the superficial peroneal nerve (SP) or repetitive electrical stimulation of SP were compared in anesthetized cats. After denervation of the foot sparing only the territory of SP terminal branches, reproducible mechanical stimulations were applied by pressure on the plantar surface of the toes via a plastic disk attached to a servo-length device, causing a mild compression of toes. This stimulus evoked small but consistent postsynaptic potentials in every peroneal motoneuron. Weak stimuli elicited only excitatory postsynaptic potentials (EPSPs), whereas increase in stimulation strength allowed distinction of three patterns of response. In about one half of the sample, mechanical stimulation or trains of 20/s electric pulses at strengths up to six times the threshold of the most excitable fibers in the nerve evoked only EPSPs. Responses to electrical stimulation appeared with 3–7 ms central latencies, suggesting oligosynaptic pathways. In another, smaller fraction of the sample, inhibitory postsynaptic potentials (IPSPs) appeared with an increase of stimulation strength, and the last fraction showed a mixed pattern of excitation and inhibition. In 24 of 32 motoneurons where electrical and mechanical effects could be compared, the responses were similar, and in 6 others, they changed from pure excitation on mechanical stimulation to mixed on electrical stimulation. With both kinds of stimulation, stronger stimulations were required to evoke inhibitory postsynaptic potentials (IPSPs), which appeared at longer central latencies than EPSPs, indicating longer interneuronal pathways. The similarity of responses to mechanical and electrical stimulation in a majority of peroneal motoneurons suggests that the effects of commonly used electrical stimulation are good predictors of the responses of peroneal motoneurons to natural skin stimulation. The different types of responses to cutaneous afferents from SP territory reflect a complex connectivity allowing modulations of cutaneous reflex responses in various postures and gaits.
Dynorphin Exerts Both Postsynaptic and Presynaptic Effects in the Globus Pallidus of the Rat
Authors: Ogura Mitsuhiro , Kita Hitoshi
Published: December 2017

The opioids contained in striato-pallidal axons are thought to play a significant role in motor control. We examined post- and presynaptic effects of the kappa (κ)-receptor agonist dynorphin A (1–13) (DYN13) on the globus pallidus (GP) neurons in rat brain slice preparations using the whole cell recording method. DYN13 hyperpolarized and decreased the input resistance of approximately one-quarter of neurons examined. All of these DYN13-sensitive neurons had medium-sized somata, large aspiny dendrites and generated repetitive firing without strong accommodation. The hyperpolarization was blocked by barium and was independent of TTX and intracellular chloride levels. The hyperpolarization was also selectively blocked by the κ-antagonist nor-binaltorphimine dihydrochloride but not by the mu- or delta-antagonists. These data suggested that DYN13 activates barium-sensitive potassium currents in some GP neurons. Low- and high-intensity stimulation of the neostriatum (Str) evoked long- and short-latency GABAergic responses, respectively. Previous data suggested that the long- and the short-latency responses were due to activation of the striato-pallidal axons and the local collaterals of pallido-striatal axons, respectively. DYN13 diminished the amplitude of both the short- and long-latency GABAergic responses in all the neurons tested. The effects of DYN13 on GABAergic postsynaptic responses were also selectively blocked by a κ-antagonist. To investigate whether the effects were pre- or postsynaptic, the effects of DYN13 on spontaneous inhibitory postsynaptic potentials (IPSPs) and TTX-independent miniature–inhibitory postsynaptic currents (IPSCs) were examined. DYN13 decreased the frequency, but not the amplitude, of spontaneous IPSCs and calcium-dependent miniature-IPSCs. However, DYN13 did not alter the cadmium-insensitive miniature-IPSCs. These results suggested that DYN13 suppressed GABA release from presynaptic terminals. This possibility was tested using a paired-stimulation test. DYN13 reduced the probability of evoking IPSCs to the first stimulation and greatly increased the success probability to the second stimulus. The amplitude of successfully evoked IPSCs was not changed with DYN13. DYN13 did not affect the excitatory postsynaptic potentials (EPSPs) or the response to iontophoretically applied GABA and glutamate. Together, these results suggest that DYN released from striato-pallidal axons controls the activity of GP neurons 1) by directly hyperpolarizing a population of neurons and 2) by presynaptically inhibiting GABA release from striato-pallidal and intrapallidal terminals.
Manual Tracking in Two Dimensions
Authors: Engel Kevin C. , Soechting John F.
Published: December 2017

Manual tracking was studied by asking subjects to follow, with their finger, a target moving on a touch-sensitive video monitor. The target initially moved in a straight line at a constant speed and then, at a random point in time, made one abrupt change in direction. The results were approximated with a simple model according to which, after a reaction time, the hand moved in a straight line to intercept the target. Both the direction of hand motion and its peak speed could be predicted by assuming a constant time to intercept. This simple model was able to account for results obtained over a broad range of target speeds as well as the results of experiments in which both the speed and the direction of the target changed simultaneously. The results of an experiment in which the target acceleration was nonzero suggested that the error signals used during tracking are related to both speed and direction but poorly (if at all) to target acceleration. Finally, in an experiment in which target velocity remained constant along one axis but the perpendicular component underwent a step change, tracking along both axes was perturbed. This last finding demonstrates that tracking in two dimensions cannot be decomposed into its Cartesian components. However, an analytical model in a hand-centered frame of reference in which speed and direction are the controlled variables could account for much of the data.
Extracellular pH Responses in CA1 and the Dentate Gyrus During Electrical Stimulation, Seizure Discharges, and Spreading Depression
Authors: Xiong Zhi-Qi , Stringer Janet L.
Published: December 2017

Since neuronal excitability is sensitive to changes in extracellular pH and there is regional diversity in the changes in extracellular pH during neuronal activity, we examined the activity-dependent extracellular pH changes in the CA1 region and the dentate gyrus. In vivo, in the CA1 region, recurrent epileptiform activity induced by stimulus trains, bicuculline, and kainic acid resulted in biphasic pH shifts, consisting of an initial extracellular alkalinization followed by a slower acidification. In vitro, stimulus trains also evoked biphasic pH shifts in the CA1 region. However, in CA1, seizure activity in vitro induced in the absence of synaptic transmission, by perfusing with 0 Ca2+/5 mM K+medium, was only associated with extracellular acidification. In the dentate gyrus in vivo, seizure activity induced by stimulation to the angular bundle or by injection of either bicuculline or kainic acid was only associated with extracellular acidification. In vitro, stimulus trains evoked only acidification. In the dentate gyrus in vitro, recurrent epileptiform activity induced in the absence of synaptic transmission by perfusion with 0 Ca2+/8 mM K+medium was associated with extracellular acidification. To test whether glial cell depolarization plays a role in the regulation of the extracellular pH, slices were perfused with 1 mM barium. Barium increased the amplitude of the initial alkalinization in CA1 and caused the appearance of alkalinization in the dentate gyrus. In both CA1 and the dentate gyrus in vitro, spreading depression was associated with biphasic pH shifts. These results demonstrate that activity-dependent extracellular pH shifts differ between CA1 and dentate gyrus both in vivo and in vitro. The differences in pH fluctuations with neuronal activity might be a marker for the basis of the regional differences in seizure susceptibility between CA1 and the dentate gyrus.
Context Estimation for Sensorimotor Control
Authors: Vetter Philipp , Wolpert Daniel M.
Published: December 2017

Human motor behavior is remarkably accurate and appropriate even though the properties of our own bodies as well as the objects we interact with vary over time. To adjust appropriately, the motor system has to estimate the context, that is the properties of objects in the world and the prevailing environmental conditions. Here we show that to determine the current context the CNS uses information from both prior knowledge of how the context might evolve over time and from the comparison of predicted and actual sensory feedback. We show that these two sources of information may be modeled within the CNS and combined to derive an accurate estimate of the context which adjusts motor command selection. This provides a novel probabilistic framework for sensorimotor control.
ROMK1 (Kir1.1) Causes Apoptosis and Chronic Silencing of Hippocampal Neurons
Authors: Nadeau H. , McKinney S. , Anderson D. J. , Lester H. A.
Published: December 2017

Lentiviral vectors were constructed to express the weakly rectifying kidney K+ channel ROMK1 (Kir1.1), either fused to enhanced green fluorescent protein (EGFP) or as a bicistronic message (ROMK1-CITE-EGFP). The channel was stably expressed in cultured rat hippocampal neurons. Infected cells were maintained for 2–4 wk without decrease in expression level or evidence of viral toxicity, although 15.4 mM external KCl was required to prevent apoptosis of neurons expressing functional ROMK1. No other trophic agents tested could prevent cell death, which was probably caused by K+loss. This cell death did not occur in glia, which were able to support ROMK1 expression indefinitely. Functional ROMK1, quantified as the nonnative inward current at −144 mV in 5.4 mM external K+blockable by 500 μM Ba2+, ranged from 1 to 40 pA/pF. Infected neurons exhibited a Ba2+-induced depolarization of 7 ± 2 mV relative to matched EGFP-infected controls, as well as a 30% decrease in input resistance and a shift in action potential threshold of 2.6 ± 0.5 mV. This led to a shift in the relation between injected current and firing frequency, without changes in spike shape, size, or timing. This shift, which quantifies silencing as a function of ROMK1 expression, was predicted from Hodgkin-Huxley models. No cellular compensatory mechanisms in response to expression of ROMK1 were identified, making ROMK1 potentially useful for transgenic studies of silencing and neurodegeneration, although its lethality in normal K+ has implications for the use of K+ channels in gene therapy.
Spiking-Bursting Activity in the Thalamic Reticular Nucleus Initiates Sequences of Spindle Oscillations in Thalamic Networks
Authors: Bazhenov M. , Timofeev I. , Steriade M. , Sejnowski T.
Published: December 2017

Recent intracellular and local field potential recordings from thalamic reticular (RE) neurons in vivo as well as computational modeling of the isolated RE nucleus suggest that, at relatively hyperpolarized levels of membrane potentials, the inhibitory postsynaptic potentials (IPSPs) between RE cells can be reversed and γ-aminobutyric acid-A (GABAA) -mediated depolarization can generate persistent spatio-temporal patterns in the RE nucleus. Here we investigate how this activity affects the spatio-temporal properties of spindle oscillations with computer models of interacting RE and thalamocortical (TC) cells. In a one-dimensional network of RE and TC cells, sequences of spindle oscillations alternated with localized patterns of spike-burst activity propagating inside the RE network. New sequences of spindle oscillations were initiated after removal of I h-mediated depolarization of the TC cells. The length of the interspindle lulls depended on the intrinsic and synaptic properties of RE and TC cells and was in the range of 3–20 s. In a two-dimensional model, GABAA-mediated 2–3 Hz oscillations persisted in the RE nucleus during interspindle lulls and initiated spindle sequences at many foci within the RE-TC network simultaneously. This model predicts that the intrinsic properties of the reticular thalamus may contribute to the synchrony of spindle oscillations observed in vivo.
Neural Representation of Salts in the Rat Solitary Nucleus: Brain Stem Correlates of Taste Discrimination
Authors: John Steven J. St. , Smith David V.
Published: December 2017

One mechanism of salt taste transduction by gustatory receptor cells involves the influx of cations through epithelial sodium channels that can be blocked by oral application of amiloride. A second mechanism is less clearly defined but seems to depend on electroneutral diffusion of the salt through the tight junctions between receptor cells; this paracellular pathway is insensitive to amiloride. Because the first mechanism is more sensitive to sodium salts and the second to nonsodium salts, these peripheral events could underlie the ability of rats to discriminate sodium from nonsodium salts on the basis of taste. Behavioral experiments indicate that amiloride, at concentrations that are tasteless to rats, impairs a rat's ability to discriminate NaCl from KCl and may do so by making both salts taste like KCl. In the present study, we examined the neural representation of NaCl and KCl (0.05–0.2 M), and mixtures of these salts with amiloride (0, 3, and 30 μM), to explore the neural correlates of this behavioral result. NaCl and KCl were represented by distinct patterns of activity in the nucleus of the solitary tract. Amiloride, in a concentration-dependent manner, changed the pattern for NaCl to one more characteristic of KCl, primarily by reducing activity in neurons responding best to NaCl and sucrose. The effect of amiloride concentration on the response to 0.1 M NaCl in NaCl-best neurons was virtually identical to its effect on behavioral discrimination performance. Modeling the effects of blocking the amiloride-insensitive pathway also resulted in highly similar patterns of activity for NaCl and KCl. These results suggest that activity in both the amiloride-sensitive and -insensitive pathways is required for the behavioral discrimination between NaCl and KCl. In the context of published behavioral data, the present results suggest that amiloride-sensitive activity alone is not sufficient to impart a unique signal for the taste of sodium salts.
Postsynaptic Receptor Occupancy During Evoked Transmission at Striatal GABAergic Synapses In Vitro
Authors: Rumpel Eva , Behrends Jan C.
Published: December 2017

The effect of benzodiazepines (BZs) on GABAA-ergic synaptic responses depends on the control receptor occupancy: the BZ-induced enhancement of receptor affinity can lead to greater peak amplitudes of quantal responses only when, under normal conditions, receptors are not fully saturated at peak. Based on this fact, receptor occupancy at the peak of spontaneous miniature inhibitory postsynaptic currents (mIPSCs) has been assessed in various mammalian neuronal preparations. To use the same principle with compound (or multiquantal), action potential–evoked IPSCs, complications introduced by quantal asynchrony in conjunction with the BZ-induced increase in the decay time of the quantal responses have to be overcome. We used a simple analytic convolution model to calculate expected changes in the rise time and amplitude of postsynaptic currents when the decay time constant, but not the peak amplitude, of the underlying quantal responses is increased, this being the expected BZ effect at saturated synapses. Predictions obtained were compared with the effect of the BZ flunitrazepam on IPSCs recorded in paired pre- and postsynaptic whole cell voltage-clamp experiments on striatal neurons in cell culture. In 22 pairs, flunitrazepam (500 nM) reliably prolonged the decay of IPSCs (49 ± 19%, mean ± SE) and in 18 of 22 cases produced an enhancement in their peak amplitude that varied markedly between 3 and 77% of control (26.0 ± 5.3%). The corresponding change in rise time, however (+0.38 ± 0.11 ms, range −0.8 to +1.3 ms) was far smaller than calculated for the observed changes in peak amplitude assuming fixed quantal size. Because therefore an increase in quantal size is required to explain our findings, postsynaptic GABAA receptors were most likely not saturated during impulse-evoked transmission at these unitary connections. The peak amplitudes of miniature IPSCs in these neurons were also increased by flunitrazepam (500 nM, +26.8 ± 6.6%), and their decay time constant was increased by 26.3 ± 7.3%. Using these values in our model led to a slight overestimate of the change in compound IPSC amplitude (+28 to +30%).
Mechanosensitive Potassium Channels in Rat Colon Sensory Neurons
Authors: Su X. , Wachtel R. E. , Gebhart G. F.
Published: December 2017

Single-channel recording techniques were used to characterize mechanosensitive channels in identified (1.1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine methanesulfonate labeled) colon sensory neurons dissociated from adult S1 dorsal root ganglia. Channels were found in 30% (7/23) of patches in a cell-attached configuration and in 43% (48/111) of excised inside-out patches. Channels were highly selective for K+, had a slope conductance of 54 pS in symmetrical solutions, and were blocked by tetraethylammonium, amiloride, and benzamil. Channels were also seen under Ca2+-free conditions. Gadolinium (Gd3+), a known blocker of mechanosensitive ion channels, did not block channel activity. Tetrodotoxin and 4-aminopyridine were also ineffective. The cytoskeletal disrupters colchicine and cytochalasin D reduced the percentage of patches containing mechanosensitive channels. These results indicate that rat colon sensory neurons contain K+-selective mechanosensitive channels that may modulate the membrane excitability induced by colonic distension.
Neural Responses in the Inferior Colliculus to Binaural Masking Level Differences Created by Inverting the Noise in One Ear
Authors: Palmer Alan R. , Jiang Dan , McAlpine David
Published: December 2017

We have measured the responses of inferior colliculus neurons in the anesthetized guinea pig to signals which in human psychophysical experiments reveal a release of masking as a result of binaural processing (the binaural masking level difference: BMLD). More specifically we have used diotic tones at 500 Hz (So) masked by noise that is either identical at the two ears (No) or inverted in one ear (Nπ). This combination of signals and noise maskers produces a prominent masking release in humans such that the So signal is about 6–12 dB more detectable in the presence of the Nπ noise than the No noise. Low-frequency inferior colliculus neurons are sensitive to the interaural delay of the masking noise and generally respond most to the components nearest their best frequency. Since most inferior colliculus neurons have peaks in their delay functions close to zero interaural time delay this means that while No noise is effective in driving the unit, Nπ noise is much less effective. As the level of an So tone was progressively increased in the presence of No and Nπ noises, the first response could be either an increase or a decrease in the activity due to the noise. However, because Nπ generated little or no activity itself, the predominant response to the So tone was an increase in discharge in this condition. Masked thresholds were defined as the point at which the standard separation D (related to the d′ of signal detection theory) = 1 in either direction. BMLDs were measured in single neurons and in the majority of units were in a direction consistent with the psychophysical observations irrespective of the direction of the discharge rate change that occurred at threshold. The lowest masked thresholds always occurred at or near the signal frequency of 500 Hz. An average value of the single unit BMLD around 500 Hz was 3.6 dB (NoSo vs. NπSo) compared with 6.6 dB for the NoSo versus NoSπ BMLD we had previously reported. This lower magnitude is consistent with the hierarchy of human psychophysical BMLDs.
Tonic and Synaptically Evoked Presynaptic Inhibition of Sensory Input to the Rat Olfactory Bulb Via GABABHeteroreceptors
Authors: Aroniadou-Anderjaska Vassiliki , Zhou Fu-Ming , Priest Catherine A. , Ennis Matthew , Shipley Michael T.
Published: December 2017

Olfactory receptor neurons of the nasal epithelium send their axons, via the olfactory nerve (ON), to the glomeruli of the olfactory bulb (OB), where the axon terminals form glutamatergic synapses with the apical dendrites of mitral and tufted cells, the output cells of the OB, and with juxtaglomerular (JG) interneurons. Many JG cells are GABAergic. Here we show that, despite the absence of conventional synapses, GABA released from JG cells activates GABABreceptors on ON terminals and inhibits glutamate release both tonically and in response to ON stimulation. Field potential recordings and current-source density analysis, as well as intracellular and whole cell recording techniques were used in rat OB slices. Baclofen (2–5 μM), a GABABagonist, completely suppressed ON-evoked synaptic responses of both mitral/tufted cells and JG cells, with no evidence for postsynaptic effects. Baclofen (0.5–1 μM) also reversed paired-pulse depression (PPD) of mitral/tufted cell responses to paired-pulse facilitation (PPF), and reduced depression of JG cell excitatory postsynaptic currents (EPSCs) during repetitive ON stimulation. These results suggest that baclofen reduced the probability of glutamate release from ON terminals. The GABABantagonists CGP35348 or CGP55845A increased mitral/tufted cell responses evoked by single-pulse ON stimulation, suggesting that glutamate release from ON terminals is tonically suppressed via GABABreceptors. The same antagonists reduced PPD of ON-evoked mitral/tufted cell responses at interstimulus intervals 50–400 ms. This finding suggests that a single ON impulse evokes sufficient GABA release, presumably from JG cells, to activate GABABreceptors on ON terminals. Thus GABABheteroreceptors on ON terminals are activated by ambient levels of extrasynaptic GABA, and by ON input to the OB. The time course of ON-evoked, GABABpresynaptic inhibition suggests that neurotransmission to M/T cells and JG cells will be significantly suppressed when ON impulses arrive in glomeruli at 2.5–20 Hz. GABABreceptor–mediated presynaptic inhibition of sensory input to the OB may play an important role in shaping the activation pattern of the OB glomeruli during olfactory coding.
Functional Mapping of Human Brain in Olfactory Processing: A PET Study
Authors: Qureshy Ahmad , Kawashima Ryuta , Imran Muhammad Babar , Sugiura Motoaki , Goto Ryoi , Okada Ken , Inoue Kentaro , Itoh Masatoshi , Schormann Thorsten , Zilles Karl , Fukuda Hiroshi
Published: December 2017

This study describes the functional anatomy of olfactory and visual naming and matching in humans, using positron emission tomography (PET). One baseline control task without olfactory or visual stimulation, one control task with simple olfactory and visual stimulation without cognition, one set of olfactory and visual naming tasks, and one set of olfactory and visual matching tasks were administered to eight normal volunteers. In the olfactory naming task (ON), odors from familiar items, associated with some verbal label, were to be named. Hence, it required long-term olfactory memory retrieval for stimulus recognition. The olfactory matching task (OM) involved differentiating a recently encoded unfamiliar odor from a sequentially presented group of unfamiliar odors. This required short-term olfactory memory retrieval for stimulus differentiation. The simple olfactory and visual stimulation resulted in activation of the left orbitofrontal region, the right piriform cortex, and the bilateral occipital cortex. During olfactory naming, activation was detected in the left cuneus, the right anterior cingulate gyrus, the left insula, and the cerebellum bilaterally. It appears that the effort to identify the origin of an odor involved semantic analysis and some degree of mental imagery. During olfactory matching, activation was observed in the left cuneus and the cerebellum bilaterally. This identified the brain areas activated during differentiation of one unlabeled odor from the others. In cross-task analysis, the region found to be specific for olfactory naming was the left cuneus. Our results show definite recruitment of the visual cortex in ON and OM tasks, most likely related to imagery component of these tasks. The cerebellar role in cognitive tasks has been recognized, but this is the first PET study that suggests that the human cerebellum may have a role in cognitive olfactory processing as well.