bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracellular QX-314 Causes Depression of Membrane Potential Oscillations in Lamprey Spinal Neurons During Fictive Locomotion
Authors: Hu Guo-Yuan , Biró Zoltán , Hill Russell H. , Grillner Sten
Published: December 2017

Spinal neurons undergo large cyclic membrane potential oscillations during fictive locomotion in lamprey. It was investigated whether these oscillations were due only to synaptically driven excitatory and inhibitory potentials or if voltage-dependent inward conductances also contribute to the depolarizing phase by using N-(2,6-dimethylphenyl carbamoylmethyl)triethylammonium bromide (QX-314) administered intracellularly during fictive locomotion. QX-314 intracellularly blocks inactivating and persistent Na+ channels, and in some neurons, effects on certain other types of channels have been reported. To detail the effects of QX-314 on Na+ and Ca2+ channels, we used dissociated lamprey neurons recorded under whole cell voltage clamp. At low intracellular concentrations of QX-314 (0.2 mM), inactivating Na+ channels were blocked and no effects were exerted on Ca2+ channels (also at 0.5 mM). At 10 mM QX-314, there was, however a marked reduction of I Ca. In the isolated spinal cord of the lamprey, fictive locomotion was induced by superfusing the spinal cord with Ringer's solution containing N-methyl-d-aspartate (NMDA), while recording the locomotor activity from the ventral roots. Simultaneously, identified spinal neurons were recorded intracellularly, while infusing QX-314 from the microelectrode. Patch electrodes cannot be used in the intact spinal cord, and therefore “sharp” electrodes were used. The amplitude of the oscillations was consistently reduced by 20–25% in motoneurons ( P < 0.05) and unidentified spinal neurons ( P < 0.005). The onset of the effect started a few minutes after impalement and reached a stable level within 30 min. These effects thus show that QX-314 causes a reduction in the amplitude of membrane potential oscillations during fictive locomotion. We also investigated whether QX-314 could affect glutamate currents by applying short pulses of glutamate from an extracellular pipette. No changes were observed. We also found no evidence for a persistent Na+ current in dissociated neurons, but these cells have a much-reduced dendritic tree. The results indicate that there is an inward conductance, which is sensitive to QX-314, during membrane potential oscillations that “boosts” the synaptic drive during fictive locomotion. Taken together, the results suggest that inactivating Na+ channels contribute to this inward conductance although persistent Na+channels, if present on dendrites, could possibly also contribute to shaping the membrane potential oscillations.
Auditory Response Properties in the Superior Paraolivary Nucleus of the Gerbil
Authors: Behrend Oliver , Brand Antje , Kapfer Christoph , Grothe Benedikt
Published: December 2017

The ascending auditory pathway is characterized by parallel processing. At the brain stem level, several structures are involved that are known to serve different well-defined functions. However, the function of one prominent brain stem nucleus, the rodent superior paraolivary nucleus (SPN) and its putative homologue in other mammals, the dorsomedial periolivary nucleus, is unknown. Based on extracellular recordings from anesthetized gerbils, we tested the role of the SPN in sound localization and temporal processing. First, the existence of binaural inputs indicates that the SPN might be involved in sound localization. Although almost half of the neurons exhibited binaural interactions (most of them excited from both sides), effects of interaural time and intensity differences (ITD; IID) were weak and ambiguous. Thus a straightforward function of SPN in sound localization appears to be implausible. Second, inputs from octopus and multipolar/stellate cells of the cochlear nucleus and from principal cells of the medial nucleus of the trapezoid body could relate to precise temporal processing in the SPN. Based on discharge types, two subpopulations of SPN cells were observed: about 60% of the neurons responded to pure tones with sustained discharges, with irregular spike patterns and no phase-locking. Only four neurons showed a regular spike pattern (“chopping”). About 40% of the neurons responded with phasic on or off discharges. Average first spike latency observed in neurons with sustained discharges was significantly shorter than that of on responders, but had a considerably higher trial-to-trial variation (“jitter”). A subpopulation of on responders showed a jitter of less than ±0.1 ms. Most neurons (66%) responded to sinusoidally amplitude-modulated sounds (SAM) with an ongoing response, phase-locked to the stimulus envelope. Again, on responders showed a significantly higher temporal precision in the phase-locked discharge compared with the sustained responders. High variability was observed among spike-rate-based modulation transfer functions. Histologically, a massive concentration of cytochemical markers for glycinergic input to SPN cells was demonstrated. Application of glycine or its blockade revealed profound effects of glycinergic inhibition on the auditory responses of SPN neurons. The existence of at least two subpopulations of neurons is in line with different subsets of SPN cells that can be distinguished morphologically. One temporally less precise population might modulate the processing of its target structures by providing a rather diffuse inhibition. In contrast, precise onresponders might provide a short, initial inhibitory pulse to its targets.
Responses of Ankle Extensor and Flexor Motoneurons to Transcranial Magnetic Stimulation
Authors: Bawa P. , Chalmers G. R. , Stewart H. , Eisen A. A.
Published: December 2017

Transcranial magnetic stimulation (TMS) of the motor cortex excites limb muscles of the contralateral side of the body. Reports of poorly defined, or a complete lack of systematic excitatory responses of soleus motoneurons compared with those of tibialis anterior (TA) motoneurons has led to the proposal that while all ankle flexor motoneurons receive strong corticomotoneuronal connections, very few soleus motoneurons do. In addition, the connections to these few motoneurons are weak. The nature of corticomotoneuronal connections onto these two motoneuron pools was re-evaluated in the following experiments. The leg area of the left motor cortex was stimulated with a large double-cone coil using Magstim 200, while surface electromyographic (EMG) and single motor unit (SMU) responses were recorded from soleus and TA muscles of healthy adult subjects. Under resting conditions, the onset (25–30 ms) and duration of concomitantly recorded short latency motor evoked potentials (MEPs) in surface EMG from both muscles were similar. The input-output relationships of the simultaneously recorded soleus and TA EMG responses showed much greater increases in TA MEPs compared with soleus MEPs with identical increases in stimulus intensity. Under resting and nonisometric conditions, a later peak with onset latency of approximately 100 ms was observed in soleus. During isometric conditions or with vibration of the TA tendon, the second soleus peak was abolished indicating reflex origin of this peak. Recordings from 42 soleus and 39 TA motor units showed clear response peaks in the peristimulus time histograms (PSTHs) of every unit. Two statistical tests were done to determine the onset and duration of response peaks in the PSTHs. With χ2 test, the duration was 6.9 ± 4.2 ms (mean ± SD) for soleus and 5.1 ± 2.1 ms for TA. Using the criterion of discerning a peak by bin counts being three SDs above background, the duration was 10.0 ± 4.4 ms for soleus and 7.8 ± 2.6 ms for TA. Results of these experiments do not suggest a lack of systematic corticomotoneuronal connections on soleus motoneurons when compared with those on TA, though some differences in the strengths of corticomotoneuronal connections onto the two pools do exist.
Vestibuloocular Reflex Dynamics During High-Frequency and High-Acceleration Rotations of the Head on Body in Rhesus Monkey
Authors: Huterer Marko , Cullen Kathleen E.
Published: December 2017

For frequencies >10 Hz, the vestibuloocular reflex (VOR) has been primarily investigated during passive rotations of the head on the body in humans. These prior studies suggest that eye movements lag head movements, as predicted by a 7-ms delay in the VOR reflex pathways. However, Minor and colleagues recently applied whole-body rotations of frequencies ≤15 Hz in monkeys and found that eye movements were nearly in phase with head motion across all frequencies. The goal of the present study was to determine whether VOR response dynamics actually differ significantly for whole-body versus head-on-body rotations. To address this question, we evaluated the gain and phase of the VOR induced by high-frequency oscillations of the head on the body in monkeys by directly measuring both head and eye movements using the magnetic search coil technique. A torque motor was used to rotate the heads of three Rhesus monkeys over the frequency range 5–25 Hz. Peak head velocity was held constant, first at ±50°/s and then ±100°/s. The VOR was found to be essentially compensatory across all frequencies; gains were near unity (1.1 at 5 Hz vs. 1.2 at 25 Hz), and phase lag increased only slightly with frequency (from 2° at 5 Hz to 11° at 25 Hz, a marked contrast to the 63° lag at 25 Hz predicted by a 7-ms VOR latency). Furthermore, VOR response dynamics were comparable in darkness and when viewing a target and did not vary with peak velocity. Although monkeys offered less resistance to the initial cycles of applied head motion, the gain and phase of the VOR did not vary for early versus late cycles, suggesting that an efference copy of the motor command to the neck musculature did not alter VOR response dynamics. In addition, VOR dynamics were also probed by applying transient head perturbations with much greater accelerations (peak acceleration >15,000°/s2) than have been previously employed. The VOR latency was between 5 and 6 ms, and mean gain was close to unity for two of the three animals tested. A simple linear model well described the VOR responses elicited by sinusoidal and transient head on body rotations. We conclude that the VOR is compensatory over a wide frequency range in monkeys and has similar response dynamics during passive rotation of the head on body as during passive rotation of the whole body in space.
Different Calcium Sources Are Narrowly Tuned to the Induction of Different Forms of LTP
Authors: Raymond Clarke R. , Redman Stephen J.
Published: December 2017

The essential role of calcium in the induction of long-term potentiation (LTP) has been well established. In particular, calcium influx via the N-methyl-d-aspartate (NMDA) receptor (NMDAR) is important for LTP induction in many pathways. However, the specific roles of other calcium sources in hippocampal LTP are less clear. The aim of the present study was to determine the appropriate conditions and extent to which non-NMDAR Ca2+sources contribute to the induction of different forms of LTP in area CA1 of hippocampal slices. Increasing numbers of theta-burst trains (1, 4, and 8 TBS) induced LTP of increasing magnitude and persistence. Inhibition of ryanodine receptors caused inhibition of weak LTP induced by 1 TBS, but had no effect on more robust forms of LTP. Inhibition of IP3 receptors inhibited moderate LTP induced by 4 TBS, but had no effect when 1 TBS or 8 TBS were used. Inhibition of L-type voltage–dependent Ca2+channels inhibited strong LTP induced by 8 TBS, but had no effect on weaker forms of LTP. These results show that different Ca2+sources have different thresholds for activation by TBS trains. Furthermore, each Ca2+source appears to be tuned to the induction of a different form of LTP. Such tuning could reflect an important link between different LTP induction and maintenance mechanisms.
ATP-Inhibition of M Current in Frog Sympathetic Neurons Involves Phospholipase C But Not Ins P3, Ca2+, PKC, orRas
Authors: Stemkowski Patrick L. , Tse Frederick W. , Peuckmann Vera , Ford Christopher P. , Colmers William F. , Smith Peter A.
Published: December 2017

Suppression of the voltage-activated, noninactivating K+conductance (M conductance; gM) by muscarinic agonists, P2Yagonists or bradykinin increases neuronal excitability. All agonist effects are mediated, at least in part, via the Gq/11class of G protein. We found, using whole cell or perforated patch recording from bullfrog sympathetic B neurons that ATP-induced suppression of gMwas attenuated by the phospholipase C (PLC) inhibitor, U73122 (IC50∼0.14 μM) but not by the inactive isomer, U73343 . The ability of extracellularly applied U73122 to inhibit PLC was confirmed by its antagonism of ATP-induced elevation of intracellular Ca2+as measured by fura-2 photometry. ATP-induced gMsuppression was not antagonized by the protein kinase C (PKC) inhibitor, chelerythrine (5 μM extracellular +10 μM intracellular), by the Ca2+-ATPase inhibitor, thapsigargin (5 μM), or by inositol trisphosphate (InsP3) receptor antagonists, heparin (∼300 μM) or xestospongin C (1.8 μM). The effect of ATP on gMwas thus dependent on PLC yet independent of PKC and of InsP3-induced release of intracellular Ca2+. We therefore tested the involvement of a PKC-independent action of diacylglycerol (DAG) that could occur via activation of Ras. This low-molecular-weight G protein is activated following DAG binding to Ras-GRP, a neuronal Ras-GTP exchange factor. However, impairment of Ras function by culturing neurons with isoprenylation inhibitors (perillic acid, 0.1 mM, or α-hydroxyfarnesyl-phosphonic acid, 10 μM) failed to affect ATP-induced gMsuppression. Inhibition of MEK (mitogen-activated protein kinase), a downstream target of Ras, by using PD 98059 (10 μM) was also ineffective. The transduction mechanism used by ATP to suppress gMin frog sympathetic neurons therefore differs from the PLC-independent mechanism used by muscarine and from the PLC and Ca2+-dependent mechanism used by bradykinin and UTP in mammalian ganglia. The possibility remains that “lipid-signaling” mechanisms, perhaps involving PLC-induced depletion of phosphatidylinositol bisphosphate, are involved in PLC-mediated inhibition of gMby ATP in amphibian sympathetic neurons.
Chronic Interleukin-6 Exposure Alters Electrophysiological Properties and Calcium Signaling in Developing Cerebellar Purkinje Neurons in Culture
Authors: Nelson Thomas E. , Ur Christina L. , Gruol Donna L.
Published: December 2017

The cytokine interleukin-6 (IL-6) is chronically expressed at elevated levels within the CNS in many neurological disorders and may contribute to the histopathological, pathophysiological, and cognitive deficits associated with such disorders. However, the effects of chronic IL-6 exposure on neuronal function in the CNS are largely unknown. Therefore using intracellular recording and calcium imaging techniques, we investigated the effects of chronic IL-6 exposure on the physiological properties of cerebellar Purkinje neurons in primary culture. Two weeks of exposure to 1,000 units/ml (U/ml) IL-6 resulted in altered electrophysiological properties of Purkinje neurons, including a significant reduction in action potential generation, an increase in input resistance, and an enhanced electrical response to the ionotropic glutamate receptor agonist, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) compared with untreated neurons. Lower concentrations of IL-6 (100 and 500 U/ml) had no effects on these electrophysiological parameters. However, neurons exposed to 500 U/ml chronic IL-6 resulted in significantly elevated resting levels of intracellular calcium as well as an increase in the intracellular calcium signal of Purkinje neurons in response to AMPA, effects not observed in neurons exposed to 1,000 U/ml chronic IL-6. Morphometric analysis revealed a lack of gross structural changes following chronic IL-6 treatment, such as in the number, size, and extent of dendritic arborization of Purkinje neurons in culture. Using immunohistochemistry, we found that cultured Purkinje neurons express both the IL-6 receptor and its intracellular signaling subunit, gp130, indicating that IL-6 may act directly on Purkinje neurons to alter their physiological properties. The present data show that chronic exposure to elevated levels of IL-6, such as occurs in various neurological diseases, produces alterations in several important physiological properties of Purkinje neurons and that these changes occur in the absence of neuronal toxicity, damage, or death. The results support the hypothesis that chronic IL-6 exposure can disrupt normal CNS function and thereby contribute to the pathophysiology associated with many neurological diseases.
Excitatory Actions of GABA Increase BDNF Expression via a MAPK-CREB–Dependent Mechanism—A Positive Feedback Circuit in Developing Neurons
Authors: Obrietan Karl , Gao Xiao-Bing , van den Pol Anthony N.
Published: December 2017

During early neuronal development, GABA functions as an excitatory neurotransmitter, triggering membrane depolarization, action potentials, and the opening of plasma membrane Ca2+channels. These excitatory actions of GABA lead to a number of changes in neuronal structure and function. Although the effects of GABA on membrane biophysics during early development have been well documented, little work has been done to examine the possible mechanisms underlying GABA-regulated plastic changes in the developing brain. This study focuses on GABA-regulated kinase activity and transcriptional control. We utilized a combination of Western blotting and immunocytochemical techniques to examine two potential downstream pathways regulated by GABA excitation: the p42/44 mitogen-activated protein kinase (MAPK) cascade and the transcription factor cyclic AMP response element binding protein (CREB). During early development of cultured hypothalamic neurons (5 days in vitro), stimulation with GABA triggered activation of the MAPK cascade and phosphorylation of CREB at Ser 133. These effects were mediated by the GABAAreceptor, since administration of the GABAAreceptor-specific agonist muscimol (50 μM) triggered pathway activation, and pretreatment with the GABAA-receptor specific antagonist bicuculline (20 μM) blocked pathway activation. Immunocytochemistry revealed a spatial and temporal correlation between activation of the MAPK cascade and CREB phosphorylation. Pretreatment with the MAPK/ERK kinase (MEK) inhibitor U0126 (10 μM) attenuated CREB phosphorylation, indicating that the MAPK pathway regulates that activation state of CREB. In contrast to the excitatory effects observed during early development, in more mature neurons, GABA functions as an inhibitory transmitter. Consistent with this observation, GABAAreceptor activation did not stimulate MAPK cascade activation or CREB phosphorylation in mature cultures (18 days in vitro). To determine whether GABAAreceptor activation during early development stimulates gene expression, we examined the inducible expression of the neurotrophin brain-derived neurotrophic factor (BDNF). Both GABA and muscimol stimulated BDNF expression, and pretreatment with U0126 attenuated GABA-induced BDNF expression. Whole cell electrophysiological recording was used to assess the effects of BDNF on GABA release. BDNF (100 ng/ml) dramatically increased the frequency of excitatory GABAergic spontaneous postsynaptic currents. Together, these data suggest a positive excitatory feedback loop between GABA and BDNF expression during early development, where GABA facilitates BDNF expression, and BDNF facilitates the synaptic release of GABA. Signaling via the MAPK cascade and the transcription factor CREB appear to play a substantial role in this process.
Electromyographic Responses to an Unexpected Load in Fast Voluntary Movements: Descending Regulation of Segmental Reflexes
Authors: Shapiro Mark B. , Gottlieb Gerald L. , Moore Charity G. , Corcos Daniel M.
Published: December 2017

This study examined the effects of unexpected loading on muscle activation during fast goal-oriented movements. We tested the hypothesis that the electromyographic (EMG) response to an unexpected load occurs at a short latency after the difference between the expected and the unexpected movement velocity exceeds a fixed threshold. Subjects performed two movement tasks as follows: 1) 30° fast elbow flexion movement with an inertial load added by a torque motor; and 2) 50° fast elbow flexion movement with no added load. These movement tasks were chosen to have similar timing parameters, such as movement time, time-to-peak velocity, and duration of the first agonist burst, while the magnitudes of the angular displacement, velocity, and acceleration were different. In task 1, in random trials a viscous load was substituted for the inertial load at movement onset. In task 2, the same viscous load was added in random trials. The earliest consistent response to the unexpected load was detected in the agonist (biceps) EMG at the same time, about 200 ms from the EMG onset, in both tasks. However, the velocity errors were different in the two tasks and no velocity error threshold dependency could be found. Therefore we reject the hypothesis that the timing of the EMG response to an unexpected load is related to a velocity error threshold. Instead, we suggest that the timing of the EMG response is primarily determined by descending regulation of segmental reflex gain.
Sleep Deprivation Impairs Long-Term Potentiation in Rat Hippocampal Slices
Authors: Campbell I. G. , Guinan M. J. , Horowitz J. M.
Published: December 2017

To determine if 12-h sleep deprivation disrupts neural plasticity, we compared long-term potentiation (LTP) in five sleep-deprived and five control rats. Thirty minutes after tetanus population spike amplitude increased 101 ± 15% in 16 slices from sleep deprived rats and 139 ± 14% in 14 slices from control rats. This significant ( P < 0.05) reduction of LTP, the first demonstration that the sleep deprivation protocol impairs plasticity in adult rats, may be due to several factors. Reduced LTP may indicate that sleep provides a period of recuperation for cellular processes underlying neural plasticity. Alternatively, the stress of sleep deprivation, as indicated by elevated blood corticosterone levels, or other non-sleep-specific factors of deprivation may contribute to the LTP reduction.
Presynaptic Current Changes at the Mossy Fiber–Granule Cell Synapse of Cerebellum During LTP
Authors: Maffei Arianna , Prestori Francesca , Rossi Paola , Taglietti Vanni , D'Angelo Egidio
Published: December 2017

The involvement of presynaptic mechanisms in the expression of long-term potentiation (LTP), an enhancement of synaptic transmission suggested to take part in learning and memory in the mammalian brain, has not been fully clarified. Although evidence for enhanced vesicle cycling has been reported, it is unknown whether presynaptic terminal excitability could change as has been observed in invertebrate synapses. To address this question, we performed extracellular focal recordings in cerebellar slices. The extracellular current consisted of a pre- (P1/N1) and postsynaptic (N2/SN) component. In ∼50% of cases, N1 could be subdivided into N1a and N1b. Whereas N1a was part of the fiber volley (P1/N1a), N1b corresponded to a Ca2+-dependent component accounting for 40–50% of N1, which could be isolated from individual mossy fiber terminals visualized with fast tetramethylindocarbocyanine perchlorate (DiI). The postsynaptic response, given its timing and sensitivity to glutamate receptor antagonists [N2 was blocked by 10 μM [1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium (NBQX) and SN by 100 μM APV +50 μM 7-Cl-kyn], corresponded to granule cell excitation. N2 and SN could be reduced by 1) Ca2+ channel blockers, 2) decreasing the Ca2+ to Mg2+ ratio, 3) paired-pulse stimulation, and 4) adenosine receptor activation. However, only the first two manipulations, which modify Ca2+ influx, were associated with N1(or N1b) reduction. LTP was induced by θ-burst mossy fiber stimulation (8 trains of 10 impulses at 100 Hz separated by 150-ms pauses). Interestingly, during LTP, both N1 (or N1b) and N2/SN persistently increased, whereas P1 (or P1/N1a) did not change. Average changes were N1 = 38.1 ± 31.9, N2 = 49.6 ± 48.8, and SN = 59.1 ± 35.5%. The presynaptic changes were not observed when LTP was prevented by synaptic inhibition, by N-methyl-d-aspartate and metabotropic glutamate receptor blockage, or by protein kinase C blockage. Moreover, the presynaptic changes were sensitive to Ca2+channel blockers (1 mM Ni2+ and 5 μM ω-CTx-MVIIC) and occluded by K+ channel blockers (1 mM tetraethylammmonium). Thus regulation of presynaptic terminal excitability may take part in LTP expression at a central mammalian synapse.
Contribution of Pedunculopontine Tegmental Nucleus Neurons to Performance of Visually Guided Saccade Tasks in Monkeys
Authors: Kobayashi Yasushi , Inoue Yuka , Yamamoto Masaru , Isa Tadashi , Aizawa Hiroshi
Published: December 2017

The cholinergic pedunculopontine tegmental nucleus (PPTN) is one of the major ascending arousal systems in the brain stem and is linked to motor, limbic, and sensory systems. Based on previous studies, we hypothesized that PPTN would be related to the integrative control of movement, reinforcement, and performance of tasks in behaving animals. To investigate how PPTN contributes to the behavioral control, we analyzed the activity of PPTN neurons during visually guided saccade tasks in three monkeys in relation to saccade preparation, execution, reward, and performance of the task. During visually guided saccades, we observed saccade-related burst (26/70) and pause neurons (19/70), indicating that a subset of PPTN neurons are related to both saccade execution and fixation. Burst neurons exhibited greater selectivity for saccade direction than pause neurons. The preferred directions for both burst and pause neurons were not aligned with either horizontal or vertical axes, nor biased strongly in either the ipsilateral or the contralateral direction. The spatial representation of the saccade-related activity of PPTN neurons is different from other brain stem saccade systems and may therefore relay saccade-related activity from different areas. Increasing discharges were observed around reward onset in a subset of neurons (22/70). These neurons responded to the freely delivered rewards within ∼140 ms. However, during the saccade task, the latencies of the responses around reward onset ranged between 100 ms before and 200 ms after the reward onset. These results suggest that the activity observed after appropriate saccade during the task may include response associated with reward. We found that the reaction time to the appearance of the fixation point (FP) was longer when the animal tended to fail in the ensuring task. This reaction time to FP appearance (RTFP) served as an index of motivation. The RTFP could be predicted by the neuronal activity of a subset of PPTN neurons (13/70) that varied their activity levels with task performance, discharging at a higher rate in successful versus error trials. A combination of responses related to saccade execution, reward delivery, and task performance was observed in PPTN neurons. We conclude from the multimodality of responses in PPTN neurons that PPTN may serve as an integrative interface between the various signals required for performing purposive behaviors.
Spike Frequency Adaptation and Neocortical Rhythms
Authors: Fuhrmann Galit , Markram Henry , Tsodyks Misha
Published: December 2017

Spike-frequency adaptation in neocortical pyramidal neurons was examined using the whole cell patch-clamp technique and a phenomenological model of neuronal activity. Noisy current was injected to reproduce the irregular firing typically observed under in vivo conditions. The response was quantified by computing the poststimulus histogram (PSTH). To simulate the spiking activity of a pyramidal neuron, we considered an integrate-and-fire model to which an adaptation current was added. A simplified model for the mean firing rate of an adapting neuron under noisy conditions is also presented. The mean firing rate model provides a good fit to both experimental and simulation PSTHs and may therefore be used to study the response characteristics of adapting neurons to various input currents. The models enable identification of the relevant parameters of adaptation that determine the shape of the PSTH and allow the computation of the response to any change in injected current. The results suggest that spike frequency adaptation determines a preferred frequency of stimulation for which the phase delay of a neuron's activity relative to an oscillatory input is zero. Simulations show that the preferred frequency of single neurons dictates the frequency of emergent population rhythms in large networks of adapting neurons. Adaptation could therefore be one of the crucial factors in setting the frequency of population rhythms in the neocortex.
L-Type Calcium Channel-Mediated Plateau Potentials in Barrelette Cells During Structural Plasticity
Authors: Lo Fu-Sun , Erzurumlu Reha S.
Published: December 2017

Development and maintenance of whisker-specific patterns along the rodent trigeminal pathway depends on an intact sensory periphery during the sensitive/critical period in development. Barrelette cells of the brain stem trigeminal nuclei are the first set of neurons to develop whisker-specific patterns. Those in the principal sensory nucleus (PrV) relay these patterns to the ventrobasal thalamus, and consequently, to the somatosensory cortex. Thus PrV barrelette cells are among the first group of central neurons susceptible to the effects of peripheral damage. Previously we showed that membrane properties of barrelette cells are distinct as early as postnatal day 1 (PND 1) and remain unchanged following peripheral denervation in newborn rat pups ( Lo and Erzurumlu 2001 ). In the present study, we investigated the changes in synaptic transmission. In barrelette cells of normal PND 1 rats, weak stimulation of the trigeminal tract (TrV) that was subthreshold for inducing Na+spikes evoked an excitatory postsynaptic potential–inhibitory postsynaptic potential (EPSP-IPSP) sequence that was similar to the responses seen in older rats ( Lo et al. 1999 ). Infraorbital nerve transection at birth did not alter excitatory and inhibitory synaptic connections of the barrelette cells. These observations suggested that local neuronal circuits are already established in PrV at birth and remain intact after deafferentation. Strong stimulation of the TrV induced a sustained depolarization (plateau potential) in denervated but not in normal barrelette neurons. The plateau potential was distinct from the EPSP-IPSP sequence by 1) a sustained (>80 ms) depolarization above −40 mV; 2) a slow decline slope (<0.1 mV/ms); 3) partially or totally inactivated Na+spikes on the plateau; and 4) a termination by a steep decay (>1 mV/ms) to a hyperpolarizing membrane level. The plateau potential was mediated by L-type Ca2+channels and triggered by a N-methyl-d-aspartate (NMDA) receptor-mediated EPSP. γ-aminobutyric acid-A (GABAA) receptor-mediated IPSP dynamically regulated the latency and duration of the plateau potential. These results indicate that after neonatal peripheral damage, central trigeminal inputs cause a large and long-lasting Ca2+influx through L-type Ca2+channels in barrelette neurons. Increased Ca2+entry may play a key role in injury-induced structural remodeling, and/or transsynaptic cell death.
Mitral Cell Temporal Response Patterns Evoked by Odor Mixtures in the Rat Olfactory Bulb
Authors: Giraudet Pascale , Berthommier Frédéric , Chaput Michel
Published: December 2017

Mammals generally have the ability to extract odor information contained in complex mixtures of molecular components. However, odor mixture processing has been studied electrophysiologically only in insects, crustaceans, and fish. As a first step toward a better understanding of this processing in high vertebrates, we studied the representation of odor mixtures in the rat olfactory bulb, i.e., the second-order level of the olfactory pathways. We compared the single-unit responses of mitral cells, the main cells of the olfactory bulb, to pure odors and to their binary mixtures. Eighty-six mitral cells were recorded in anesthetized freely breathing rats stimulated with five odorants and their 10 binary mixtures. The spontaneous activity and the odor-evoked responses were characterized by their temporal distribution of activity along the respiratory cycle, i.e., by cycle-triggered histograms. Ninety percent of the mixtures were found to evoke a response when at least one of their two components evoked a response. Mixture-evoked patterns were analyzed to describe the modalities of the combination of patterns evoked by the two components. In most of the cases, the mixture pattern was closely similar to one of the component patterns. This dominance of a component over the other one was related to the responsiveness of the cell to the individual components of the mixture, to the molecular nature of the stimulus, and to the coarse shape of individual response patterns. This suggests that the components of binary mixtures may be encoded simultaneously by different odor-specific temporal distributions of activity.
Electrophysiological Analysis of Synaptic Transmission in Central Neurons ofDrosophilaLarvae
Authors: Rohrbough Jeffrey , Broadie Kendal
Published: December 2017

We report functional neuronal and synaptic transmission properties in DrosophilaCNS neurons. Whole cell current- and voltage-clamp recordings were made from dorsally positioned neurons in the larval ventral nerve cord. Comparison of neuronal Green Fluorescent Protein markers and intracellular dye labeling revealed that recorded cells consisted primarily of identified motor neurons. Neurons had resting potentials of −50 to −60 mV and fired repetitive action potentials (APs) in response to depolarizing current injection. Acetylcholine application elicited large excitatory responses and AP bursts that were reversibly blocked by the nicotinic receptor antagonist d-tubocurarine (dtC). GABA and glutamate application elicited similar inhibitory responses that reversed near normal resting potential and were reversibly blocked by the chloride channel blocker picrotoxin. Multiple types of endogenous synaptically driven activity were present in most neurons, including fast spontaneous synaptic events resembling unitary excitatory postsynaptic currents (EPSCs) and sustained excitatory currents and potentials. Sustained forms of endogenous activity ranged in amplitude from smaller subthreshold “intermediate” sustained events to large “rhythmic” events that supported bursts of APs. Electrical stimulation of peripheral nerves or focal stimulation of the neuropil evoked sustained responses and fast EPSCs similar to endogenous events. Endogenous activity and evoked responses required external Ca2+and were reversibly blocked by dtC application, indicating that cholinergic synaptic transmission directly underlies observed activity. Synaptic current amplitude and frequency were reduced in shibire conditional dynamin mutants and increased in dunce cAMP phosphodiesterase mutants. These results complement and advance those of recent functional studies in Drosophila embryonic neurons and demonstrate the feasibility of in-depth synaptic transmission and plasticity studies in the Drosophila CNS.
Associative Interactions Within the Superficial Layers of the Entorhinal Cortex of the Guinea Pig
Authors: Biella Gerardo , Uva Laura , Hofmann Ulrich G. , De Curtis Marco
Published: December 2017

Associative fiber systems in the entorhinal cortex (EC) have been extensively studied in different mammals with tracing techniques. The largest contingent of intra-EC cortico-cortical fibers runs in the superficial layers and is distributed predominantly within longitudinal cortical bands. We studied the patterns of intrinsic EC connectivity in the in vitro isolated guinea pig brain preparation by performing current-source density analysis of field potential laminar profiles recorded with multi-channel silicon probes. The response pattern evoked by stimulation of the lateral olfactory tract was utilized to identify the lateral (l-EC) and medial (m-EC) entorhinal cortex. Stimulation of the deep layers did not evoke consistent responses. Local stimulation of the superficial layers in different portions of the EC induced an early, possibly direct response restricted to layer II–III in the close proximity to the stimulating electrode, followed by a late potential in the superficial layer I, that propagated at distance with a progressively increasing latency. The monosynaptic nature of the delayed response was verified by applying a pairing test. The results demonstrated that stimulation in the rostral-medial part of the EC generated activity restricted to the rostral pole of the l-EC, stimulation of the m-EC induced an associative activation that propagated rostrocaudally within the m-EC, stimulation of the caudal pole of the m-EC induced an additional response directed laterally, and stimulation of the lateral band of the EC determined a prominent longitudinal propagation of neuronal activity, but also induced associative potentials that propagated medially. The results are in partial agreement with the general picture derived from the anatomical studies performed in different species. Even though the largest associative interactions between superficial layers are restricted within either the m-EC or the l-EC, both rostral and caudal stimuli in the EC region close to the rhinal sulcus induced activity that propagated across the border between l- and m-EC.
GluR2-Dependent Properties of AMPA Receptors Determine the Selective Vulnerability of Motor Neurons to Excitotoxicity
Authors: Van Damme P. , Van den Bosch L. , Van Houtte E. , Callewaert G. , Robberecht W.
Published: December 2017

AMPA receptor-mediated excitotoxicity has been implicated in the selective motor neuron loss in amyotrophic lateral sclerosis. In some culture models, motor neurons have been shown to be selectively vulnerable to AMPA receptor agonists due to Ca2+influx through Ca2+-permeable AMPA receptors. Because the absence of GluR2 in AMPA receptors renders them highly permeable to Ca2+ ions, it has been hypothesized that the selective vulnerability of motor neurons is due to their relative deficiency in GluR2. However, conflicting evidence exists about the in vitro and in vivo expression of GluR2 in motor neurons, both at the mRNA and at the protein level. In this study, we quantified electrophysiological properties of AMPA receptors, known to be dependent on the relative abundance of GluR2: sensitivity to external polyamines, rectification index, and relative Ca2+ permeability. Cultured rat spinal cord motor neurons were compared with dorsal horn neurons (which are resistant to excitotoxicity) and with motor neurons that survived an excitotoxic insult. Motor neurons had a higher sensitivity to external polyamines, a lower rectification index, and a higher relative Ca2+ permeability ratio than dorsal horn neurons. These findings confirm that motor neurons are relatively deficient in GluR2. The AMPA receptor properties correlated well with each other and with the selective vulnerability of motor neurons because motor neurons surviving an excitotoxic event had similar characteristics as dorsal horn neurons. These data indicate that the relative abundance of GluR2 in functional AMPA receptors may be a major determinant of the selective vulnerability of motor neurons to excitotoxicity in vitro.
Optical Imaging of Long-Lasting Depolarization on Burst Stimulation in Area CA1 of Rat Hippocampal Slices
Authors: Tominaga Takashi , Tominaga Yoko , Ichikawa Michinori
Published: December 2017

Postsynaptic depolarization of dendrites paired with spike generation at the soma is considered to be a central mechanism of long-term potentiation (LTP) induction and a prime example of a Hebbian synapse. This pairing, however, has never been actually demonstrated on tetanic stimulation. Optical imaging of neural activity with a voltage-sensitive dye (VSD) is one potentially suitable method for examining this pairing. It is possible with optical recording to examine simultaneously the excitation of postsynaptic neurons at multiple sites. Thus the pairing of spike generation at the soma and dendritic depolarization can be examined with population level optical recording in highly laminar structures such as the hippocampal slice preparation. For example, one can correlate the optical signals obtained from cell layers with the activity of the soma, and, similarly, optical signals from stratum radiatum can be correlated with the activity of the apical dendrite, even though one cannot calibrate the optical signals in terms of actual membrane potential. Using the VSD aminonaphthylethenylpyridinium in rat hippocampal slices, we aimed to examine the pairing. Standard tetanic stimulation (100 Hz, 1 s) that elicited LTP in the field excitatory postsynaptic potential (fEPSP) resulted in a long-lasting depolarizing optical signal (about 2 s) that spread progressively along the known input pathway of CA1. The time course of this long-lasting depolarization was similar to that recorded intracellularly and to that reflected in the fEPSP. The long-lasting depolarization was insensitive tod,l-2-amino-5-phosphonovaleric acid (d,l-APV, 50 μM), but d,l-APV inhibited the induction of LTP; this allowed us to increase the signal-to-noise ratio of the optical signal by averaging several trials. Using this improved optical signal, we confirmed that postsynaptic cells practically “missed” spikes during tetanic stimulation in most parts of CA1, which had been suggested in the intracellular recordings. Intracellular recordings revealed a 23% reduction in input resistance, which might explain the failed spike generation at the soma via shunting. A steep spatial convergence of the depolarization along the transverse axis of area CA1 was observed. In contrast to the response resulting from a standard 100-Hz tetanus, broader activation, and paired depolarization with somatic spikes was observed on θ-burst stimulation. Overall we concluded that postsynaptic spike generation, at least in synchronous form, has less effect on LTP induction with standard tetanic stimulation, while θ-burst tetanic stimulation can elicit pairing of dendritic depolarization and somatic discharge.
Synchronization of Ca2+ Oscillations Among Primate LHRH Neurons and Nonneuronal Cells In Vitro
Authors: Richter T. A. , Keen K. L. , Terasawa E.
Published: December 2017

Periodic release of luteinizing hormone-releasing hormone (LHRH) from the hypothalamus is essential for normal reproductive function. Pulsatile LHRH release appears to result from the synchronous activity of LHRH neurons. However, how the activity of these neurons is synchronized to release LHRH peptide in a pulsatile manner is unclear. Because there is little evidence of physical coupling among LHRH neurons in the hypothalamus, we hypothesized that the activity of LHRH neurons might be coordinated by indirect intercellular communication via intermediary (nonneural) cells rather than direct interneural coupling. In this study, we used an in vitro preparation of LHRH neurons derived from the olfactory placode of monkey embryos to assess whether nonneuronal cells, play a role in coordinating LHRH neuronal activity. We found that cultured LHRH neurons and nonneuronal cells both exhibit spontaneous oscillations in the concentration of intracellular Ca2+([Ca2+]i) at similar frequencies. Moreover, [Ca2+]i oscillations in both types of cell were periodically synchronized. Synchronized [Ca2+]i oscillations spread as intercellular Ca2+ waves across fields of cells that included LHRH neurons and nonneuronal cells, although waves spread at a higher velocity among LHRH neurons. These results suggest that LHRH neurons and nonneuronal cells are functionally integrated and that nonneuronal cells could be involved in synchronizing the activity of the LHRH neurosecretory network.
Extracellular Stimulation of Central Neurons: Influence of Stimulus Waveform and Frequency on Neuronal Output
Authors: McIntyre Cameron C. , Grill Warren M.
Published: December 2017

The objective of this project was to examine the influence of stimulus waveform and frequency on extracellular stimulation of neurons with their cell bodies near the electrode (local cells) and fibers of passage in the CNS. Detailed computer-based models of CNS cells and axons were developed that accurately reproduced the dynamic firing properties of mammalian motoneurons including afterpotential shape, spike-frequency adaptation, and firing frequency as a function of stimulus amplitude. The neuron models were coupled to a three-dimensional finite element model of the spinal cord that solved for the potentials generated in the tissue medium by an extracellular electrode. Extracellular stimulation of the CNS with symmetrical charge balanced biphasic stimuli resulted in activation of fibers of passage, axon terminals, and local cells around the electrode at similar thresholds. While high stimulus frequencies enhanced activation of fibers of passage, a much more robust technique to achieve selective activation of targeted neuronal populations was via alterations in the stimulus waveform. Asymmetrical charge-balanced biphasic stimuli, consisting of a long-duration low-amplitude cathodic prepulse phase followed by a short-duration high-amplitude anodic stimulus phase, enabled selective activation of local cells. Conversely, an anodic prepulse phase followed by a cathodic stimulus phase enabled selective activation of fibers of passage. The threshold for activation of axon terminals in the vicinity of the electrode was lower than the threshold for direct activation of local cells, independent of the stimulus waveform. As a result, stimulation induced trans-synaptic influences (indirect depolarization/hyperpolarization) on local cells altered their neural output, and this indirect effect was dependent on stimulus frequency. If the indirect activation of local cells was inhibitory, there was little effect on the stimulation induced neural output of the local cells. However, if the indirect activation of the local cells was excitatory, attempts to activate selectively fibers of passage over local cells was limited. These outcomes provide a biophysical basis for understanding frequency-dependent outputs during CNS stimulation and provide useful tools for selective stimulation of the CNS.