bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of Group III mGluRs Inhibits GABAergic and Glutamatergic Transmission in the Substantia Nigra Pars Reticulata
Authors: Wittmann Marion , Marino Michael J. , Bradley Stefania Risso , Conn P. Jeffrey
Published: December 2017

The GABAergic projection neurons of the substantia nigra pars reticulata (SNr) exert an important influence on the initiation and control of movement. The SNr is a primary output nucleus of the basal ganglia (BG) and is controlled by excitatory inputs from the subthalamic nucleus (STN) and inhibitory inputs from the striatum and globus pallidus. Changes in the output of the SNr are believed to be critically involved in the development of a variety of movement disorders. Anatomical studies reveal that metabotropic glutamate receptors (mGluRs) are highly expressed throughout the BG. Interestingly, mRNA for group III mGluRs are highly expressed in STN, striatum, and globus pallidus, and immunocytochemical studies have shown that the group III mGluR proteins are present in the SNr. Thus it is possible that group III mGluRs play a role in the modulation of synaptic transmission in this nucleus. We performed whole cell patch-clamp recordings from nondopaminergic SNr neurons to investigate the effect of group III mGluR activation on excitatory and inhibitory transmission in the SNr. We report that activation of group III mGluRs by the selective agonist l(+)-2-amino-4-phosphonobutyric acid (l-AP4, 100 μM) decreases inhibitory synaptic transmission in the SNr. Miniature inhibitory postsynaptic currents studies and paired-pulse studies reveal that this effect is mediated by a presynaptic mechanism. Furthermore we found that l-AP4 (500 μM) also reduces excitatory synaptic transmission at the STN-SNr synapse by action on presynaptically localized group III mGluRs. The finding that mGluRs modulate the major inputs to SNr neurons suggests that these receptors may play an important role in motor function and could provide new targets for the development of pharmacological treatments of movement disorders.
Increased and Decreased Muscle Tone With Orexin (Hypocretin) Microinjections in the Locus Coeruleus and Pontine Inhibitory Area
Authors: Kiyashchenko Lyudmila I. , Mileykovskiy Boris Y. , Lai Yuan-Y. , Siegel Jerome M.
Published: December 2017

Orexin-A (OX-A) and orexin-B (OX-B) (hypocretin 1 and hypocretin 2) are synthesized in neurons of the perifornical, dorsomedial, lateral, and posterior hypothalamus. The locus coeruleus (LC) receives the densest extrahypothalamic projections of the orexin (OX) system. Recent evidence suggests that descending projections of the LC have a facilitatory role in the regulation of muscle tone. The pontine inhibitory area (PIA), located ventral to LC, receives a moderate OX projection and participates in the suppression of muscle tone in rapid-eye-movement sleep. We have examined the role of OX-A and -B in muscle-tone control using microinjections (0.1 μM to 1 mM, 0.2 μl) into the LC and PIA in decerebrate rats. OX-A and -B microinjections into the LC produced ipsi- or bilateral hindlimb muscle-tone facilitation. The activity of LC units was correlated with the extent of hindlimb muscle-tone facilitation after OX microinjections (100 μM, 1 μl) into fourth ventricle. Microinjections of OX-A and -B into the PIA produced muscle-tone inhibition. We did not observe any significant difference in the effect of OX-A and -B on muscle tone at either site. Our data suggest that OX release activates LC units and increases noradrenergic tonus in the CNS. Moreover, OX-A and -B may also regulate the activity of pontine cholinoceptive and cholinergic neurons participating in muscle-tone suppression. Loss of OX function may therefore disturb both facilitatory and inhibitory motor processes.
Effect of Temperature on Endplate Potential Rundown and Recovery in Rat Diaphragm
Authors: Moyer Michelle , van Lunteren Erik
Published: December 2017

The amplitude of neuromuscular junction end-plate potentials (EPPs) decreases quickly within a train but recovers nearly completely from train to train during intermittent stimulation. Rundown has been shown to be dependent not only on the rate of transmitter release but also on the rate of replenishment of the depleted neurotransmitter at the site of release. Two groups of processes have been proposed for synaptic vesicle recycling, both of which involve multiple energy-requiring steps and enzymatic reactions and which therefore would be expected to be very temperature-sensitive. The present study tested the hypothesis that low temperature therefore increases the rate of EPP amplitude rundown. Studies were performed in vitro on rat diaphragm and used μ-conotoxin to allow normal-sized EPPs to be recorded from intact fibers. EPP amplitude rundown during intermittent stimulation at 20 and 50 Hz (duty cycle 333 ms) was greater at 20°C than it was at 37°C. Initially, temperature affected only intra-train rundown but, over longer periods of stimulation, both intra- and inter-train rundown were significantly accelerated by cold temperature. Cumulative EPP amplitudes were calculated by successively adding the amplitudes of each EPP during the stimulation period to provide an estimate of total neurotransmitter release in the neuromuscular junction. The cumulative EPP amplitude was significantly lower at 20°C than it was at 37°C during both 20 and 50 Hz stimulation. These data indicate that the mechanism involved in EPP amplitude rundown and recovery is temperature-sensitive, with a greater decrement in EPP amplitude at cold than at warm temperatures.
Pharmacological and Biophysical Characterization of Voltage-Gated Calcium Currents in the Endopiriform Nucleus of the Guinea Pig
Authors: Brevi Sara , de Curtis Marco , Magistretti Jacopo
Published: December 2017

The endopiriform nucleus (EPN) is a well-defined structure that is located deeply in the piriform region at the border with the striatum and is characterized by dense intrinsic connections and prominent projections to piriform and limbic cortices. The EPN has been proposed to promote synchronization of large populations of neurons in the olfactory cortices via the activation of transient depolarizations possibly mediated by Ca2+spikes. It is known that principal cells in the EPN express both a low- and high-voltage–activated (HVA) Ca2+currents. We further characterized HVA conductances possibly related to Ca2+-spike generation in the EPN with a whole cell, patch-clamp study on neurons acutely dissociated from the EPN of the guinea pig. To study HVA currents in isolation, experiments were performed from a holding potential of −60 mV, using Ba2+as the permeant ion. Total Ba2+currents ( IBa) evoked by depolarizing square pulses peaked at 0/+10 mV and were completely abolished by 200 μM Cd2+. The pharmacology of HVA IBas was analyzed by applying saturating concentrations of specific Ca2+-channel blockers. The L-type blocker nifedipine (10 μM; n = 11), the N-type–channel blocker ω-conotoxin GVIA (0.5 μM; n = 24), and the P/Q-type blocker ω-conotoxin MVIIC (1 μM; n = 16) abolished fractions of total IBas equal on average to 24.7 ± 5.4%, 27.1 ± 3.4%, and 22.2 ± 2.4%, respectively (mean ± SE). The simultaneous application of the three blockers reduced IBaby 68.5 ± 6.6% ( n = 10). Nifedipine-sensitive currents and most N- and P/Q-type currents were slowly decaying, the average fractional persistence after 300 ms of steady depolarization being 0.77 ± 0.02, 0.60 ± 0.06, and 0.68 ± 0.04, respectively. The residual, blocker-resistant (R-type) currents were consistently faster inactivating, with an average fractional persistence after 300 ms of 0.30 ± 0.08. Fast-decaying R-type currents also displayed a more negative threshold of activation (by about 10 mV) than non–R-type HVA currents. These results demonstrate that EPN neurons express multiple pharmacological components of the HVA Ca2+currents and point to the existence of an R-type current with specific functional properties including fast inactivation kinetics and intermediate threshold of activation.
Early Auditory Experience Induces Frequency-Specific, Adaptive Plasticity in the Forebrain Gaze Fields of the Barn Owl
Authors: Miller Greg L. , Knudsen Eric I.
Published: December 2017

Binaural acoustic cues such as interaural time and level differences (ITDs and ILDs) are used by many species to determine the locations of sound sources. The relationship between cue values and locations in space is frequency dependent and varies from individual to individual. In the current study, we tested the capacity of neurons in the forebrain localization pathway of the barn owl to adjust their tuning for binaural cues in a frequency-dependent manner in response to auditory experience. Auditory experience was altered by raising young owls with a passive acoustic filtering device that caused frequency-dependent changes in ITD and ILD. Extracellular recordings were made in normal and device-reared owls to characterize frequency-specific ITD and ILD tuning in the auditory archistriatum (AAr), an output structure of the forebrain localization pathway. In device-reared owls, individual sites in the AAr exhibited highly abnormal, frequency-dependent variations in ITD tuning, and across the population of sampled sites, there were frequency-dependent shifts in the representation of ITD. These changes were in a direction that compensated for the acoustic effects of the device on ITD and therefore tended to restore a normal representation of auditory space. Although ILD tuning was degraded relative to normal at many sites in the AAr of device-reared owls, the representation of frequency-specific ILDs across the population of sampled sites was shifted in the adaptive direction. These results demonstrate that early auditory experience shapes the representation of binaural cues in the forebrain localization pathway in an adaptive, frequency-dependent manner.
Reliability of Monosynaptic Sensory Transmission in Brain Stem Neurons In Vitro
Authors: Doyle Mark W. , Andresen Michael C.
Published: December 2017

The timing of events within the nervous system is a critical feature of signal processing and integration. In neurotransmission, the synaptic latency, the time between stimulus delivery and appearance of the synaptic event, is generally thought to be directly related to the complexity of that pathway. In horizontal brain stem slices, we examined synaptic latency and its shock-to-shock variability (synaptic jitter) in medial nucleus tractus solitarius (NTS) neurons in response to solitary tract (ST) electrical activation. Using a visualized patch recording approach, we activated ST 1–3 mm from the recorded neuron with short trains (50–200 Hz) and measured synaptic currents under voltage clamp. Latencies ranged from 1.5 to 8.6 ms, and jitter values (SD of intraneuronal latency) ranged from 26 to 764 μs ( n = 49). Surprisingly, frequency of synaptic failure was not correlated with either latency or jitter ( P > 0.147; n = 49). Despite conventional expectations, no clear divisions in latency were found from the earliest arriving excitatory postsynaptic currents (EPSCs) to late pharmacologically polysynaptic responses. Shortest latency EPSCs (<3 ms) were mediated by non– N-methyl-d-aspartate (non-NMDA) glutamate receptors. Longer latency responses were a mix of excitatory and inhibitory currents including non-NMDA EPSCs and GABAa receptor–mediated currents (IPSC). All synaptic responses exhibited prominent frequency-dependent depression. In a subset of neurons, we labeled sensory boutons by the anterograde fluorescent tracer, DiA, from aortic nerve baroreceptors and then recorded from anatomically identified second-order neurons. In identified second-order NTS neurons, ST activation evoked EPSCs with short to moderate latency (1.9–4.8 ms) but uniformly minimal jitter (31 to 61 μs) that were mediated by non-NMDA receptors but had failure rates as high as 39%. These monosynaptic EPSCs in identified second-order neurons were significantly different in latency and jitter than GABAergic IPSCs (latency, 2.95 ± 0.71 vs. 5.56 ± 0.74 ms, mean ± SE, P = 0.027; jitter, 42.3 ± 6.5 vs. 416.3 ± 94.4 μs, P = 0.013, n = 4, 6, respectively), but failure rates were similar (27.8 ± 9.0 vs. 9.7 ± 4.4%, P = 0.08, respectively). Such results suggest that jitter and not absolute latency or failure rate is the most reliable discriminator of mono- versus polysynaptic pathways. The results suggest that brain stem sensory pathways may differ in their principles of integration compared with cortical models and that this importantly impacts synaptic performance. The unique performance properties of the sensory-NTS pathway may reflect stronger axosomatic synaptic processing in brain stem compared with dendritically weighted models typical in cortical structures and thus may reflect very different strategies of spatio-temporal integration in this NTS region and for autonomic regulation.
Acidosis-Stimulated Neurons of the Medullary Raphe Are Serotonergic
Authors: Wang Wengang , Tiwari Jyoti K. , Bradley Stefania Risso , Zaykin Rey V. , Richerson George B.
Published: December 2017

Neurons of the medullary raphe project widely to respiratory and autonomic nuclei and contain co-localized serotonin, thyrotropin-releasing hormone (TRH), and substance P, three neurotransmitters known to stimulate ventilation. Some medullary raphe neurons are highly sensitive to pH and CO2and have been proposed to be central chemoreceptors. Here it was determined whether these chemosensitive neurons are serotonergic. Cells were microdissected from the rat medullary raphe and maintained in primary cell culture for 13–70 days. Immunoreactivity for serotonin, substance P, and TRH was present in these cultures. All acidosis-stimulated neurons ( n = 22) were immunoreactive for tryptophan hydroxylase (TpOH-IR), the rate-limiting enzyme for serotonin biosynthesis, whereas all acidosis-inhibited neurons ( n= 16) were TpOH-immunonegative. The majority of TpOH-IR medullary raphe neurons (73%) were stimulated by acidosis. The electrophysiological properties of TpOH-IR neurons in culture were similar to those previously reported for serotonergic neurons in vivo and in brain slices. These properties included wide action potentials (4.55 ± 0.5 ms) with a low variability of the interspike interval, a postspike afterhyperpolarization (AHP) that reversed 25 mV more positive than the Nernst potential for K+, prominent A current, spike frequency adaptation and a prolonged AHP after a depolarizing pulse. Thus the intrinsic cellular properties of serotonergic neurons were preserved in cell culture, indicating that the results obtained using this in vitro approach are relevant to serotonergic neurons in vivo. These results demonstrate that acidosis-stimulated neurons of the medullary raphe contain serotonin. We propose that serotonergic neurons initiate a homeostatic response to changes in blood CO2that includes increased ventilation and modulation of autonomic function.
Single-Unit Activity in Cortical Area MST Associated With Disparity-Vergence Eye Movements: Evidence for Population Coding
Authors: Takemura A. , Inoue Y. , Kawano K. , Quaia C. , Miles F. A.
Published: December 2017

Single-unit discharges were recorded in the medial superior temporal area (MST) of five behaving monkeys. Brief (230-ms) horizontal disparity steps were applied to large correlated or anticorrelated random-dot patterns (in which the dots had the same or opposite contrast, respectively, at the two eyes), eliciting vergence eye movements at short latencies [65.8 ± 4.5 (SD) ms]. Disparity tuning curves, describing the dependence of the initial vergence responses (measured over the period 50–110 ms after the step) on the magnitude of the steps, resembled the derivative of a Gaussian, the curves obtained with correlated and anticorrelated patterns having opposite sign. Cells with disparity-related activity were isolated using correlated stimuli, and disparity tuning curves describing the dependence of these initial neuronal responses (measured over the period of 40–100 ms) on the magnitude of the disparity step were constructed ( n = 102 cells). Using objective criteria and the fuzzy c-means clustering algorithm, disparity tuning curves were sorted into four groups based on their shapes. A post hoc comparison indicated that these four groups had features in common with four of the classes of disparity-selective neurons in striate cortex, but three of the four groups appeared to be part of a continuum. Most of the data were obtained from two monkeys, and when the disparity tuning curves of all the individual neurons recorded from either monkey were summed together, they fitted the disparity tuning curve for that same animal's vergence responses remarkably well ( r 2: 0.93, 0.98). Fifty-six of the neurons recorded from these two monkeys were also tested with anticorrelated patterns, and all showed significant modulation of their activity ( P < 0.005, 1-way ANOVA). Further, when all of the disparity tuning curves obtained with these patterns from either monkey were summed together, they too fitted the disparity tuning curve for that same animal's vergence responses very well ( r 2: 0.95, 0.96). Indeed, the summed activity even reproduced idiosyncratic differences in the vergence responses of the two monkeys. Based on these and other observations on the temporal coding of events, we hypothesize that the magnitude, direction, and time course of the initial vergence velocity responses associated with disparity steps applied to large patterns are all encoded in the summed activity of the disparity-sensitive cells in MST. Latency data suggest that this activity in MST occurs early enough to play an active role in the generation of vergence eye movements at short latencies.
Auditory Edge Detection: A Neural Model for Physiological and Psychoacoustical Responses to Amplitude Transients
Authors: Fishbach Alon , Nelken Israel , Yeshurun Yehezkel
Published: December 2017

Primary segmentation of visual scenes is based on spatiotemporal edges that are presumably detected by neurons throughout the visual system. In contrast, the way in which the auditory system decomposes complex auditory scenes is substantially less clear. There is diverse physiological and psychophysical evidence for the sensitivity of the auditory system to amplitude transients, which can be considered as a partial analogue to visual spatiotemporal edges. However, there is currently no theoretical framework in which these phenomena can be associated or related to the perceptual task of auditory source segregation. We propose a neural model for an auditory temporal edge detector, whose underlying principles are similar to classical visual edge detector models. Our main result is that this model reproduces published physiological responses to amplitude transients collected at multiple levels of the auditory pathways using a variety of experimental procedures. Moreover, the model successfully predicts physiological responses to a new set of amplitude transients, collected in cat primary auditory cortex and medial geniculate body. Additionally, the model reproduces several published psychoacoustical responses to amplitude transients as well as the psychoacoustical data for amplitude edge detection reported here for the first time. These results support the hypothesis that the response of auditory neurons to amplitude transients is the correlate of psychoacoustical edge detection.
Local Opiate Withdrawal in Locus Coeruleus Neurons In Vitro
Authors: Ivanov Alexander , Aston-Jones Gary
Published: December 2017

Noradrenergic neurons of the brain nucleus locus coeruleus (LC) become hyperactive during opiate withdrawal. It has been uncertain to what extent such hyperactivity reflects changes in intrinsic properties of these cells. The effects of withdrawal from chronic morphine on the activity of LC neurons were studied using intracellular recordings in rat brain slices. LC neurons in slices from chronically morphine-treated rats exhibited more than twice the frequency of spontaneous action potentials after naloxone compared with LC neurons from control rats. However, after naloxone treatment, the resting membrane potential (MP) of LC neurons from dependent rats was not significantly different from that in control rats. Neither resting MP nor spontaneous discharge rate (SDR) was altered by naloxone in LC neurons from control rats. Neither kynurenic acid nor a cocktail of glutamate and GABA antagonists (6-cyano-7-nitroquinoxalene-2,3-dione + 2-amino-5-phosphonopentanoic acid + bicuculline) blocked the hyperactivity of LC neurons precipitated by naloxone in slices from morphine-dependent rats. The effects of ouabain on MP and SDR were similar in LC neurons from control and morphine-dependent rats. These results indicate that an adaptive change in glutamatergic or GABAergic synaptic mechanisms or altered Na/K pump activity does not underlie the withdrawal-induced activation of LC neurons in vitro. Specific inhibitors of protein kinase A [Rp-cAMPS or N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide (H-89)] partially suppressed the withdrawal hyperactivity of LC neurons, and activators of cAMP (forskolin) or protein kinase A (Sp-cAMPS) increased the discharge rate of LC neurons from control rats. These results suggest that upregulation of cAMP-dependent protein kinase A during chronic morphine treatment is involved in the withdrawal-induced hyperactivity of LC neurons.
Modulation of Excitability inAplysiaTail Sensory Neurons by Tyrosine Kinases
Authors: Purcell Angela L. , Carew Thomas J.
Published: December 2017

Tyrosine kinases have recently been shown to modulate synaptic plasticity and ion channel function. We show here that tyrosine kinases can also modulate both the baseline excitability state of Aplysia tail sensory neurons (SNs) as well as the excitability induced by the neuromodulator serotonin (5HT). First, we examined the effects of increasing and decreasing tyrosine kinase activity in the SNs. We found that tyrosine kinase inhibitors decrease baseline SN excitability in addition to attenuating the increase in excitability induced by 5HT. Conversely, functionally increasing cellular tyrosine kinase activity in the SNs by either inhibiting opposing tyrosine phosphatase activity or by direct injection of an active tyrosine kinase (Src) induces increases in SN excitability in the absence of 5HT. Second, we examined the interaction between protein kinase A (PKA), which is known to mediate 5HT-induced excitability changes in the SNs, and tyrosine kinases, in the enhancement of SN excitability. We found that the tyrosine kinases function downstream of PKA activation since tyrosine kinase inhibitors reduce excitability induced by activators of PKA. Finally, we examined the role of tyrosine kinases in other forms of 5HT-induced plasticity in the SNs. We found that while tyrosine kinase inhibitors attenuate excitability produced by 5HT, they have no effect on short-term facilitation (STF) of the SN-motor neuron (MN) synapse induced by 5HT. Thus tyrosine kinases modulate different forms of SN plasticity independently. Such differential modulation would have important consequences for activity-dependent plasticity in a variety of neural circuits.
Dynamic Modulation of Excitation and Inhibition During Stimulation at Gamma and Beta Frequencies in the CA1 Hippocampal Region
Authors: Bracci Enrico , Vreugdenhil Martin , Hack Stephen P. , Jefferys John G. R.
Published: December 2017

Fast oscillations at gamma and beta frequency are relevant to cognition. During this activity, excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) are generated rhythmically and synchronously and are thought to play an essential role in pacing the oscillations. The dynamic changes occurring to excitatory and inhibitory synaptic events during repetitive activation of synapses are therefore relevant to fast oscillations. To cast light on this issue in the CA1 region of the hippocampal slice, we used a train of stimuli, to the pyramidal layer, comprising 1 s at 40 Hz followed by 2–3 s at 10 Hz, to mimic the frequency pattern observed during fast oscillations. Whole cell current-clamp recordings from CA1 pyramidal neurons revealed that individual stimuli at 40 Hz produced EPSPs riding on a slow biphasic hyperpolarizing-depolarizing waveform. EPSP amplitude initially increased; it then decreased concomitantly with the slow depolarization and with a large reduction in membrane resistance. During the subsequent 10-Hz train: the cells repolarized, EPSP amplitude and duration increased to above control, and no IPSPs were detected. In the presence of GABAA receptor antagonists, the slow depolarization was blocked, and EPSPs of constant amplitude were generated by 10-Hz stimuli. Altering pyramidal cell membrane potential affected the time course of the slow depolarization, with the peak being reached earlier at more negative potentials. Glial recordings revealed that the trains were associated with extracellular potassium accumulation, but the time course of this event was slower than the neuronal depolarization. Numerical simulations showed that intracellular chloride accumulation (due to massive GABAergic activation) can account for these observations. We conclude that synchronous activation of inhibitory synapses at gamma frequency causes a rapid chloride accumulation in pyramidal neurons, decreasing the efficacy of inhibitory potentials. The resulting transient disinhibition of the local network leads to a short-lasting facilitation of polysynaptic EPSPs. These results set constraints on the role that synchronous, rhythmic IPSPs may play in pacing oscillations at gamma frequency in the CA1 hippocampal region.
Gravitoinertial Force Magnitude and Direction Influence Head-Centric Auditory Localization
Authors: DiZio Paul , Held Richard , Lackner James R. , Shinn-Cunningham Barbara , Durlach Nathaniel
Published: December 2017

We measured the influence of gravitoinertial force (GIF) magnitude and direction on head-centric auditory localization to determine whether a true audiogravic illusion exists. In experiment 1, supine subjects adjusted computer-generated dichotic stimuli until they heard a fused sound straight ahead in the midsagittal plane of the head under a variety of GIF conditions generated in a slow-rotation room. The dichotic stimuli were constructed by convolving broadband noise with head-related transfer function pairs that model the acoustic filtering at the listener's ears. These stimuli give rise to the perception of externally localized sounds. When the GIF was increased from 1 to 2 g and rotated 60° rightward relative to the head and body, subjects on average set an acoustic stimulus 7.3° right of their head's median plane to hear it as straight ahead. When the GIF was doubled and rotated 60° leftward, subjects set the sound 6.8° leftward of baseline values to hear it as centered. In experiment 2, increasing the GIF in the median plane of the supine body to 2 g did not influence auditory localization. In experiment 3, tilts up to 75° of the supine body relative to the normal 1 g GIF led to small shifts, 1–2°, of auditory setting toward the up ear to maintain a head-centered sound localization. These results show that head-centric auditory localization is affected by azimuthal rotation and increase in magnitude of the GIF and demonstrate that an audiogravic illusion exists. Sound localization is shifted in the direction opposite GIF rotation by an amount related to the magnitude of the GIF and its angular deviation relative to the median plane.
Influence of Expectation of Different Rewards on Behavior-Related Neuronal Activity in the Striatum
Authors: Hassani Oum K. , Cromwell Howard C. , Schultz Wolfram
Published: December 2017

This study investigated how different expected rewards influence behavior-related neuronal activity in the anterior striatum. In a spatial delayed-response task, monkeys reached for a left or right target and obtained a small quantity of one of two juices (apple, grenadine, orange, lemon, black currant, or raspberry). In each trial, an initial instruction picture indicated the behavioral target and predicted the reward. Nonmovement trials served as controls for movement relationships. Consistent preferences in special reward choice trials and differences in anticipatory licks, performance errors, and reaction times indicated that animals differentially expected the rewards predicted by the instructions. About 600 of >2,500 neurons in anterior parts of caudate nucleus, putamen, and ventral striatum showed five forms of task-related activations, comprising responses to instructions, spatial or nonspatial activations during the preparation or execution of the movement, and activations preceding or following the rewards. About one-third of the neurons showed different levels of task-related activity depending on which liquid reward was predicted at trial end. Activations were either higher or lower for rewards that were preferred by the animals as compared with nonpreferred rewards. These data suggest that the expectation of an upcoming liquid reward may influence a fraction of task-related neurons in the anterior striatum. Apparently the information about the expected reward is incorporated into the neuronal activity related to the behavioral reaction leading to the reward. The results of this study are in general agreement with an account of goal-directed behavior according to which the outcome should be represented already at the time at which the behavior toward the outcome is performed.
Stimulation of Na-K-2Cl Cotransporter in Neurons by Activation of Non-NMDA Ionotropic Receptor and Group-I mGluRs
Authors: Schomberg Stacey L. , Su Gui , Haworth Robert A. , Sun Dandan
Published: December 2017

In a previous study, we found that Na+-K+-2Cl−cotransporter in immature cortical neurons was stimulated by activation of the ionotropic N-methyl-d-aspartate (NMDA) glutamate receptor in a Ca2+-dependent manner. In this report, we investigated whether the Na+-K+-2Cl−cotransporter in immature cortical neurons is stimulated by non-NMDA glutamate receptor–mediated signaling pathways. Expression of the Na+-K+-2Cl−cotransporter and metabotropic glutamate receptors (mGluR1 and 5) was detected in cortical neurons via immunoblotting and immunofluorescence staining. Significant stimulation of cotransporter activity was observed in the presence of both trans-(±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid ( trans-ACPD) (10 μM), a metabotropic glutamate receptor (mGluR) agonist, and (RS)-3,5-dihydroxyphenylglycine (DHPG) (20 μM), a selective group-I mGluR agonist. Both trans-ACPD and DHPG-mediated effects on the cotransporter were eradicated by bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid–AM, a Ca2+chelator. In addition, DHPG-induced stimulation of the cotransporter activity was inhibited in the presence of mGluRs antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) (1 mM) and also with selective mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) (100 μM). A DHPG-induced rise in intracellular Ca2+in cortical neurons was detected with Fura-2. Moreover, DHPG-mediated stimulation of the cotransporter was abolished by inhibition of Ca2+/CaM kinase II. Interestingly, the cotransporter activity was increased by activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. These results suggest that the Na+-K+-2Cl−cotransporter in immature cortical neurons is stimulated by group-I mGluR- and AMPA-mediated signal transduction pathways. The effects are dependent on a rise of intracellular Ca2+.
Cerebral Blood-Flow Changes Induced by Paired-Pulse Transcranial Magnetic Stimulation of the Primary Motor Cortex
Authors: Strafella A. P. , Paus T.
Published: December 2017

Positron emission tomography (PET) was used to assess changes in regional cerebral blood flow (CBF) induced by paired-pulse transcranial magnetic stimulation (TMS) of primary motor cortex (M1). The study was performed in eight normal volunteers using two Magstim-200 stimulators linked with a Bistim module. A circular TMS coil was held in the scanner by a mechanical arm and located over the left M1. Surface electrodes were used to record motor evoked potentials (MEPs) from the contralateral first dorsal interosseous muscle (FDI). Cortical excitability was evaluated in the relaxed FDI using a paired conditioning-test stimulus paradigm with two interstimulus intervals (ISIs): 3 and 12 ms. The subjects were scanned three times during each of the following four conditions: 1) baseline with no TMS (BASE); 2) single-pulse TMS (TMSsing); 3) 3-ms paired-pulse TMS (TMS3); and 4) 12-ms paired-pulse TMS (TMS12). CBF and peak-to-peak MEP amplitudes were measured over each 60-s scanning period. To assess TMS-induced changes in CBF, a t-statistic map was generated by first subtracting the single-pulse TMS condition from the 3- and 12-ms paired-pulse TMS conditions and then correlating the CBF differences, respectively, with the amount of suppression and facilitation of the EMG responses. A significant positive correlation was observed between the CBF difference (TMS3-TMSsing) and the amount of suppression of EMG response, as well as between the CBF difference (TMS12-TMSsing) and the amount of facilitation of EMG response. This positive correlation was observed in the left M1, left lateral premotor cortex, and right M1 in the case of 3-ms paired-pulse TMS, but only in the left M1 in the case of 12-ms paired-pulse TMS. The above pattern of CBF response to paired-pulse TMS supports the possibility that suppression and facilitation of the EMG response are mediated by different populations of cortical interneurons.
Modeling V1 Disparity Tuning to Time-Varying Stimuli
Authors: Chen Yuzhi , Wang Yunjiu , Qian Ning
Published: December 2017

Most models of disparity selectivity consider only the spatial properties of binocular cells. However, the temporal response is an integral component of real neurons' activities, and time-varying stimuli are often used in the experiments of disparity tuning. To understand the temporal dimension of V1 disparity representation, we incorporate a specific temporal response function into the disparity energy model and demonstrate that the binocular interaction of complex cells is separable into a Gabor disparity function and a positive time function. We then investigate how the model simple and complex cells respond to widely used time-varying stimuli, including motion-in-depth patterns, drifting gratings, moving bars, moving random-dot stereograms, and dynamic random-dot stereograms. It is found that both model simple and complex cells show more reliable disparity tuning to time-varying stimuli than to static stimuli, but similarities in the disparity tuning between simple and complex cells depend on the stimulus. Specifically, the disparity tuning curves of the two cell types are similar to each other for either drifting sinusoidal gratings or moving bars. In contrast, when the stimuli are dynamic random-dot stereograms, the disparity tuning of simple cells is highly variable, whereas the tuning of complex cells remains reliable. Moreover, cells with similar motion preferences in the two eyes cannot be truly tuned to motion in depth regardless of the stimulus types. These simulation results are consistent with a large body of extant physiological data, and provide some specific, testable predictions.
Effects of Bis(7)-Tacrine on Spontaneous Synaptic Activity and on the Nicotinic ACh Receptor of Torpedo Electric Organ
Authors: Ros Esteve , Aleu Jordi , Gomez De Aranda Inmaculada , Cantí Carles , Pang Yuan-Ping , Marsal Jordi , Solsona Carles
Published: December 2017

Bis(7)-tacrine is a potent acetylcholinesterase inhibitor in which two tacrine molecules are linked by a heptylene chain. We tested the effects of bis(7)-tacrine on the spontaneous synaptic activity. Miniature endplate potentials (MEPPs) were recorded extracellularly on slices of electric organ of Torpedo marmorata. Bis(7)-tacrine, at a concentration of 100 nM, increased the magnitudes that describe MEPPs: amplitude, area, rise time, rate of rise, and half-width. We also tested the effect of bis(7)-tacrine on nicotinic acetylcholine receptors by analyzing the currents elicited by acetylcholine (100 μM) in Torpedo electric organ membranes transplanted in Xenopus laevis oocytes. Bis(7)-tacrine inhibited the acetylcholine-induced currents in a reversible manner (IC50 = 162 nM). The inhibition of nicotinic acetylcholine receptors was not voltage dependent, and bis(7)-tacrine increased the desensitization of nicotinic acetylcholine receptors. The Hill coefficient for bis(7)-tacrine was −0.72 ± 0.02, indicating that bis(7)-tacrine binds to the nicotinic acetylcholine receptor in a molecular ratio of 1:1, but does not affect the binding of α-bungarotoxin with the nicotinic acetylcholine receptor. In conclusion, bis(7)-tacrine greatly increases the spontaneous quantal release from peripheral cholinergic terminals at a much lower concentration than tacrine. Bis(7)-tacrine also blocks acetylcholine-induced currents of Torpedo electric organ, although the mechanism is different from that of tacrine: bis(7)-tacrine enhances desensitization, whereas tacrine reduces it.
Sensitivity of Auditory Cortical Neurons to Locations of Signals and Competing Noise Sources
Authors: Furukawa Shigeto , Middlebrooks John C.
Published: December 2017

The present study examined cortical parallels to psychophysical signal detection and sound localization in the presence of background noise. The activity of single units or of small clusters of units was recorded in cortical area A2 of chloralose-anesthetized cats. Signals were 80-ms click trains that varied in location in the horizontal plane around the animal. Maskers were continuous broadband noises. In the focal masker condition, a single masker source was tested at various azimuths. In the diffuse masker condition, uncorrelated noise was presented from two speakers at ±90° lateral to the animal. For about 2/3 of units (“type A”), the presence of the masker generally reduced neural sensitivity to signals, and the effects of the masker depended on the relative locations of signal and masker sources. For the remaining 1/3 of units (“type B”), the masker reduced spike rates at low signal levels but often augmented spike rates at higher signal levels. Increases in spike rates of type B units were most common for signal sources in front of the ear contralateral to the recording site but tended to be independent of masker source location. For type A units, masker effects could be modeled as a shift toward higher levels of spike-rate- and spike-latency-versus-level functions. For a focal masker, the shift size decreased with increasing separation of signal and masker. That result resembled psychophysical spatial unmasking, i.e., improved signal detection by spatial separation of the signal from the noise source. For the diffuse masker condition, the shift size generally was constant across signal locations. For type A units, we examined the effects of maskers on cortical signaling of sound-source location, using an artificial-neural-network (ANN) algorithm. First, an ANN was trained to estimate the signal location in the quiet condition by recognizing the spike patterns of single units. Then we tested ANN responses for spike patterns recorded under various masker conditions. Addition of a masker generally altered spike patterns and disrupted ANN identification of signal location. That disruption was smaller, however, for signal and masker configurations in which the masker did not severely reduce units' spike rates. That result compared well with the psychophysical observation that listeners maintain good localization performance as long as signals are clearly audible.
Contribution of the Hyperpolarization-Activated Current (I h) to Membrane Potential and GABA Release in Hippocampal Interneurons
Authors: Lupica Carl R. , Bell James A. , Hoffman Alexander F. , Watson Patricia L.
Published: December 2017

Intrinsic GABAergic interneurons provide inhibitory input to the principal neurons of the hippocampus. The majority of interneurons located in stratum oriens (s.o.) of the CA1 region express the hyperpolarization-activated cation current known as I h. In an effort to elucidate the role of this current in regulating the baseline excitability of these neurons and its participation in the regulation of the release of GABA onto CA1 pyramidal neurons, we utilized whole cell electrophysiological recordings from both populations of cells. In voltage-clamp experiments, hyperpolarization of the interneuron membrane initiated a large inward current with an estimated activation threshold of 51.6 ± 7.6 mV and a half-maximal voltage of −73.0 ± 7.0 mV. This current was blocked by bath application of the I h inhibitors ZD 7288 (50 μM) or cesium (2 mM). Current-clamp experiments at the interneuron resting membrane potential (−61.3 ± 1.2 mV) revealed a significant hyperpolarization, a decrease in the rate of spontaneous action potential discharge, an increase in the cellular input resistance, and the elimination of rebound afterdepolarizations during blockade of I h with ZD 7288 (50 μM). The hyperpolarizing effect of ZD 7288 was also substantially larger in interneurons clamped near −80 mV using current injection through the pipette. In addition to neurons exhibiting I h, recordings were obtained from a small population of s.o. interneurons that did not exhibit this current. These cells demonstrated resting membrane potentials that were significantly more negative (−73.6 ± 5.5 mV) than those observed in neurons expressing I h, suggesting that this current contributes to more depolarized membrane potentials in these cells. Recordings from postsynaptic pyramidal neurons demonstrated that blockade of I h with ZD 7288 caused a substantial reduction (∼43%) in the frequency of spontaneous action potential-dependent inhibitory postsynaptic currents (IPSCs), without altering their average amplitude. However, miniature action-potential-independent IPSC frequency, amplitude, and decay kinetics were unaltered by ZD 7288. These data suggest that I h is active at the resting membrane potential in s.o. interneurons and as a result contributes to the spontaneous activity of these cells and to the tonic inhibition of CA1 pyramidal neurons in the hippocampus.
Induction of Long-Term Depression in Cerebellar Purkinje Cells Requires a Rapidly Turned Over Protein
Authors: Karachot Laddawan , Shirai Yoshinori , Vigot Réjan , Yamamori Tetsuo , Ito Masao
Published: December 2017

Evidence is presented indicating that the induction of long-term depression (LTD) in Purkinje cells (PCs) requires a rapidly turned over protein(s) during a critical time period within 15 min after the onset of LTD-inducing stimulation and that synthesis of this protein is maintained by mRNAs supplied via transcription. LTD was induced in granule cell axon (GA)-to-PC synapses by stimulation of these synapses at 1 Hz for 5 min in conjunction with the climbing fibers (CFs) forming synapses on the same PCs and represented by a persistent reduction in the GA-induced excitatory postsynaptic potentials (EPSPs). Not only a prolonged but also a brief (5 min) pulse application of translational inhibitors (anisomycin, puromycin, or cycloheximide) effectively blocked the LTD induction. Pulses applied during the period from 30 min before to 10 min after the onset of conjunctive stimulation blocked the LTD induction, but those applied 15 min after were ineffective. The three translational inhibitors blocked the LTD induction similarly, suggesting that the effect is due to their common action of inhibiting protein synthesis. Infusion of a mRNA cap analogue (7-methyl GTP) into PCs also blocked LTD induction, ensuring that the postsynaptic protein synthesis within PCs is required for LTD induction. Transcriptional inhibitors, actinomycin D and 5,6-dichloro-l-β-d-ribofuranosyl-benzimidazole, also blocked the LTD induction, but this effect was apparent when 5-min pulses of the transcriptional inhibitors preceded the conjunctive stimulation by 30 min or more. This time lag of 30 min is presumed to be required for depletion of the protein(s) required for LTD induction. The presently observed effects of translational and transcriptional inhibitors on the LTD induction are of temporal characteristics corresponding to their depressant effects on the type-1 metabotropic glutamate-receptor (mGluR1)-mediated slow EPSPs in PCs as we have reported recently. An antagonist of mGluR1s [(RS)-1-aminoindan-1,5-dicarboxylic acid], however, did not block LTD induction when it was applied during the 10-min period following conjunctive stimulation, where translational inhibitors effectively blocked LTD induction. This discrepancy in time course suggests that the rapidly turned over protein(s) required for LTD induction is involved in a process occurring downstream of the activation of mGluR1s.
Nitric Oxide Modulates Ca2+ Channels in Dorsal Root Ganglion Neurons Innervating Rat Urinary Bladder
Authors: Yoshimura Naoki , Seki Satoshi , de Groat William C.
Published: December 2017

The effect of a nitric oxide (NO) donor on high-voltage-activated Ca2+ channel currents ( I Ca) was examined using the whole cell patch-clamp technique in L6–S1 dorsal root ganglion (DRG) neurons innervating the urinary bladder. The neurons were labeled by axonal transport of a fluorescent dye, Fast Blue, injected into the bladder wall. Approximately 70% of bladder afferent neurons exhibited tetrodotoxin (TTX)-resistant action potentials (APs), and 93% of these neurons were sensitive to capsaicin, while the remaining neurons had TTX-sensitive spikes and were insensitive to capsaicin. The peak current density of nimodipine-sensitive L-type Ca2+ channels activated by depolarizing pulses (0 mV) from a holding potential of −60 mV was greater in bladder afferent neurons with TTX-resistant APs (39.2 pA/pF) than in bladder afferent neurons with TTX-sensitive APs (28.9 pA/pF), while the current density of ω-conotoxin GVIA-sensitive N-type Ca2+channels was similar (43–45 pA/pF) in both types of neurons. In both types of neurons, the NO donor, S-nitroso- N-acetylpenicillamine (SNAP) (500 μM), reversibly reduced (23.4–26.6%) the amplitude of I Ca elicited by depolarizing pulses to 0 mV from a holding potential of −60 mV. SNAP-induced inhibition of I Ca was reduced by 90% in the presence of ω-conotoxin GVIA but was unaffected in the presence of nimodipine, indicating that NO-induced inhibition of I Ca is mainly confined to N-type Ca2+ channels. Exposure of the neurons for 30 min to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 μM), an inhibitor of NO-stimulated guanylyl cyclase, prevented the SNAP-induced reduction in I Ca. Extracellular application of 8-bromo-cGMP (1 mM) mimicked the effects of NO donors by reducing the peak amplitude of I Ca(28.6% of reduction). Action potential configuration and firing frequency during depolarizing current pulses were not altered by the application of SNAP (500 μM) in bladder afferent neurons with TTX-resistant and -sensitive APs. These results indicate that NO acting via a cGMP signaling pathway can modulate N-type Ca2+ channels in DRG neurons innervating the urinary bladder.