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The spiking activity of auditory nerve fibers (ANFs) transmits information about the acoustic environment from the cochlea to the central auditory system. Increasing age leads to degeneration of cochlear tissues, including the sensory hair cells and stria vascularis. Here, we aim to identify the functional effects of such age-related cochlear pathologies of ANFs. Rate-level functions (RLFs) were recorded from single-unit ANFs of young adult ( n = 52, 3-12 months) and quiet-aged ( n = 24, >36 months) Mongolian gerbils of either sex. RLFs were used to determine sensitivity and spontaneous rates (SRs) and were classified into flat-saturating, sloping-saturating, and straight categories, as previously established. A physiologically based cochlear model, adapted for the gerbil, was used to simulate the effects of cochlear degeneration on ANF physiology. In ANFs tuned to low frequencies (<3.5 kHz), SR was lower in those of aged gerbils, while an age-related loss of low-SR fibers was evident in ANFs tuned to high frequencies. These changes in SR distribution did not affect the typical SR versus sensitivity correlation. The distribution of RLF types among low-SR fibers, however, shifted toward that of high-SR fibers, specifically showing more fast-saturating and fewer sloping-saturating RLFs. A modeled striatal degeneration, which affects the combined inner hair cell and synaptic output, reduced SR but left RLF type unchanged. An additional reduced basilar membrane gain, which decreased sensitivity, explained the changed RLF types. Overall, the data indicated age-related changes in the characteristics of single ANFs that blurred the established relationships between SR and RLF types. NEW & NOTEWORTHY Auditory nerve fibers, which connect the cochlea to the central auditory system, change their encoding of sound level in aged gerbils. In addition to a general shift to higher levels, indicative of decreased sensitivity, level coding was also differentially affected in fibers with low- and high-spontaneous rates. Loss of low-spontaneous rate fibers, combined with a general decrease of spontaneous rate, further blurs the categorization of auditory nerve fiber types in the aged gerbil.

The excitability of large nerve fibers is reduced when their membrane potential is slowly depolarizing, i.e., the fibers display accommodation. The aim of this study was to assess accommodation in small (mainly Aδ) and large (Aβ) cutaneous sensory nerve fibers using the perception threshold tracking (PTT) technique. Linearly increasing ramp currents (1 ms-200 ms) were used to assess the excitability of the nerve fibers by cutaneous electrical stimulation. To investigate the PPT technique's ability to preferentially activate different fiber types, topical application of lidocaine/prilocaine (EMLA) or a placebo cream was applied. By means of computational modeling, the underlying mechanisms governing the perception threshold in the two fiber types was studied. The axon models included the voltage-gated ion channels: transient TTX-sensitive sodium current, transient TTX-resistant sodium current (Na TTXr ), persistent sodium current, delayed rectifier potassium channel (K Dr ), slow potassium channel, and hyperpolarization-activated current. Large fibers displayed accommodation, whereas small fibers did not display accommodation ( P < 0.05). For the pin electrode, a significant interaction was observed between cream (EMLA or placebo) and pulse duration ( P < 0.05); for the patch electrode, there was no significant interaction between cream and duration, which supports the pin electrode's preferential activation of small fibers. The results from the computational model suggested that differences in accommodation between the two fiber types may originate from selective expression of voltage-gated ion channels, particularly the transient Na TTXr and/or K Dr . The PTT technique could assess the excitability changes during accommodation in different nerve fibers. Therefore, the PTT technique may be a useful tool for studying excitability in nerve fibers in both healthy and pathological conditions. NEW & NOTEWORTHY When large nerve fibers are stimulated by long, slowly increasing electrical pulses, interactive mechanisms counteract the stimulation, which is called accommodation. The perception threshold tracking technique was able to assess accommodation in both small and large fibers. The novelty of this study is that large fibers displayed accommodation, whereas small fibers did not. Additionally, the difference in accommodation between the fiber could be linked to expression of voltage-gated ion channels by means of computational modeling.

Tactile feature extraction is essential to guide the dexterous manipulation of objects. The longstanding theory is that geometric features at each location of contact between hand and object are extracted from the spatial layout of the response of populations of tactile nerve fibers. However, recent evidence suggests that some features (e.g., edge orientation) are extracted very rapidly (<200 ms), casting doubt that this information relies on a spatial code, which ostensibly requires integrating responses over time. An alternative hypothesis is that orientation is conveyed in precise temporal spiking patterns. Here we simulate, using a recently developed and validated model, the responses of the two relevant subpopulations of tactile fibers from the entire human fingertip (~800 afferents) to edges indented into the skin. We show that edge orientation can be quickly (<50 ms) and accurately (<3°) decoded from the spatial pattern of activation across the afferent population, starting with the very first spike. Next, we implement a biomimetic decoder of edge orientation, consisting of a bank of oriented Gabor filters, designed to mimic the documented responses of cortical neurons. We find that the biomimetic approach leads to orientation decoding performance that approaches the limit set by optimal decoders and is actually more robust to changes in other stimulus features. Finally, we show that orientation signals, measured from single units in the somatosensory cortex of nonhuman primates (2 macaque monkeys, 1 female), follow a time course consistent with that of their counterparts in the nerve. We conclude that a spatial code is fast and accurate enough to support object manipulation. NEW & NOTEWORTHY The dexterous manipulation of objects relies on the rapid and accurate extraction of the objects' geometric features by the sense of touch. Here we simulate the responses of all the nerve fibers that innervate the fingertip when an edge is indented into the skin and characterize the time course over which signals about its orientation evolve in this neural population. We show that orientation can be rapidly and accurately decoded from the spatial pattern of afferent activation using spatial filters that mimic the response properties of neurons in cortical somatosensory neurons along a time course consistent with that observed in cortex. We conclude that the classical model of tactile feature extraction is rapid and accurate enough to support object manipulation.

A method is described that, for the first time, allows instantaneous estimation of the Ia fiber input to human soleus motoneurons following electrical stimulation of the tibial nerve. The basis of the method is to determine the thresholds of the most and least excitable 1a fibers to electrical stimulation, and to treat the intervening thresholds as having a normal distribution about the mean; the validity of this approach is discussed. It was found that, for the same Ia fiber input, the percentage of soleus motoneurons contributing to the H (Hoffmann)-reflex differed considerably among subjects; when the results were pooled, however, there was an approximately linear relationship between Ia input and motoneuron output. Weak extension of the great toe diminished the soleus motoneuron reflex discharge in all but 2 of 16 subjects; the results for weak ankle plantarflexion were less consistent, but overall, there was a reduction in soleus motoneuron output also. The methodology should provide new insights into disorders of movement and tone, especially as it permits estimates of motoneuron depolarization to be made. NEW & NOTEWORTHY Assuming a normal distribution of Ia fiber thresholds to electrical stimulation and using the H-reflex, we determined for the first time an Ia input-α-motoneuron output relationship for the human soleus muscle. The relationship varies greatly among subjects but, overall, is approximately linear. Minimal contraction of a toe muscle alters the relationship dramatically, probably due to presynaptic inhibition of Ia fibers. Drawing on the literature, we can calculate changes in α-motoneuron membrane potential.

Roughness is the most salient perceptual dimension of surface texture but has no well-defined physical basis. We seek to determine the neural determinants of tactile roughness in the somatosensory nerves. Specifically, we record the patterns of activation evoked in tactile nerve fibers of anesthetized Rhesus macaques to a large and diverse set of natural textures and assess what aspect of these patterns of activation can account for psychophysical judgments of roughness, obtained from human observers. We show that perceived roughness is determined by the variation in the population response, weighted by fiber type. That is, a surface will feel rough to the extent that the activity varies across nerve fibers and varies across time within nerve fibers. We show that this variation-based neural code can account not only for magnitude estimates of roughness but also for roughness discrimination performance. NEW & NOTEWORTHY Our sense of touch endows us with an exquisite sensitivity to the microstructure of surfaces, the most salient aspect of which is roughness. We analyze the responses evoked in tactile fibers of monkeys by natural textures and compare them to judgments of roughness obtained for the same textures from human observers. We then describe how texture signals from three populations of nerve fibers are integrated to culminate in a percept of roughness., (Copyright © 2017 the American Physiological Society.)

Neurotrophic factors play an important role in the regulation of functional properties of sensory neurons under normal and pathological conditions. The GDNF family member neurturin is one such factor that has been linked to modulating responsiveness to peripheral stimuli. Neurturin binds to the GFRα2 receptor, a receptor found primarily in isolectin B 4 -expressing polymodal cutaneous nociceptors. Previous work has shown that knockout of GFRα2 alters heat, but not mechanical, responses in dissociated sensory neurons and reduces pain-related behaviors during the second phase of the formalin test. Research has also shown that overexpression of neurturin in basal keratinocytes increases behavioral responsiveness to mechanical stimulation and innocuous cooling of the skin without affecting noxious heat responses. Here we directly examined the impact of neurturin overexpression on cutaneous afferent function. We compared physiological responses of individual sensory neurons to mechanical and thermal stimulation of the skin, using an ex vivo skin-nerve-dorsal root ganglion-spinal cord preparation produced from neurturin-overexpressing (NRTN/OE) mice and wild-type littermate controls. We found that neurturin overexpression increases responsiveness to innocuous mechanical stimuli in A-fiber nociceptors, alters thermal responses in the polymodal subpopulation of C-fiber sensory neurons, and changes the relative numbers of mechanically sensitive but thermally insensitive C-fiber afferents. These results demonstrate the potential roles of different functional groups of sensory neurons in the behavioral changes observed in mice overexpressing cutaneous neurturin and highlight the importance of neurturin in regulating cutaneous afferent response properties. NEW & NOTEWORTHY GDNF family neurotrophic factors regulate the development and function of primary sensory neurons. Of these, neurturin has been shown to modulate mechanical and cooling sensitivity behaviorally. Here we show that overexpression of neurturin in basal keratinocytes regulates mechanical responsiveness in A-fiber primary sensory neurons while increasing the overall numbers of cold-sensing units. Results demonstrate a crucial role for cutaneous neurturin in modulating responsiveness to peripheral stimuli at the level of the primary afferent., (Copyright © 2017 the American Physiological Society.)

A region of cerebellar lobules V and VI makes strong loop connections with the primary motor (M1) and premotor (PM) cortical areas and is assumed to play essential roles in limb motor control. To examine its functional role, we compared the activities of its input, intermediate, and output elements, i.e., mossy fibers (MFs), Golgi cells (GoCs), and Purkinje cells (PCs), in three monkeys performing wrist movements in two different forearm postures. The results revealed distinct steps of information processing. First, MF activities displayed temporal and directional properties that were remarkably similar to those of M1/PM neurons, suggesting that MFs relay near copies of outputs from these motor areas. Second, all GoCs had a stereotyped pattern of activity independent of movement direction or forearm posture. Instead, GoC activity resembled an average of all MF activities. Therefore, inhibitory GoCs appear to provide a filtering function that passes only prominently modulated MF inputs to granule cells. Third, PCs displayed highly complex spatiotemporal patterns of activity, with coordinate frames distinct from those of MF inputs and directional tuning that changed abruptly before movement onset. The complexity of PC activities may reflect rapidly changing properties of the peripheral motor apparatus during movement. Overall, the cerebellar cortex appears to transform a representation of outputs from M1/PM into different movement representations in a posture-dependent manner and could work as part of a forward model that predicts the state of the peripheral motor apparatus., (Copyright © 2016 the American Physiological Society.)

Axon conduction fidelity is important for signal transmission and has been studied in various axons, including the Schaffer collateral axons of the hippocampus. Previously, we reported that high-frequency stimulation (HFS) depresses Schaffer collateral excitability when assessed by whole-cell recordings from CA3 pyramidal cells but induces biphasic excitability changes (increase followed by decrease) in extracellular recordings of CA1 fiber volleys. Here, we examined responses from proximal (whole-cell or field-potential recordings from CA3 pyramidal cell somata) and distal (field-potential recordings from CA1 stratum radiatum) portions of the Schaffer collaterals during HFS and burst stimulation in hippocampal slices. Whole-cell and dual-field-potential recordings using 10-100-Hz HFS revealed frequency-dependent changes like those previously described, with higher frequencies producing more drastic changes. Dual-field-potential recordings revealed substantial differences in the response to HFS between proximal and distal regions of the Schaffer collaterals, with proximal axons depressing more strongly and only distal axons showing an initial excitability increase. Because CA3 pyramidal neurons normally fire in short bursts rather than long high-frequency trains, we repeated the dual recordings using 100-1,000-ms interval burst stimulation. Burst stimulation produced changes similar to those during HFS, with shorter intervals causing more drastic changes and substantial differences observed between proximal and distal axons. We suggest that functional differences between proximal and distal Schaffer collaterals may allow selective filtering of nonphysiological activity while maximizing successful conduction of physiological activity throughout an extensive axonal arbor., (Copyright © 2015 the American Physiological Society.)

Although it has been suggested that the cerebellum functions to predict the sensory consequences of motor commands, how such predictions are implemented in cerebellar circuitry remains largely unknown. A detailed and relatively complete account of predictive mechanisms has emerged from studies of cerebellum-like sensory structures in fish, suggesting that comparisons of the cerebellum and cerebellum-like structures may be useful. Here we characterize electrophysiological response properties of Purkinje cells in a region of the cerebellum proper of weakly electric mormyrid fish, the posterior caudal lobe (LCp), which receives the same mossy fiber inputs and projects to the same target structures as the electrosensory lobe (ELL), a well-studied cerebellum-like structure. We describe patterns of simple spike and climbing fiber activation in LCp Purkinje cells in response to motor corollary discharge, electrosensory, and proprioceptive inputs and provide evidence for two functionally distinct Purkinje cell subtypes within LCp. Protocols that induce rapid associative plasticity in ELL fail to induce plasticity in LCp, suggesting differences in the adaptive functions of the two structures. Similarities and differences between LCp and ELL are discussed in light of these results., (Copyright © 2014 the American Physiological Society.)

Cerebellar Purkinje cells are excited by two afferent pathways: climbing and mossy fibers. Climbing fibers evoke large "complex spikes" (CSs) that discharge at low frequencies. Mossy fibers synapse on granule cells whose parallel fibers excite Purkinje cells and may contribute to the genesis of "simple spikes" (SSs). Both afferent systems convey vestibular information to folia 9c-10. After making a unilateral labyrinthectomy (UL) in mice, we tested how the discharge of CSs and SSs was changed by the loss of primary vestibular afferent mossy fibers during sinusoidal roll tilt. We recorded from cells identified by juxtacellular neurobiotin labeling. The UL preferentially reduced vestibular modulation of CSs and SSs in folia 8-10 contralateral to the UL. The effects of a UL on Purkinje cell discharge were similar in folia 9c-10, to which vestibular primary afferents project, and in folia 8-9a, to which they do not project, suggesting that vestibular primary afferent mossy fibers were not responsible for the UL-induced alteration of SS discharge. UL also induced reduced vestibular modulation of stellate cell discharge contralateral to the UL. We attribute the decreased modulation to reduced vestibular modulation of climbing fibers. In summary, climbing fibers modulate CSs directly and SSs indirectly through activation of stellate cells. Whereas vestibular primary afferent mossy fibers cannot account for the modulated discharge of SSs or stellate cells, the nonspecific excitation of Purkinje cells by parallel fibers may set an operating point about which the discharges of SSs are sculpted by climbing fibers.

The trigeminal ganglia (TG) innervate a heterogeneous set of highly sensitive and exposed tissues. Weak, innocuous stimuli can evoke pain as a normal response in some areas such as the cornea. This observation implies, however, the capability of low-threshold mechanoreceptors, inducing pain in the normal condition. To clarify this matter, the present study correlates the electrical signature (both fiber conduction velocity and somatic electrical properties) with receptor field, mechanical threshold, and temperature responsiveness of sensory afferents innervating tissues with dissimilar sensitivity (skin vs. cornea) in the trigeminal domain. Intracellular recordings were obtained in vivo from 148 neurons of the left TG of 62 mice. In 111 of these neurons, the peripheral receptor field was successfully localized: 96 of them innervated the hairy skin, while the remaining 15 innervated the cornea. The electrical signature was defined and peripheral responses correlated with tissue target. No high threshold neurons were found in the cornea. Moreover, the electrical signature of corneal afferents resembles nociceptive neurons in the skin. TG skin afferents showed similar membrane electrical signature and sensory modality as skin afferents from dorsal root ganglion, although TG afferents exhibited a shorter duration of afterhyperpolarization then those previously described in dorsal root ganglion. These data suggest than new or different ways to classify and study TG sensory neurons may be required.

Owls use interaural time differences (ITDs) to locate a sound source. They compute ITD in a specialized neural circuit that consists of axonal delay lines from the cochlear nucleus magnocellularis (NM) and coincidence detectors in the nucleus laminaris (NL). Recent physiological recordings have shown that tonal stimuli induce oscillatory membrane potentials in NL neurons (Funabiki K, Ashida G, Konishi M. J Neurosci 31: 15245-15256, 2011). The amplitude of these oscillations varies with ITD and is strongly correlated to the firing rate. The oscillation, termed the sound analog potential, has the same frequency as the stimulus tone and is presumed to originate from phase-locked synaptic inputs from NM fibers. To investigate how these oscillatory membrane potentials are generated, we applied recently developed signal-to-noise ratio (SNR) analysis techniques (Kuokkanen PT, Wagner H, Ashida G, Carr CE, Kempter R. J Neurophysiol 104: 2274-2290, 2010) to the intracellular waveforms obtained in vivo. Our theoretical prediction of the band-limited SNRs agreed with experimental data for mid- to high-frequency (>2 kHz) NL neurons. For low-frequency (≤2 kHz) NL neurons, however, measured SNRs were lower than theoretical predictions. These results suggest that the number of independent NM fibers converging onto each NL neuron and/or the population-averaged degree of phase-locking of the NM fibers could be significantly smaller in the low-frequency NL region than estimated for higher best-frequency NL.

An essential component of mechanical hyperalgesia resulting from tissue injury is an enhanced excitability of nociceptive neurons, termed mechanical sensitization. Local application of opioids to inflamed rat paws attenuates mechanical hyperalgesia and reduces electrical excitability of C-fiber nociceptors in acute injury. Here, we examined the effects of the opioid receptor agonist fentanyl on the mechanical coding properties of not only C- but also A-fiber nociceptors innervating the rat hind paw in a model of chronic pain, i.e., 4 days after Freund's complete adjuvant-induced inflammation. The peripheral mechanosensitive terminals of C-fibers (n = 143), A-fibers (n = 79), and low-threshold mechanoreceptors (n = 25) were characterized using the in vitro skin-nerve preparation from the saphenous nerve. Although mechanical activation thresholds were not changed, discharges to suprathreshold mechanical stimuli were elevated significantly in both A- and C-fiber nociceptors from inflamed tissue. In addition, the proportion of nociceptors as well as the frequency of spontaneous discharges in A (14% vs. 0%)- and C (28% vs. 8%)-fibers were increased in inflamed compared with normal tissue. Fentanyl inhibited responses to suprathreshold stimuli in a significantly higher proportion of not only C (36% vs. 7%)- but also A (41% vs. 8%)-fibers in inflamed tissue in a naloxone-reversible and concentration-dependent manner. Our results demonstrate that mechanical sensitization persists in chronic inflammation, in correlation with behavioral hyperalgesia. Opioid sensitivity of both A- and C-fibers is markedly augmented. This is consistent with an upregulation or enhanced functionality of opioid receptors located at the peripheral terminals of sensitized nociceptors.

Neurons of the medial superior olive (MSO) code for the azimuthal location of low-frequency sound sources via a binaural coincidence detection system operating on microsecond time scales. These neurons are morphologically simple and stereotyped, and anatomical studies have indicated a functional segregation of excitatory and inhibitory inputs between cellular compartments. It is thought that this morphological arrangement holds important implications for the computational task of these cells. To date, however, there has been no functional investigation into synaptic input sites or functional receptor distributions on mature neurons of the MSO. Here, functional neurotransmitter receptor maps for amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA), N-methyl-D-aspartate (NMDA), glycine (Gly), and ionotropic γ-aminobutyric acid (GABA(A)) receptors (Rs) were compared and complemented by their corresponding synaptic input map. We find in MSO neurons from postnatal day 20-35 gerbils that AMPARs and their excitatory inputs target the soma and dendrites. Functional GlyRs and their inhibitory inputs are predominantly refined to the somata, although a pool of functional GlyRs is present extrasynaptically on MSO dendrites. GABA(A)R responses are present throughout the cell but lack direct synaptic contact indicating an involvement in volume transmission. NMDARs are present both synaptically and extrasynaptically with an overall distribution similar to GlyRs. Interestingly, even at physiological temperatures these functional NMDARs can be potentiated by synaptically released Gly. The functional receptor and synaptic input maps produced here led to the identification of a cross talk between transmitter systems and raises the possibility that extrasynaptic receptors could be modulating leak conductances as a homeostatic mechanism.

The parallel fibers (PFs) in the cerebellar cortex extend several millimeters along a folium in the mediolateral direction. The PFs are orthogonal to and cross several parasagittal zones defined by the olivocerebellar and corticonuclear pathways and the expression of molecular markers on Purkinje cells (PCs). The functions of these two organizations remain unclear, including whether the bands respond similarly or differentially to PF input. By using flavoprotein imaging in the anesthetized mouse in vivo, this study demonstrates that high-frequency PF stimulation, which activates a beamlike response at short latency, also evokes patches of activation at long latencies. These patches consist of increased fluorescence along the beam at latencies of 20-25 s with peak activation at 35 s. The long-latency patches are completely blocked by the type 1 metabotropic glutamate receptor (mGluR(1)) antagonist LY367385. Conversely, the AMPA and NMDA glutamate receptor antagonists DNQX and APV have little effect. Organized in parasagittal bands, the long-latency patches align with zebrin II-positive PC stripes. Additional Ca(2+) imaging demonstrates that the patches reflect increases in intracellular Ca(2+). Both the PLCβ inhibitor U73122 and the ryanodine receptor inhibitor ryanodine completely block the long-latency patches, indicating that the patches are due to Ca(2+) release from intracellular stores. Robust, mGluR(1)-dependent long-term potentiation (LTP) of the patches is induced using a high-frequency PF stimulation conditioning paradigm that generates LTP of PF-PC synapses. Therefore, the parasagittal bands, as defined by the molecular compartmentalization of PCs, respond differentially to PF inputs via mGluR(1)-mediated release of internal Ca(2+).

Golgi cells (GoCs) are the primary inhibitory interneurons of the granular layer of the cerebellum. Their inhibition of granule cells is central to operate the relay of excitatory inputs to the cerebellar cortex. Parallel fibers (PFs) establish synapses to the GoCs in the molecular layer; these synapses contain AMPA, N-methyl-D-aspartate (NMDA), and mostly group II metabotropic glutamate receptors. Long-term changes in the efficacy of synaptic transmission at the PF-GoC synapse have not been described previously. We used whole cell patch-clamp recordings of GoCs in acute rat cerebellar slices to study synaptic plasticity. We report that high-frequency burst stimulation of PFs, using a current-clamp or voltage-clamp induction protocol, gave rise to long-term depression (LTD) at the PF-GoC synapse. This form of LTD was not associated with persistent changes of paired-pulse ratio, suggesting a postsynaptic origin. Furthermore, LTD induction was not dependent on activation of NMDA receptors. PF-GoC LTD does require activation of specifically group II metabotropic glutamate receptors and of protein kinase A.

Auditory nerve fibers are the major source of excitation to the three groups of principal cells of the ventral cochlear nucleus (VCN), bushy, T stellate, and octopus cells. Shock-evoked excitatory postsynaptic currents (eEPSCs) in slices from mice showed systematic differences between groups of principal cells, indicating that target cells contribute to determining pre- and postsynaptic properties of synapses from spiral ganglion cells. Bushy cells likely to be small spherical bushy cells receive no more than three, most often two, excitatory inputs; those likely to be globular bushy cells receive at least four, most likely five, inputs. T stellate cells receive 6.5 inputs. Octopus cells receive >60 inputs. The N-methyl-d-aspartate (NMDA) components of eEPSCs were largest in T stellate, smaller in bushy, and smallest in octopus cells, and they were larger in neurons from younger than older mice. The average AMPA conductance of a unitary input is 22 ± 15 nS in both groups of bushy cells, <1.5 nS in octopus cells, and 4.6 ± 3 nS in T stellate cells. Sensitivity to philanthotoxin (PhTX) and rectification in the intracellular presence of spermine indicate that AMPA receptors that mediate eEPSCs in T stellate cells contain more GluR2 subunits than those in bushy and octopus cells. The AMPA components of eEPSCs were briefer in bushy (0.5 ms half-width) than in T stellate and octopus cells (0.8-0.9 ms half-width). Widening of eEPSCs in the presence of cyclothiazide (CTZ) indicates that desensitization shortens eEPSCs. CTZ-insensitive synaptic depression of the AMPA components was greater in bushy and octopus than in T stellate cells.

Trace eyelid conditioning is a form of associative learning that requires several forebrain structures and cerebellum. Previous work suggests that at least two conditioned stimulus (CS)-driven signals are available to the cerebellum via mossy fiber inputs during trace conditioning: one driven by and terminating with the tone and a second driven by medial prefrontal cortex (mPFC) that persists through the stimulus-free trace interval to overlap in time with the unconditioned stimulus (US). We used electric stimulation of mossy fibers to determine whether this pattern of dual inputs is necessary and sufficient for cerebellar learning to express normal trace eyelid responses. We find that presenting the cerebellum with one input that mimics persistent activity observed in mPFC and the lateral pontine nuclei during trace eyelid conditioning and another that mimics tone-elicited mossy fiber activity is sufficient to produce responses whose properties quantitatively match trace eyelid responses using a tone. Probe trials with each input delivered separately provide evidence that the cerebellum learns to respond to the mPFC-like input (that overlaps with the US) and learns to suppress responding to the tone-like input (that does not). This contributes to precisely timed responses and the well-documented influence of tone offset on the timing of trace responses. Computer simulations suggest that the underlying cerebellar mechanisms involve activation of different subsets of granule cells during the tone and during the stimulus-free trace interval. These results indicate that tone-driven and mPFC-like inputs are necessary and sufficient for the cerebellum to learn well-timed trace conditioned responses.

The normal development of sensory perception in mammals depends on appropriate sensory experience between birth and maturity. Numerous reports have shown that trimming some or all of the large mystacial vibrissa (whiskers) on one side of the face after birth has a detrimental effect on the maturation of cortical function. The objective of the present study was to understand the differences that occur after unilateral whisker trimming compared with those that occur after bilateral deprivation. Physiological deficits produced by bilateral trimming (BD) of all whiskers for 2 mo after birth were compared with the deficits produced by unilateral trimming (UD) for the same period of time using extracellular recording under urethan anesthesia from single cells in rat barrel cortex. Fast spiking (FSUs) and regular spiking (RSUs) units were separated and their properties compared in four subregions identified by histological reconstructions of the electrode penetrations, namely: layer IV barrel and septum, and layers II/III above a barrel and above a septum. UD upregulated responses in layer IV septa and in layers II/III above septa and perturbed the timing of responses to whisker stimuli. After BD, nearly all responses were decreased, and poststimulus latencies were increased. Circuit changes are proposed as an argument for how inputs arising from the spared whiskers project to the undeprived cortex and, via commissural fibers, could upregulate septal responses after UD. Following BD, more global neural deficits create a signature difference in the outcome of UD and BD in rat barrel cortex.

Touch is initiated by diverse somatosensory afferents that innervate the skin. The ability to manipulate and classify receptor subtypes is prerequisite for elucidating sensory mechanisms. Merkel cell-neurite complexes, which distinguish shapes and textures, are experimentally tractable mammalian touch receptors that mediate slowly adapting type I (SAI) responses. The assessment of SAI function in mutant mice has been hindered because previous studies did not distinguish SAI responses from slowly adapting type II (SAII) responses, which are thought to arise from different end organs, such as Ruffini endings. Thus we sought methods to discriminate these afferent types. We developed an epidermis-up ex vivo skin-nerve chamber to record action potentials from afferents while imaging Merkel cells in intact receptive fields. Using model-based cluster analysis, we found that two types of slowly adapting receptors were readily distinguished based on the regularity of touch-evoked firing patterns. We identified these clusters as SAI (coefficient of variation = 0.78 +/- 0.09) and SAII responses (0.21 +/- 0.09). The identity of SAI afferents was confirmed by recording from transgenic mice with green fluorescent protein-expressing Merkel cells. SAI receptive fields always contained fluorescent Merkel cells (n = 10), whereas SAII receptive fields lacked these cells (n = 5). Consistent with reports from other vertebrates, mouse SAI and SAII responses arise from afferents exhibiting similar conduction velocities, receptive field sizes, mechanical thresholds, and firing rates. These results demonstrate that mice, like other vertebrates, have two classes of slowly adapting light-touch receptors, identify a simple method to distinguish these populations, and extend the utility of skin-nerve recordings for genetic dissection of touch receptor mechanisms.

The present study investigates for the first time in any teleost the amino acid specificity and sensitivity of single glossopharyngeal (cranial nerve IX) fibers that innervate taste buds within the oropharyngeal cavity. These results are contrasted with similar data obtained from facial (cranial nerve VII) fibers that innervate extraoral taste buds. The major finding is that functional differences are clearly evident between taste fibers of these two cranial nerves. Catfish possess the most extensive distribution of taste buds found in vertebrates. Taste buds on the external body surface are exclusively innervated by VII, whereas IX, along with the vagus (X), innervate the vast majority of taste buds within the oropharyngeal cavity. Responses to the l-isomers of alanine (Ala), arginine (Arg), and proline (Pro), the three most stimulatory amino acids that bind to independent taste receptors, were obtained from 90 single VII and 64 single IX taste fibers. This study confirmed a previous investigation that the amino acid responsive VII fibers consist of two major groups, the Ala and Arg clusters containing taste fibers having thresholds in the ηM range. In contrast, the present study indicates the amino acid responsive IX taste system is dominated by taste fibers responsive to Pro and to Pro and Arg, respectively, has a reduced percentage of Ala fibers, and is less sensitive than VII. The present electrophysiological results are consistent with previous experiments, indicating that the extraoral taste system is essential for appetitive behavior, whereas oropharyngeal taste buds are critical for consummatory behavior.

Pavlovian eyeblink conditioning is a useful experimental model for studying adaptive timing, an important aspect of skilled movements. The conditioned response (CR) is precisely timed to occur just before the onset of the expected unconditioned stimulus (US). The timing can be changed immediately, however, by varying parameters of the conditioned stimulus (CS). It has previously been shown that increasing the intensity of a peripheral CS or the frequency of a CS consisting of a train of stimuli to the mossy fibers shortens the latency of the CR. The adaptive timing of behavioral CRs probably reflects the timing of an underlying learned inhibitory response in cerebellar Purkinje cells. It is not known how the latency of this Purkinje cell CR is controlled. We have recorded form Purkinje cells in conditioned decerebrate ferrets while increasing the intensity of a peripheral CS or the frequency of a mossy fiber CS. We observe changes in the timing of the Purkinje cell CR that match the behavioral effects. The results are consistent with the effect of CS parameters on behavioral CR latency being caused by corresponding changes in Purkinje cell CRs. They suggest that synaptic temporal summation may be one of several mechanisms underlying adaptive timing of movements.

The granular layer of cerebellum has been long hypothesized to perform combinatorial operations on incoming signals. Although this assumption is at the basis of main computational theories of cerebellum, it has never been assessed experimentally. Here, by applying high-resolution voltage-sensitive dye imaging techniques, we show that simultaneous activation of two partially overlapping mossy fiber bundles (either with single pulses or high-frequency bursts) can cause combined excitation and combined inhibition, which are compatible with the concepts of coincidence detection and spatial pattern separation predicted by theory. Combined excitation appeared as an area in which the combination of two inputs is greater than the arithmetic sum of the individual inputs and was enhanced by gamma-aminobutyric acid type A (GABA(A)) receptor blockers. Combined inhibition was manifest as an area where two inputs combined resulted in a reduction to less than half of the activity evoked from either one of the two inputs alone and was prevented by GABA(A) receptor blockers. The combinatorial responses occupied small granular layer regions (approximately 30 microm diameter), with combined inhibition being interspersed among extended areas of combined excitation. Moreover, the combinatorial effects lasted for tens of milliseconds and combined inhibition occurred only after termination of the stimuli. These combinatorial operations, if engaged by natural input patterns in vivo, may be important to influence incoming impulses organizing spatiotemporal spike sequences to be relayed to Purkinje cells.

The contribution of reflexes from the large myelinated afferents in the control of normal and perturbed gait in humans is a highly debated issue. One way to investigate this topic is by studying normal and perturbed gait in patients lacking large myelinated fibers in the distal limb (Charcot-Marie-Tooth [CMT] type 1A disease). Such patients should have delayed and decreased reflexes if the latter depend on these large myelinated fibers. To elicit the reflexes, both patients and controls had to step on a platform that was either at the same level or lowered by 5 cm. In control subjects, landing on a level surface induced short-latency responses in the biceps femoris and tibialis anterior muscles, whereas such responses were largely absent in the patients. Similarly, stepping down unexpectedly induced a very fast muscle synergy, leading to a brake of the forward propulsion in the controls, which was significantly reduced and delayed (on average 32 ms) in the patients. The observed changes correlated with both sensory and motor deficits. Nevertheless, it is concluded that the results are primarily related to the sensory deficits, since the delayed or absent responses appeared in both upper and lower leg muscles, whereas only the latter showed motor deficits. The data are taken as evidence that large-diameter afferents from the distal leg are essential for fast reflex activations induced by stepping on a level or lowered surface unexpectedly.

One contention within the field of neuroimaging concerns the character of the depicted activity: Does it represent neuronal action potential generation (i.e., spiking) or postsynaptic excitation? This question is related to the metabolic costs of different aspects of neurosignaling. The cerebellar cortex is well suited for addressing this problem because synaptic input to and spiking of the principal cell, the Purkinje cell (PC), are spatially segregated. Also, PCs are pacemakers, able to generate spikes endogenously. We examined the contributions to cerebellar cortical oxygen consumption (CMRO2) of postsynaptic excitation and PC spiking during evoked and ongoing neuronal activity in the rat. By inhibiting excitatory synaptic input using ionotropic glutamate receptor blockers, we found that the increase in CMRO2 evoked by parallel fiber (PF) stimulation depended entirely on postsynaptic excitation. In contrast, PC spiking was largely responsible for the increase in CMRO2 when ongoing neuronal activity was increased by gamma-aminobutyric acid type A receptor blockade. In this case, CMRO2 increased equally during PC spiking with excitatory synaptic activity as during PC pacemaker spiking without excitatory synaptic input. Subsequent inhibition of action potential propagation and neurotransmission by blocking voltage-gated Na+-channels eliminated the increases in CMRO2 due to PF stimulation and increased PC spiking, but left a large fraction of CMRO2, i.e., basal CMRO2, intact. In conclusion, whereas basal CMRO2 in anesthetized animals did not seem to be related to neurosignaling, increases in CMRO2 could be induced by all aspects of neurosignaling. Our findings imply that CMRO2 responses cannot a priori be assigned to specific neuronal activities.

In vertebrate auditory systems, the conversion from graded receptor potentials across the hair-cell membrane into stochastic spike trains of the auditory nerve (AN) fibers is performed by ribbon synapses. The statistics underlying this process constrain auditory coding but are not precisely known. Here, we examine the distributions of interspike intervals (ISIs) from spontaneous activity of AN fibers of the barn owl (Tyto alba), a nocturnal avian predator whose auditory system is specialized for precise temporal coding. The spontaneous activity of AN fibers, with the exception of those showing preferred intervals, is commonly thought to result from excitatory events generated by a homogeneous Poisson point process, which lead to spikes unless the fiber is refractory. We show that the ISI distributions in the owl are better explained as resulting from the action of a brief refractory period ( approximately 0.5 ms) on excitatory events generated by a homogeneous stochastic process where the distribution of interevent intervals is a mixture of an exponential and a gamma distribution with shape factor 2, both with the same scaling parameter. The same model was previously shown to apply to AN fibers in the cat. However, the mean proportions of exponentially versus gamma-distributed intervals in the mixture were different for cat and owl. Furthermore, those proportions were constant across fibers in the cat, whereas they covaried with mean spontaneous rate and with characteristic frequency in the owl. We hypothesize that in birds, unlike in mammals, more than one ribbon may provide excitation to most fibers, accounting for the different proportions, and that variation in the number of ribbons may underlie the variation in the proportions.

Endocannabinoids are lipid retrograde messengers that can be released by postsynaptic depolarization and/or activation of certain metabotropic receptors. We review a recent report that activation of metabotropic 5-HT2 receptors by endogenous serotonin induces the release of endocannabinoids in the olivary nucleus and suppresses glutamatergic input through a presynaptic action. This serotonin-endocannabinoid interaction has implications in the pathophysiology of pain and mental illness and raises the possibility that drugs targeting the 5-HT2 receptor may act by modulating endocannabinoid release.

Acute alcohol consumption causes deficits in motor coordination and gait, suggesting an involvement of cerebellar circuits, which play a role in the fine adjustment of movements and in motor learning. It has previously been shown that ethanol modulates inhibitory transmission in the cerebellum and affects synaptic transmission and plasticity at excitatory climbing fiber (CF) to Purkinje cell synapses. However, it has not been examined thus far how acute ethanol application affects long-term depression (LTD) and long-term potentiation (LTP) at excitatory parallel fiber (PF) to Purkinje cell synapses, which are assumed to mediate forms of cerebellar motor learning. To examine ethanol effects on PF synaptic transmission and plasticity, we performed whole cell patch-clamp recordings from Purkinje cells in rat cerebellar slices. We found that ethanol (50 mM) selectively blocked PF-LTD induction, whereas it did not change the amplitude of excitatory postsynaptic currents at PF synapses. In contrast, ethanol application reduced voltage-gated calcium currents and type 1 metabotropic glutamate receptor (mGluR1)-dependent responses in Purkinje cells, both of which are involved in PF-LTD induction. The selectivity of these effects is emphasized by the observation that ethanol did not impair PF-LTP and that PF-LTP could readily be induced in the presence of the group I mGluR antagonist AIDA or the mGluR1a antagonist LY367385. Taken together, these findings identify calcium currents and mGluR1-dependent signaling pathways as potential ethanol targets and suggest that an ethanol-induced blockade of PF-LTD could contribute to the motor coordination deficits resulting from alcohol consumption.

Spontaneous activity and frequency threshold tuning curves were studied in thousands of auditory nerve fibers in chinchilla. The frequency distribution of spontaneous activity rates is strongly bimodal for auditory nerve fibers with characteristic frequency <3 kHz but only mildly bimodal for the entire sample. Spontaneous activity rates and thresholds at the characteristic frequency are inversely related. Auditory-nerve fibers with low spontaneous rate have tuning curves with lower tip-to-tail ratios and more sharply tuned tips than the tuning curves of fibers with high spontaneous rates. It is shown here that this dependence of tuning on spontaneous rates is consistent with a previously unnoticed nonmonotonic dependence on iso-velocity criterion of the frequency tuning of basilar membrane vibrations.

Here we have systematically characterized the stimulus response properties of mechanosensitive sensory fibers in the mouse saphenous nerve. We tested mechanoreceptors and nociceptors with defined displacement stimuli of varying amplitude and velocity. For each sensory afferent investigated we measured the mechanical latency, which is the delay between the onset of a ramp displacement and the first evoked spike, corrected for conduction delay. Mechanical latency plotted as a function of stimulus strength was very characteristic for each receptor type and was very short for rapidly adapting mechanoreceptors (<11 ms) but very long in myelinated and unmyelinated nociceptors (49-114 ms). Increasing the stimulus speed decreased mechanical latency in all receptor types with the notable exception of C-fiber nociceptors, in which mean mechanical latency was not reduced less, similar100 ms, even with very fast ramp stimuli (2,945 microm/s). We examined stimulus response functions and mechanical latency at two different temperatures (24 and 32 degrees C) and found that stimulus response properties of almost all mechanoreceptors were not altered in this range. A notable exception to this rule was found for C-fibers in which mechanical latency was substantially increased and stimulus response functions decreased at lower temperatures. We calculated Q(10) values for mechanical latency in C-fibers to be 5.1; in contrast, the Q(10) value for conduction velocity for the same fibers was 1.4. Finally, we examined the effects of short-term inflammation (2-6 h) induced by carrageenan on nociceptor and mechanoreceptor sensitivity. We did not detect robust changes in mechanical latency or stimulus response functions after inflammation that might have reflected mechanical sensitization under the conditions tested.

A number of studies have been interpreted to support the view that the inferior olive climbing fibers send periodic signals to the cerebellum to time and pace behavior. In a direct test of this hypothesis in macaques performing nonperiodic tasks, we analyzed continuous recordings of complex spikes from the lateral cerebellar hemisphere. We found no periodicity outside of a 100-ms relative refractory period.

The contribution of gustation to the perception of food requires an understanding of how neurons represent mixtures of taste qualities. In the periphery, separate groups of fibers, labeled by the stimulus that evokes the best (largest) response, appear to respond to each component of a mixture. In the brain, identification of analogous groups of neurons is hampered by trial-to-trial variability in response magnitude. In addition, convergence of different fiber types onto central neurons may complicate the classification scheme. To investigate these issues, electrophysiological responses to four tastants: sucrose, NaCl, HCl, and quinine, and their binary mixtures were recorded from 56 cells in the nucleus of the solitary tract (NTS, the 1st synapse in the central gustatory pathway) of the anesthetized rat. For 36 of these cells, all 10 stimuli were repeated at least five times (range: 5-23; median = 10). Results showed that 39% of these cells changed their best stimulus across stimulus repetitions, suggesting that response magnitude (firing rate) on any given trial produces an ambiguous message. Averaged across replicate trials, mixture responses most often approximated the response to the more effective component of the mixture. Cells that responded best to a taste mixture rather than any single-component tastant were identified. These cells were more broadly tuned than were cells that responded best to single-component stimuli and showed evidence of convergence from more than one best stimulus fiber type. Functionally, mixture-best cells may amplify the neural signal produced by unique configurations of basic taste qualities.

II. Auditory nerve. Low-frequency neurons in the inferior colliculus (IC) show a damped oscillatory response as a function of interaural time differences (ITDs) of broadband noise. It was previously shown that several features of such noise-delay functions are well predicted by the composite curve, generated by the linear summation of responses to tones with varying ITD. This indicates a surprising degree of linearity at the midbrain level of the auditory pathway. A similar comparison between responses to tones and to noise has not been made at a more peripheral, monaural level and it is therefore unclear to what extent this linearity reflects peripheral physiology. Here, we compare cat auditory nerve responses to broadband noise and to isolevel tones. We constructed shuffled autocorrelograms for responses to tones and summed across frequencies to obtain a monaural composite curve. We then compare this composite curve to the shuffled autocorrelogram of responses to broadband noise and find that the match between tonal and noise responses is poorer at the level of the auditory nerve than at the level of the IC. The apparent linearity of responses in the IC is thus even more surprising than was apparent from its original report because it results from mechanisms interposed between the auditory nerve and the IC.

Neurons in the dorsal cochlear nucleus (DCN) exhibit strong nonlinearities in spectral processing. Low-order models that transform the stimulus spectrum into discharge rate using a combination of first- and second-order weighting of the spectrum (quadratic models) usually fail to predict responses to novel stimuli for principal neurons in the DCN, even though they work well in ventral cochlear nucleus. Here we investigate the effects of spectral contrast on the performance of such models. Typically, the models fail for stimuli with natural-sound-like spectral contrasts (~12 dB), but have good prediction performance at small (3-dB) contrasts. The weights also typically increase substantially in amplitude at smaller spectral contrast. These changes in weight size with contrast are partly inherited from similar effects seen in auditory nerve fibers, but there must be additional effects from inhibitory circuits in the DCN. These results provide insight into the reasons for the poor performance of spectrotemporal receptive field (STRF) models in predicting responses of auditory neurons. Because the general shapes of the weights do not change between low and high contrast, they also suggest that STRFs may capture meaningful properties of neural receptive fields, even though they do not do well at predicting responses.

The cerebellum of the mormyrid fish consists of three major divisions: the valvula, the central lobes, and the caudal lobes. Several studies have focused on the central lobes and the valvula, but little is known about the caudal lobes. The mormyrid caudal lobe includes anterior and posterior components. The anterior caudal lobe is associated with the lateral line and eighth nerve end organs, whereas the posterior caudal lobe is associated with the electrosensory system. The present study examines the physiology and pharmacology of morphologically identified Purkinje cells and efferent cells in an in vitro slice preparation of the posterior caudal lobe. We found that the Purkinje cells in the posterior caudal lobe can be classified into three subtypes based on both their morphology and on their physiological responses to intracellular current injection and to synaptic inputs from parallel fibers and climbing fibers. Similarities and differences between the physiology of the caudal lobe and that of other regions of the mormyrid cerebellum and the mammalian cerebellum are discussed.

The growth-associated protein, GAP-43, is an axonally localized neuronal protein with high expression in the developing brain and in regenerating neurites. Mice that lack GAP-43 (GAP-43 -/-) fail to form a whisker-related barrel map. In this study, we use GAP-43 -/- mice to examine GAP-43 synaptic function in the context of thalamocortical synapse development and cortical barrel map formation. Examination of thalamocortical synaptic currents in an acute brain slice preparation and in autaptic thalamic neurons reveals that GAP-43 -/- synapses have larger alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR)-mediated currents than controls despite similar AMPAR function and normal probability of vesicular release. Interestingly, GAP-43 -/- synapses are less sensitive to blockade by a competitive glutamate receptor antagonist, suggesting higher levels of neurotransmitter in the cleft during synaptic transmission. Field excitatory postsynaptic potentials (EPSPs) from GAP-43 -/- thalamocortical synapses reveal a reduced fiber response, and anatomical analysis shows reduced thalamic innervation of barrel cortex in GAP-43 -/- mice. Despite this fact synaptic responses in the field EPSPs are similar in GAP-43 -/- mice and wild-type littermate controls, and the ratio of AMPAR-mediated to N-methyl-d-aspartate receptor (NMDAR)-mediated currents (AMPAR:NMDAR ratio) is larger than normal. This suggests that GAP-43 -/- mice form fewer thalamocortical synapses in layer IV because of decreased anatomical innervation of the cortex, but the remaining contacts are individually stronger possibly due to increased neurotransmitter concentration in the synaptic cleft. Together, these results indicate that in addition to its well known role in axonal pathfinding GAP-43 plays a functional role in regulating neurotransmitter release.

Intracellular recordings were made from nerve fibers in the posterior ampullary nerve near the neuroepithelium. Calyx-bearing afferents were identified by their distinctive efferent-mediated responses. Such fibers receive inputs from both type I and type II hair cells. Type II inputs are made by synapses on the outer face of the calyx ending and on the boutons of dimorphic fibers. Quantal activity, consisting of brief mEPSPs, is reduced by lowering the external concentration of Ca2+ and blocked by the AMPA-receptor antagonist CNQX. Poisson statistics govern the timing of mEPSPs, which occur at high rates (250-2,500/s) in the absence of mechanical stimulation. Excitation produced by canal-duct indentation can increase mEPSP rates to nearly 5,000/s. As the rate increases, mEPSPs can change from a monophasic depolarization to a biphasic depolarizing-hyperpolarizing sequence, both of whose components are blocked by CNQX. Blockers of voltage-gated currents affect mEPSP size, which is decreased by TTX and is increased by linopirdine. mEPSP size decreases severalfold after impalement. The size decrease, although it may be triggered by the depolarization occurring during impalement, persists even at hyperpolarized membrane potentials. Nonquantal transmission is indicated by shot-noise calculations and by the presence of voltage modulations after quantal activity is abolished pharmacologically. An ultrastructural study shows that inner-face inputs from type I hair cells outnumber outer-face inputs from type II hair cells by an almost 6:1 ratio.

The last few years have seen an increase in the variety of in vivo experiments used for studying cerebellar physiological mechanisms. A combination of ketamine and xylazine has become a particularly popular form of anesthesia. However, because nonanesthetized control conditions are lacking in these experiments, so far there has been no evaluation of the effects of these drugs on the physiological activity in the cerebellar neuronal network. In the present study, we used the mossy fiber, parallel fiber, and climbing fiber field potentials evoked in the nonanesthetized, decerebrated rat to serve as a control condition against which the effects of intravenous drug injections could be compared. All anesthetics were applied at doses required for normal maintenance of anesthesia. We found that ketamine substantially depressed the evoked N3 field potential, which is an indicator of the activity in the parallel fiber synapses (-40%), and nearly completely abolished evoked climbing fiber field potentials (-90%). Xylazine severely depressed the N3 field (-75%) and completely abolished the climbing fiber field (-100%). In a combination commonly used for general anesthesia (20:1), ketamine-xylazine injections also severely depressed the N3 field (-75%) and nearly completely abolished the climbing fiber field (-90%). We also observed that lowered body and surface temperatures (<34 degrees C) resulted in a substantial depression of the N3 field (-50%). These results urge for some caution in the interpretations of studies on cerebellar network physiology performed in animals anesthetized with these drugs.

The nature of the synaptic connection from the auditory nerve onto the cochlear nucleus neurons has a profound impact on how sound information is transmitted. Short-term synaptic plasticity, by dynamically modulating synaptic strength, filters information contained in the firing patterns. In the sound-localization circuits of the brain stem, the synapses of the timing pathway are characterized by strong short-term depression. We investigated the short-term synaptic plasticity of the inputs to the bird's cochlear nucleus angularis (NA), which encodes intensity information, by using chick embryonic brain slices and trains of electrical stimulation. These excitatory inputs expressed a mixture of short-term facilitation and depression, unlike those in the timing nuclei that only depressed. Facilitation and depression at NA synapses were balanced such that postsynaptic response amplitude was often maintained throughout the train at high firing rates (>100 Hz). The steady-state input rate relationship of the balanced synapses linearly conveyed rate information and therefore transmits intensity information encoded as a rate code in the nerve. A quantitative model of synaptic transmission could account for the plasticity by including facilitation of release (with a time constant of approximately 40 ms), and a two-step recovery from depression (with one slow time constant of approximately 8 s, and one fast time constant of approximately 20 ms). A simulation using the model fit to NA synapses and auditory nerve spike trains from recordings in vivo confirmed that these synapses can convey intensity information contained in natural train inputs.

The contribution of Purkinje cells to cerebellar motor coordination and learning is determined in part by the chronic and acute effects of climbing fiber (CF) afferents. Whereas the chronic effects of CF discharge, such as the depression of conjunctive parallel fiber (PF) inputs, are well established, the acute cellular functions of CF discharge remain incompletely understood. In rat cerebellar slices, we show that CF discharge presented at physiological frequencies substantially modifies the frequency and pattern of Purkinje cell spike output in vitro. Repetitive CF discharge converts a spontaneous trimodal pattern of output characteristic of Purkinje cells in vitro to a more naturalistic nonbursting pattern consisting of spike trains interrupted by short CF-evoked pauses or longer pauses associated with state transitions. All effects of CF discharge could be reproduced in the presence of synaptic blockers by using current injections to simulate complex spike depolarizations, revealing that CF-evoked changes in Purkinje cell output can occur independently of network activation. Rather postsynaptic changes are sufficient to account for the CF-evoked block of trimodal activity and include at least the activation of Ca(2+)-dependent K(+) channels. Furthermore by controlling the frequency of Purkinje cell spike output over three discrete firing levels, CF discharge modulates the gain of Purkinje cell responsiveness to PF inputs in vitro through postsynaptic mechanisms triggered by the complex spike depolarization. The ability for CF discharge to acutely modulate diverse aspects of Purkinje cell output provides important insights into the probable cellular factors contributing to motor disturbances following CF denervation.

This essay looks at two papers published by Ed Perl and co-workers that identified specifically nociceptive neurons in the periphery and superficial dorsal horn. Bessou P and Perl ER. Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli. J Neurophysiol 32: 1025-1043 1969. Christensen BN and Perl ER. Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn. J Neurophysiol 33: 293-307 1970.

We investigated the possible contribution of signals carried by vestibular-nerve afferents to long-term processes of vestibular compensation after unilateral labyrinthectomy. Semicircular canal afferents were recorded from the contralesional nerve in three macaque monkeys before [horizontal (HC) = 67, anterior (AC) = 66, posterior (PC) = 50] and 1-12 mo after (HC = 192, AC = 86, PC = 57) lesion. Vestibular responses were evaluated using passive sinusoidal rotations with frequencies of 0.5-15 Hz (20-80 degrees /s) and fast whole-body rotations reaching velocities of 500 degrees /s. Sensitivities to nonvestibular inputs were tested by: 1) comparing responses during active and passive head movements, 2) rotating the body with the head held stationary to activate neck proprioceptors, and 3) encouraging head-restrained animals to attempt to make head movements that resulted in the production of neck torques of < or =2 Nm. Mean resting discharge rate before and after the lesion did not differ for the regular, D (dimorphic)-irregular, or C (calyx)-irregular afferents. In response to passive rotations, afferents showed no change in sensitivity and phase, inhibitory cutoff, and excitatory saturation after unilateral labyrinthectomy. Moreover, head sensitivities were similar during voluntary and passive head rotations and responses were not altered by neck proprioceptive or efference copy signals before or after the lesion. The only significant change was an increase in the proportion of C-irregular units postlesion, accompanied by a decrease in the proportion of regular afferents. Taken together, our findings show that changes in response properties of the vestibular afferent population are not likely to play a major role in the long-term changes associated with compensation after unilateral labyrinthectomy.

The vestibular semicircular canals are responsible for detection of rotational head motion although the precise mechanisms underlying the transduction and encoding of movement information are still under study. In the present investigation, we utilized neural tracers and immunohistochemistry to quantitatively examine the topology and afferent innervation patterns of the horizontal semicircular canal crista (HCC) in pigeons (Columba livia). Two hundred and eighty-six afferents from five horizontal canal organs were identified of which 92 units were sufficiently labeled and isolated to perform anatomical reconstructions. In addition, a three-dimensional contour map of the crista was constructed. Bouton afferents were located only in the peripheral regions of the receptor epithelium. Bouton afferents had the most complex innervation patterns with significantly longer and more numerous branches as well as a higher branch order than any other fiber type. Bouton fibers also contained significantly more bouton terminals than did dimorph afferents. Calyx afferents were located only in the apex and central planar regions. Calyx fibers had the largest axonal diameters yet the smallest fiber lengths and innervation areas, the fewest number of branches, the lowest branch order, and the fewest total number of terminals of all fiber types. Dimorph afferents were located throughout the central crista with afferent terminations that were larger and more complex than calyx fibers but less so than bouton fibers. Overall, the pigeon HCC morphology and innervation shares many common features with those of other animal classes.

It is known that a subset of taste cells generate action potentials in response to taste stimuli. However, responsiveness of these cells to particular tastants remains unknown. In the present study, by using a newly developed extracellular recording technique, we recorded action potentials from the basolateral membrane of single receptor cells in response to taste stimuli applied apically to taste buds isolated from mouse fungiform papillae. By this method, we examined taste-cell responses to stimuli representing the four basic taste qualities (NaCl, Na saccharin, HCl, and quinine-HCl). Of 72 cells responding to taste stimuli, 48 (67%) responded to one, 22 (30%) to two, and 2 (3%) to three of four taste stimuli. The entropy value presenting the breadth of responsiveness was 0.158 +/- 0.234 (mean +/- SD), which was close to that for the nerve fibers (0.183 +/- 0.262). In addition, the proportion of taste cells predominantly sensitive to each of the four taste stimuli, and the grouping of taste cells based on hierarchical cluster analysis, were comparable with those of chorda tympani (CT) fibers. The occurrence of each class of taste cells with different taste responsiveness to the four taste stimuli was not significantly different from that of CT fibers except for classes with broad taste responsiveness. These results suggest that information derived from taste cells generating action potentials may provide the major component of taste information that is transmitted to gustatory nerve fibers.

This essay looks at the historical significance of two APS classic papers that are freely available online: Sperry RW. Optic nerve regeneration with return of vision in anurans. J Neurophysiol 7: 57-69, 1944 (http://jn.physiology.org/cgi/reprint/7/1/57). Sperry RW. Restoration of vision after crossing of optic nerves and after contralateral transplantation of eye. J Neurophysiol 8: 15-28, 1945 (http://jn.physiology.org/cgi/reprint/8/1/15).

A seizure-paralysis repertoire characteristic of Drosophila "bang-sensitive" mutants can be evoked electroconvulsively in tethered flies, in which behavioral episodes are associated with synchronized spike discharges in different body parts. Flight muscle DLMs (dorsal longitudinal muscles) display a stereotypic sequence of initial and delayed bouts of discharges (ID and DD), interposed with giant fiber (GF) pathway failure and followed by a refractory period. We examined how seizure susceptibility and discharge patterns are modified in various K(+) and Na(+) channel mutants. Decreased numbers of Na(+) channels in nap(ts) flies drastically reduced susceptibility to seizure induction, eliminated ID, and depressed DD spike generation. Mutations of different K(+) channels led to differential modifications of the various components in the repertoire. Altered transient K(+) currents in Sh(133) and Hk mutants promoted ID induction. However, only Sh(133) but not Hk mutations increased DD seizure and GF pathway failure durations. Surprisingly, modifications in sustained K(+) currents in eag and Shab mutants increased thresholds for DD induction and GF pathway failure. Nevertheless, both eag and Shab, like Sh(133), increased DD spike generation and recovery time from GF pathway failure. Interactions between channel mutations with the bang-sensitive mutation bss demonstrated the role of membrane excitability in stress-induced seizure-paralysis behavior. Seizure induction and discharges were suppressed by nap(ts) in bss nap double mutants, whereas Sh heightened seizure susceptibility in bss Sh(133) and bss Sh(M) double mutants. Our results suggest that individual seizure repertoire components reflect different neural network activities that could be differentially altered by mutations of specific ion channel subunits.

Although listeners are sensitive to interaural time differences (ITDs) in the envelope of high-frequency sounds, both ITD discrimination performance and the extent of lateralization are poorer for high-frequency sinusoidally amplitude-modulated (SAM) tones than for low-frequency pure tones. Psychophysical studies have shown that ITD discrimination at high frequencies can be improved by using novel transposed-tone stimuli, formed by modulating a high-frequency carrier by a half-wave-rectified sinusoid. Transposed tones are designed to produce the same temporal discharge patterns in high-characteristic frequency (CF) neurons as occur in low-CF neurons for pure-tone stimuli. To directly test this hypothesis, we compared responses of auditory-nerve fibers in anesthetized cats to pure tones, SAM tones, and transposed tones. Phase locking was characterized using both the synchronization index and autocorrelograms. With both measures, phase locking was better for transposed tones than for SAM tones, consistent with the rationale for using transposed tones. However, phase locking to transposed tones and that to pure tones were comparable only when all three conditions were met: stimulus levels near thresholds, low modulation frequencies (<250 Hz), and low spontaneous discharge rates. In particular, phase locking to both SAM tones and transposed tones substantially degraded with increasing stimulus level, while remaining more stable for pure tones. These results suggest caution in assuming a close similarity between temporal patterns of peripheral activity produced by transposed tones and pure tones in both psychophysical studies and neurophysiological studies of central neurons.

Granule cells and parallel fiber circuits in the dorsal cochlear nucleus (DCN) play a role in integration of multimodal sensory with auditory inputs. The activity of granule cells is regulated through inhibitory connections made by Golgi cells. Golgi cells in turn probably receive parallel fiber inputs and regulate activity of the DCN. We have investigated the electrophysiological properties of Golgi cells using the whole cell patch-clamp method in slices made from transgenic mice that express green fluorescent protein driven by the promotor of metabotropic glutamate receptor subtype 2. Stimulation of auditory nerve fibers (ANFs) and of parallel fibers evoked glutamatergic excitatory postsynaptic currents (EPSC) through AMPA receptors. The strengths and latencies of these inputs differed, however. ANF stimulation evoked EPSCs after 4.7 +/- 0.4 ms, whereas parallel fiber stimulation evoked EPSCs after 1.4 +/- 0.2 ms that were on average 2.5 times as large. The multiple peaks and prolonged activity suggest the presence of polysynaptic connections between ANFs and Golgi cells. Agonists for group II metabotropic glutamate receptors (mGluRs) and for muscarinic receptors induced membrane hyperpolarization and suppressed the firing of Golgi cells by activating G-protein-coupled inward rectifier K(+) (GIRK) channels. These results strongly suggest that Golgi cells were regulated through the combined activities of glutamatergic and cholinergic synapses, which presumably regulated the temporal firing patterns of granule cells and through them the activity of principal cells of the DCN.

Nucleus magnocellularis (NM) is one of the subnuclei of the avian cochlear nucleus and has a role of extracting the temporal information of sound from the auditory nerve fibers (ANFs). Neurons in NM are varied along the tonotopic axis in synaptic transmission and membrane excitability and are high-fidelity relay neurons at the high to middle characteristic frequency (CF) regions. Here we have compared the firing properties between ANFs and NM neurons in vivo and found that at high but not near threshold intensities, spike firings are more phase-locked in NM than in ANFs in the CF region <500 Hz. Moreover, NM shows reduced occurrence of multiple spikes within one cycle of sound stimuli and higher vector strength than ANF. The improved phase-locked firing nature of NM is discussed in relation to the in vitro findings of small EPSCs in the low CF neurons (Fukui and Ohmori 2004). It is concluded that NM neurons are not simple relay neurons in the low CF region but are coincidence detectors of monoaural synaptic inputs that improve the synchronization of spike firing to auditory inputs.

The Scn8a gene encodes the voltage-gated Na channel alpha subunit Na(V)1.6, which is widely expressed throughout the nervous system. Global null mutations that eliminate Scn8a in all cells result in severe motor dysfunction and premature death, precluding analysis of the physiological role of Na(V)1.6 in different neuronal types. To test the effect of cerebellar Na(V)1.6 on motor coordination in mice, we used the Cre-lox system to eliminate Scn8a expression exclusively in Purkinje neurons (Purkinje KO) and/or granule neurons (granule KO). Whereas granule KO mice had only minor behavioral defects, adult Purkinje KO mice exhibited ataxia, tremor, and impaired coordination. These disorders were exacerbated in double mutants lacking Scn8a in both Purkinje and granule cells (double KO). In Purkinje cells isolated from adult Purkinje KO and double KO but not granule KO mice, the ratio of resurgent-to-transient tetrodotoxin- (TTX)-sensitive Na current amplitudes decreased from approximately 15 to approximately 5%. In cerebellar slices, Purkinje cell spontaneous and maximal firing rates were reduced 10-fold and twofold relative to control in Purkinje KO and double KO but not granule KO mice. Additionally, short-term plasticity of high-frequency parallel fiber EPSCs was altered relative to control in Purkinje KO and double KO but not granule KO mice. These data suggest that the specialized kinetics of Purkinje Na channels depend directly on Scn8a expression. The loss of these channels leads to a decrease in Purkinje cell firing rates as well as a modification of the synaptic properties of afferent parallel fibers, with the ultimate consequence of disrupting motor behavior.