Journal of Neurophysiology current issue

Introducing Neuro Forum, a Section for Young Neurophysiologists

Linden, D. J. — 2008-09-08

Behavioral States, Network States, and Sensory Response Variability

Fontanini, A., Katz, D. B. — 2008-09-08

We review data demonstrating that single-neuron sensory responses change with the states of the neural networks (indexed in terms of spectral properties of local field potentials) in which those neurons are embedded. We start with broad network changes—different levels of anesthesia and sleep—and then move to studies demonstrating that the sensory response plasticity associated with attention and experience can also be conceptualized as functions of network state changes. This leads naturally to the recent data that can be interpreted to suggest that even brief experience can change sensory responses via changes in network states and that trial-to-trial variability in sensory responses is a nonrandom function of network fluctuations, as well. We suggest that the CNS may have evolved specifically to deal with stimulus variability and that the coupling with network states may be central to sensory processing.

Receptor Synergy From Thin Fiber Muscle Afferents. Focus on "Dorsal Root Ganglion Neurons Innervating Skeletal Muscle Respond to Physiological Combinations of Protons, ATP, and Lactate Mediated by ASIC, P2X, and TRPV1"

Kaufman, M. P., Hayes, S. G. — 2008-09-08

Speed-Curvature Relations in Speech Production Challenge the 1/3 Power Law

Perrier, P., Fuchs, S. — 2008-09-08

Relations between tangential velocity and trajectory curvature are analyzed for tongue movements during speech production in the framework of the 1/3 power law, discovered by Viviani and colleagues for arm movements. In 2004, Tasko and Westbury found for American English that the power function provides a good account of speech kinematics, but with an exponent that varies across articulators. The present work aims at broadening Tasko and Westbury's study 1) by analyzing speed–curvature relations for various languages (French, German, Mandarin) and for a biomechanical tongue model simulating speech gestures at various speaking rates and 2) by providing for each speaker or each simulated speaking rate a comparison of results found for the complete set of movements with those found for each movement separately. It is found that the 1/3 power law offers a fair description of the global speed–curvature relations for all speakers and all languages, when articulatory speech data are considered in their whole. This is also observed in the simulations, where the motor control model does not specify any kinematic property of the articulatory paths. However, the refined analysis for individual movements reveals numerous exceptions to this law: the velocity always decreases when curvature increases, but the slope in the log–log representation is variable. It is concluded that the speed–curvature relation is not controlled in speech movements and that it accounts only for general properties of the articulatory movements, which could arise from vocal tract dynamics or/and from stochastic characteristics of the measured signals.

Dorsal Root Ganglion Neurons Innervating Skeletal Muscle Respond to Physiological Combinations of Protons, ATP, and Lactate Mediated by ASIC, P2X, and TRPV1

Light, A. R., Hughen, R. W., Zhang, J., Rainier, J., Liu, Z., Lee, J. — 2008-09-08

The adequate stimuli and molecular receptors for muscle metaboreceptors and nociceptors are still under investigation. We used calcium imaging of cultured primary sensory dorsal root ganglion (DRG) neurons from C57Bl/6 mice to determine candidates for metabolites that could be the adequate stimuli and receptors that could detect these stimuli. Retrograde DiI labeling determined that some of these neurons innervated skeletal muscle. We found that combinations of protons, ATP, and lactate were much more effective than individually applied compounds for activating rapid calcium increases in muscle-innervating dorsal root ganglion neurons. Antagonists for P2X, ASIC, and TRPV1 receptors suggested that these three receptors act together to detect protons, ATP, and lactate when presented together in physiologically relevant concentrations. Two populations of muscle-innervating DRG neurons were found. One responded to low metabolite levels (likely nonnoxious) and used ASIC3, P2X5, and TRPV1 as molecular receptors to detect these metabolites. The other responded to high levels of metabolites (likely noxious) and used ASIC3, P2X4, and TRPV1 as their molecular receptors. We conclude that a combination of ASIC, P2X5 and/or P2X4, and TRPV1 are the molecular receptors used to detect metabolites by muscle-innervating sensory neurons. We further conclude that the adequate stimuli for muscle metaboreceptors and nociceptors are combinations of protons, ATP, and lactate.

Ethanol Effects on Dopaminergic Ventral Tegmental Area Neurons During Block of Ih: Involvement of Barium-Sensitive Potassium Currents

McDaid, J., McElvain, M. A., Brodie, M. S. — 2008-09-08

The dopaminergic neurons of the ventral tegmental area (DA VTA neurons) are important for the rewarding and reinforcing properties of drugs of abuse, including ethanol. Ethanol increases the firing frequency of DA VTA neurons from rats and mice. Because of a recent report on block of ethanol excitation in mouse DA VTA neurons with ZD7288, a selective blocker of the hyperpolarization-activated cationic current I_h, we examined the effect of ZD7288 on ethanol excitation in DA VTA neurons from C57Bl/6J and DBA/2J mice and Fisher 344 rats. Ethanol (80 mM) caused only increases in firing rate in mouse DA VTA neurons in the absence of ZD7288, but in the presence of ZD7288 (30 µM), ethanol produced a more transient excitation followed by a decrease of firing. This same biphasic phenomenon was observed in DA VTA neurons from rats in the presence of ZD7288 only at very high ethanol concentrations (160–240 mM) but not at lower pharmacologically relevant concentrations. The longer latency ethanol-induced inhibition was not observed in DA VTA neurons from mice or rats in the presence of barium (100 µM), which blocks G protein–linked potassium channels (GIRKs) and other inwardly rectifying potassium channels. Ethanol may have a direct effect to increase an inhibitory potassium conductance, but this effect of ethanol can only decrease the firing rate if I_h is blocked.

Monoaminergic Modulation of the Na+-Activated K+ Channel in Kenyon Cells Isolated From the Mushroom Body of the Cricket (Gryllus bimaculatus) Brain

Aoki, K., Kosakai, K., Yoshino, M. — 2008-09-08

Recent studies have suggested that octopamine (OA) and dopamine (DA) play important roles in mediating the reward and punishment signals, respectively, in olfactory learning in insect. However, their target molecules and the signaling mechanisms are not fully understood. In this study, we showed for the first time that OA and DA modulate the Na⁺-activated K⁺ (K_Na) channels in an opposite way in Kenyon cells isolated from the mushroom body of the cricket, Gryllus bimaculatus. Patch-clamp recordings showed that the single-channel conductance of the K_Na channel was about 122 pS with high K⁺ in the patch pipettes. The channel was found to be activated by intracellular Na⁺ but less activated by Li⁺. K⁺ channel blockers TEA and quinidine reduced the open probability (Po) of this channel. Bath application of OA and DA respectively increased and decreased the Po of K_Na channel currents. An increase and a decrease in Po of K_Na channels were also observed by applying the membrane-permeable analogs 8-Br-cyclic-AMP and 8-Br-cGMP, respectively. Furthermore, it was revealed that cAMP-induced increase and cGMP-induced decrease in Po were attenuated by the specific protein kinase A (PKA) inhibitor H-89 and protein kinase G (PKG) inhibitor KT5823, respectively. These results indicate that the K_Na channel is a target molecule for OA and DA and that cAMP/PKA and cGMP/PKG signaling pathways are also involved in the modulation of K_Na channels.

Detecting the Unique Representation of Motor-Unit Action Potentials in the Surface Electromyogram

Farina, D., Negro, F., Gazzoni, M., Enoka, R. M. — 2008-09-08

This study investigated the relative proportion of motor-unit action potentials that are uniquely represented in the simulated and experimental surface electromyogram (EMG). Two hundred motor units were simulated in a cylindrical anatomical system. Action potentials for each motor unit were generated with a model and then compared with those of other motor units. Pairs of motor units were considered indistinguishable and the motor units not uniquely represented in the surface EMG, when the difference in the mean energy for the pair of potentials was <5%. The anatomical conditions and recording configurations had a substantial influence on the percentage of motor units that could be uniquely identified in the simulated EMG. For example, a single monopolar channel could discriminate only 3.4% of motor units in the simulated population, whereas a system with 81 Laplacian channels arranged in a grid could discriminate 83.8% of the motor units under the same conditions. The simulation results were confirmed with populations of motor units recorded experimentally from the abductor digiti minimi muscle of eight healthy men. Furthermore, the relative proportion of uniquely identified motor units in the simulated signal was only moderately related to motor-unit size and distance from the electrodes. These results indicate the upper limit for detection of individual motor units from the surface EMG and show that a few channels of surface EMG recordings are not sufficient to study single motor units. The noninvasive identification of motor units from the surface EMG requires the use of multiple channels of information.

Noxious Lingual Stimulation Influences the Excitability of the Face Primary Motor Cerebral Cortex (Face MI) in the Rat

Adachi, K., Murray, G. M., Lee, J.-C., Sessle, B. J. — 2008-09-08

The mechanisms whereby orofacial pain affects motor function are poorly understood. The aims were to determine whether 1) lingual algesic chemical stimulation affected face primary motor cerebral cortex (face MI) excitability defined by intracortical microstimulation (ICMS); and 2) any such effects were limited to the motor efferent MI zones driving muscles in the vicinity of the noxious stimulus. Ketamine-anesthetized Sprague–Dawley male rats were implanted with electromyographic (EMG) electrodes into anterior digastric, masseter, and genioglossus muscles. In 38 rats, three microelectrodes were located in left face MI at ICMS-defined sites for evoking digastric and/or genioglossus responses. ICMS thresholds for evoking EMG activity from each site were determined every 15 min for 1 h, then the right anterior tongue was infused (20 µl, 120 µl/h) with glutamate (1.0 M, n = 18) or isotonic saline (n = 7). Subsequently, ICMS thresholds were determined every 15 min for 4 h. In intact control rats (n = 13), ICMS thresholds were recorded over 5 h. Only left and right genioglossus ICMS thresholds were significantly increased (≤350%) in the glutamate infusion group compared with intact and isotonic saline groups (P < 0.05). These dramatic effects of glutamate on ICMS-evoked genioglossus activity contrast with its weak effects only on right genioglossus activity evoked from the internal capsule or hypoglossal nucleus. This is the first documentation that intraoral noxious stimulation results in prolonged neuroplastic changes manifested as a decrease in face MI excitability. These changes appear to occur predominantly in those parts of face MI that provide motor output to the orofacial region receiving the noxious stimulation.

Superior Colliculus Control of Vibrissa Movements

Hemelt, M. E., Keller, A. — 2008-09-08

This study tested the role of the superior colliculus in generating movements of the mystacial vibrissae—whisking. First, we compared the kinematics of whisking generated by the superior colliculus with those generated by the motor cortex. We found that in anesthetized rats, microstimulation of the colliculus evoked a sustained vibrissa protraction, whereas stimulation of motor cortex produced rhythmic protractions. Movements generated by the superior colliculus are independent of motor cortex and can be evoked at lower thresholds and shorter latencies than those generated by the motor cortex. Next we tested the hypothesis that the colliculus is acting as a simple reflex loop with the neurons that drive vibrissa movement receiving sensory input evoked by vibrissa contacts. We found that most tecto-facial neurons do not receive sensory input. Not only did these neurons not spike in response to sensory stimulation, but field potential analysis revealed that subthreshold sensory inputs do not overlap spatially with tecto-facial neurons. Together these findings suggest that the superior colliculus plays a pivotal role in vibrissa movement—regulating vibrissa set point and whisk amplitude—but does not function as a simple reflex loop. With the motor cortex controlling the whisking frequency, the superior colliculus control of set point and amplitude would account for the main parameters of voluntary whisking.

Short-Term Synaptic Depression and Recovery at the Mature Mammalian Endbulb of Held Synapse in Mice

Wang, Y., Manis, P. B. — 2008-09-08

The endbulb of Held synapses between the auditory nerve fibers (ANF) and cochlear nucleus bushy neurons convey fine temporal information embedded in the incoming acoustic signal. The dynamics of synaptic depression and recovery is a key in regulating synaptic transmission at the endbulb synapse. We studied short-term synaptic depression and recovery in mature (P22-38) CBA mice with stimulation rates that were comparable to sound-driven activities recorded in vivo. Synaptic depression in mature mice is less severe (~40% at 100 Hz) than reported for immature animals and the depression is predominately due to depletion of releasable vesicles. Recovery from depression depends on the rate of activity and accumulation of intracellular Ca²⁺ at the presynaptic terminal. With a regular stimulus train at 100 Hz in 2 mM external [Ca²⁺], the recovery from depletion was slow (_slow, ~2 s). In contrast, a fast (_fast, ~25 ms), Ca²⁺-dependent recovery followed by a slower recovery (_slow, ~2 s) was seen when stimulus rates or external [Ca²⁺] increased. In normal [Ca²⁺], recovery from a 100-Hz Poisson-like train is rapid, suggesting that Poisson-like trains produce a higher internal [Ca²⁺] than regular trains. Moreover, the fast recovery was slowed by approximately twofold in the presence of calmidazolium, a Ca²⁺/calmodulin inhibitor. Our results suggest that endbulb synapses from high spontaneous firing rate auditory nerve fibers normally operate in a depressed state. The accelerated synaptic recovery during high rates of activity is likely to ensure that reliable synaptic transmission can be achieved at the endbulb synapse.

A Novel Type of Auditory Responses: Temporal Dynamics of 40-Hz Steady-State Responses Induced by Changes in Sound Localization

Ross, B. — 2008-09-08

Magnetoencephalographic responses to 40-Hz amplitude-modulated tones of 4-s duration were recorded in young, middle-aged, and older healthy participants. Interaural phase difference (IPD) in the sound carrier was changed during stimulus presentation from 0 to 180°, resulting in perceptual change from focal to spacious sound. The stimulus modulation elicited synchronized gamma-band oscillations, the 40-Hz auditory steady-state response (ASSR). Equivalent current dipoles were localized in primary auditory cortices. Waveforms of cortical activity showed a decrement in ASSR amplitude 100 ms after stimulus IPD change and modification of ASSR phase, which was maximally 90°, corresponding to 6-ms delay. Time courses of ASSR phase deviation constituted a novel auditory response. The amount of ASSR phase change decreased with increasing stimulus frequency and revealed upper limits for physiological IPD detection. Thresholds for IPD detection were found close to 1,500 Hz in the young, around 1,250 Hz in the middle-aged group, and around 1,000 Hz in the older group. Whereas the ASSR change response revealed aging-related decline of binaural hearing, the amplitude of 40-Hz response and the size of the ASSR change response were not affected by aging. Additional ASSR change responses were recorded at a high rate of stimulus changes every 400 ms. ASSR response detection at this rate was superior to response detection based on the auditory-evoked P1–N1–P2 response. Responses to changes from focal to spacious sound were larger than those in the reverse direction. The ASSRs were interpreted in relation to oscillatory gamma-band activity representing auditory object representation.

Control of Neuronal Persistent Activity by Voltage-Dependent Dendritic Properties

Idoux, E., Eugene, D., Chambaz, A., Magnani, C., White, J. A., Moore, L. E. — 2008-09-08

Neural integrators and working memory rely on persistent activity, a widespread neural phenomenon potentially involving persistent sodium conductances. Using a unique combination of voltage-clamp, dynamic-clamp, and frequency-domain techniques, we have investigated the role of voltage-dependent conductances on the dendritic electrotonic structure of neurons of the prepositus hypoglossi nucleus (PHN), which is known to be involved in oculomotor integration. The PHN contains two main neuronal populations: type B neurons with a double afterhyperpolarization and type D neurons, which not only are oscillatory but also have a greater electrotonic length than that of type B neurons. The persistent sodium conductance is present in all PHN neurons, although its effect on the dynamic electrotonic structure is shown to significantly differ in the two major cell types present in the nucleus. The electrotonic differences are such that the persistent sodium conductance can be almost perfectly manipulated in a type B neuron using an on-line dynamic clamp to add or subtract virtual sodium ion channels. The dynamic-clamp results are confirmed by data-fitted models, which suggest that the persistent sodium conductance has two different roles depending on its somatic versus dendritic location: perisomatic conductances could play a major role in maintaining action potential discharge and dendritic conductances would be more involved in other computational properties, such as those involving remote synaptic processing or bistable events.

Smooth Pursuit Eye Movements to Isoluminant Targets

2008-09-08

At slow speeds, chromatic isoluminant stimuli are perceived to move much slower than comparable luminance stimuli. We investigated whether smooth pursuit eye movements to isoluminant stimuli show an analogous slowing. Beside pursuit speed and latency, we studied speed judgments to the same stimuli during fixation and pursuit. Stimuli were either large sine wave gratings or small Gaussians blobs moving horizontally at speeds between 1 and 11°/s. Targets were defined by luminance contrast or color. Confirming prior studies, we found that speed judgments of isoluminant stimuli during fixation showed a substantial slowing when compared with luminance stimuli. A similarly strong and significant effect of isoluminance was found for pursuit initiation: compared with luminance targets of matched contrasts, latencies of pursuit initiation were delayed by 50 ms at all speeds and eye accelerations were reduced for isoluminant targets. A small difference was found between steady-state eye velocities of luminance and isoluminant targets. For comparison, we measured latencies of saccades to luminance and isoluminant stimuli under similar conditions, but the effect of isoluminance was only found for pursuit. Parallel psychophysical experiments revealed that different from speed judgments of moving isoluminant stimuli made during fixation, judgments during pursuit are veridical for the same stimuli at all speeds. Therefore information about target speed seems to be available for pursuit eye movements and speed judgments during pursuit but is degraded for perceptual speed judgments during fixation and for pursuit initiation.

Pitch Representations in the Auditory Nerve: Two Concurrent Complex Tones

Larsen, E., Cedolin, L., Delgutte, B. — 2008-09-08

Pitch differences between concurrent sounds are important cues used in auditory scene analysis and also play a major role in music perception. To investigate the neural codes underlying these perceptual abilities, we recorded from single fibers in the cat auditory nerve in response to two concurrent harmonic complex tones with missing fundamentals and equal-amplitude harmonics. We investigated the efficacy of rate-place and interspike-interval codes to represent both pitches of the two tones, which had fundamental frequency (F0) ratios of 15/14 or 11/9. We relied on the principle of scaling invariance in cochlear mechanics to infer the spatiotemporal response patterns to a given stimulus from a series of measurements made in a single fiber as a function of F0. Templates created by a peripheral auditory model were used to estimate the F0s of double complex tones from the inferred distribution of firing rate along the tonotopic axis. This rate-place representation was accurate for F0s 900 Hz. Surprisingly, rate-based F0 estimates were accurate even when the two-tone mixture contained no resolved harmonics, so long as some harmonics were resolved prior to mixing. We also extended methods used previously for single complex tones to estimate the F0s of concurrent complex tones from interspike-interval distributions pooled over the tonotopic axis. The interval-based representation was accurate for F0s 900 Hz, where the two-tone mixture contained no resolved harmonics. Together, the rate-place and interval-based representations allow accurate pitch perception for concurrent sounds over the entire range of human voice and cat vocalizations.

Doing Without Learning: Stimulation of the Frontal Eye Fields and Floccular Complex Does Not Instruct Motor Learning in Smooth Pursuit Eye Movements

Heuer, H. W., Tokiyama, S., Lisberger, S. G. — 2008-09-08

Under natural conditions, motor learning is instructed by sensory feedback. We have asked whether sensory signals that indicate motor errors are necessary to instruct learning or if the motor signals related to movements normally driven by sensory error signals would be sufficient. We measured eye movements in trained rhesus monkeys while employing electrical microstimulation of the floccular complex of the cerebellum and the smooth eye movement region of the frontal eye fields to alter ongoing pursuit eye movements. Repeated electrical stimulation at fixed times after the onset of target motion and pursuit failed to cause any learning that was retained beyond the time period used to instruct learning. Learning was not uncovered when the target was stabilized with respect to the moving eye to prevent competition between instructive signals created by electrical stimulation and visual image motion signals evoked when stimulation drove the eye away from the tracking target. We suggest that signals emanating from motor-related structures in the pursuit circuit do not instruct learning. Instead, instructive sensory error signals seem to be necessary.

A Neural Correlate of Motivational Conflict in the Superior Colliculus of the Macaque

Isoda, M., Hikosaka, O. — 2008-09-08

Behavior is controlled by both external instructions and internal motives, but the actions demanded by each may be different. A common consequence of such a conflict is a delay in decision making and subsequent motor responses. It is unknown, however, what neural mechanisms underlie motivational conflict and associated response delay. To answer this question, we recorded single-neuron activity in the superior colliculus (SC) as macaque monkeys performed a visually guided, asymmetrically rewarded saccade task. A peripheral spot of light at one of two opposing positions was illuminated to indicate a saccade target. In a given block of trials, one position was associated with a big reward and the other with a small reward. The big-reward position was alternated across blocks. Behavioral analyses revealed that small-reward trials created a conflict between the instructed saccade to one position and the internally motivated, yet invalid saccade to the opposite position. We found that movement neurons in the SC temporally exhibited bursting activity after the appearance of the small-reward target opposite their movement field. This transient activity predicted the amount of response delay for upcoming saccades. Our data suggest that motivational conflict activates movement neurons in both colliculi, thereby delaying saccade initiation through intercollicular inhibitory interactions.

Diencephalic Locomotor Region in the Lamprey--Afferents and Efferent Control

Menard, A., Grillner, S. — 2008-09-08

In vertebrates, locomotion can be initiated by stimulation of the diencephalic locomotor region (DLR). Little is known of the different forebrain regions that provide input to the neurons in DLR. In the lamprey, it had been shown previously that DLR provides monosynaptic input to reticulospinal neurons, which in turn elicit rhythmic ventral root activity at the spinal level. To show that actual locomotor movements are produced from DLR, we use a semi-intact preparation in which the brain stem is exposed and the head fixed, while the body is left to generate actual swimming movements. DLR stimulation induced symmetric locomotor movements with an undulatory wave transmitted along the body. To explore if DLR is under tonic GABAergic input under resting conditions, as in mammals, GABAergic antagonists and agonists were locally administered into DLR. Injections of GABA agonists inhibited locomotion, whereas GABA antagonists facilitated the induction of locomotion. These findings suggest that GABAergic projections provide tonic inhibition that once turned off can release locomotion. Double-labeling experiments were carried out to identify GABAergic projections to the DLR. Populations of GABAergic projection neurons to DLR originated in the caudoventral portion of the medial pallium, the lateral and dorsal pallium, and the striatal area. These different GABAergic projection neurons, which also project to other brain stem motor centers, may represent the basal ganglia output to DLR. Moreover, electrical stimulation of striatum induced long-lasting plateau potentials in reticulospinal cells and associated locomotor episodes dependent on DLR being intact, suggesting that striatum may act via the basal ganglia output identified here.

Using a Model to Assess the Role of the Spatiotemporal Pattern of Inhibitory Input and Intrasegmental Electrical Coupling in the Intersegmental and Side-to-Side Coordination of Motor Neurons by the Leech Heartbeat Central Pattern Generator

Garcia, P. S., Wright, T. M., Cunningham, I. R., Calabrese, R. L. — 2008-09-08

Previously we presented a quantitative description of the spatiotemporal pattern of inhibitory synaptic input from the heartbeat central pattern generator (CPG) to segmental motor neurons that drive heartbeat in the medicinal leech and the resultant coordination of CPG interneurons and motor neurons. To begin elucidating the mechanisms of coordination, we explore intersegmental and side-to-side coordination in an ensemble model of all heart motor neurons and their known synaptic inputs and electrical coupling. Model motor neuron intrinsic properties were kept simple, enabling us to determine the extent to which input and electrical coupling acting together can account for observed coordination in the living system in the absence of a substantive contribution from the motor neurons themselves. The living system produces an asymmetric motor pattern: motor neurons on one side fire nearly in synchrony (synchronous), whereas on the other they fire in a rear-to-front progression (peristaltic). The model reproduces the general trends of intersegmental and side-to-side phase relations among motor neurons, but the match with the living system is not quantitatively accurate. Thus realistic (experimentally determined) inputs do not produce similarly realistic output in our model, suggesting that motor neuron intrinsic properties may contribute to their coordination. By varying parameters that determine electrical coupling, conduction delays, intraburst synaptic plasticity, and motor neuron excitability, we show that the most important determinant of intersegmental and side-to-side phase relations in the model was the spatiotemporal pattern of synaptic inputs, although phasing was influenced significantly by electrical coupling.

Metamorphosis-Induced Changes in the Coupling of Spinal Thoraco-Lumbar Motor Outputs During Swimming in Xenopus laevis

Beyeler, A., Metais, C., Combes, D., Simmers, J., Le Ray, D. — 2008-09-08

Anuran metamorphosis includes a complete remodeling of the animal's biomechanical apparatus, requiring a corresponding functional reorganization of underlying central neural circuitry. This involves changes that must occur in the coordination between the motor outputs of different spinal segments to harmonize locomotor and postural functions as the limbs grow and the tail regresses. In premetamorphic Xenopus laevis tadpoles, axial motor output drives rostrocaudally propagating segmental myotomal contractions that generate propulsive body undulations. During metamorphosis, the anterior axial musculature of the tadpole progressively evolves into dorsal muscles in the postmetamorphic froglet in which some of these back muscles lose their implicit locomotor function to serve exclusively in postural control in the adult. To understand how locomotor and postural systems interact during locomotion in juvenile Xenopus, we have investigated the coordination between postural back and hindlimb muscle activity during free forward swimming. Axial/dorsal muscles, which contract in bilateral alternation during undulatory swimming in premetamorphic tadpoles, change their left-right coordination to become activated in phase with bilaterally synchronous hindlimb extensions in locomoting juveniles. Based on in vitro electrophysiological experiments as well as specific spinal lesions in vivo, a spinal cord region was delimited in which propriospinal interactions are directly responsible for the coordination between leg and back muscle contractions. Our findings therefore indicate that dynamic postural adjustments during adult Xenopus locomotion are mediated by local intraspinal pathways through which the lumbar generator for hindlimb propulsive kicking provides caudorostral commands to thoracic spinal circuitry controlling the dorsal trunk musculature.

Tone-Specific and Nonspecific Plasticity of the Auditory Cortex Elicited by Pseudoconditioning: Role of Acetylcholine Receptors and the Somatosensory Cortex

Ji, W., Suga, N. — 2008-09-08

Experience-dependent plastic changes in the central sensory systems are due to activation of both the sensory and neuromodulatory systems. Nonspecific changes of cortical auditory neurons elicited by pseudoconditioning are quite different from tone-specific changes of the neurons elicited by auditory fear conditioning. Therefore the neural circuit evoking the nonspecific changes must also be different from that evoking the tone-specific changes. We first examined changes in the response properties of cortical auditory neurons of the big brown bat elicited by pseudoconditioning with unpaired tonal (CS_u) and electric leg (US_u) stimuli and found that it elicited nonspecific changes to CS_u (a heart-rate decrease, an auditory response increase, a broadening of frequency tuning, and a decrease in threshold) and, in addition, a small tone-specific change to CS_u (a small short-lasting best-frequency shift) only when CS_u frequency was 5 kHz lower than the best frequency of a recorded neuron. We then examined the effects of drugs on the cortical changes elicited by the pseudoconditioning. The development of the nonspecific changes was scarcely affected by atropine (a muscarinic cholinergic receptor antagonist) and mecamylamine (a nicotinic cholinergic receptor antagonist) applied to the auditory cortex and by muscimol (a GABA_A-receptor agonist) applied to the somatosensory cortex. However, these drugs abolished the small short-lasting tone-specific change as they abolished the large long-lasting tone-specific change elicited by auditory fear conditioning. Our current results indicate that, different from the tone-specific change, the nonspecific changes depend on neither the cholinergic neuromodulator nor the somatosensory cortex.

Choosing Where to Attend and the Medial Frontal Cortex: An fMRI Study

Taylor, P. C. J., Rushworth, M. F. S., Nobre, A. C. — 2008-09-08

To investigate how we orient our spatial attention, previous studies have recorded neural activity while participants are instructed where to attend. Here we contrast this classical instructed attention condition with a novel condition in which the focus of voluntary attention is not specified by the experimenter but rather is freely chosen by the participant. Central cues prompted fixating participants either to choose which of two peripheral spatial locations to covertly attend or formed an instruction. Either type of cueing initiated selective attention demonstrated behaviorally by enhanced performance at a visual detection task in comparison to a separate divided attention condition. We used functional magnetic resonance imaging to measure which areas were more active during choice than instruction. Choosing where to attend activated a large cluster of medial frontal cortical regions similar to those that have been previously implicated in the free selection of overt action. We then addressed a potential confound in contrasting choice with instruction: participants may remember their behavior more when choosing. In a separate block, and interleaved with choice trials, "memory" trials were introduced in which participants were instructed to remember where they had attended on the previous trial. The presupplementary eye fields and lateral frontal eye fields were specialized for choice-guided attentional orienting over and above any memory confound. This evidence suggests a common mechanism may underlie free selection, whether for covert attention or overt saccades.

Dynamic Population Coding of Category Information in Inferior Temporal and Prefrontal Cortex

Meyers, E. M., Freedman, D. J., Kreiman, G., Miller, E. K., Poggio, T. — 2008-09-08

Most electrophysiology studies analyze the activity of each neuron separately. While such studies have given much insight into properties of the visual system, they have also potentially overlooked important aspects of information coded in changing patterns of activity that are distributed over larger populations of neurons. In this work, we apply a population decoding method to better estimate what information is available in neuronal ensembles and how this information is coded in dynamic patterns of neural activity in data recorded from inferior temporal cortex (ITC) and prefrontal cortex (PFC) as macaque monkeys engaged in a delayed match-to-category task. Analyses of activity patterns in ITC and PFC revealed that both areas contain "abstract" category information (i.e., category information that is not directly correlated with properties of the stimuli); however, in general, PFC has more task-relevant information, and ITC has more detailed visual information. Analyses examining how information coded in these areas show that almost all category information is available in a small fraction of the neurons in the population. Most remarkably, our results also show that category information is coded by a nonstationary pattern of activity that changes over the course of a trial with individual neurons containing information on much shorter time scales than the population as a whole.

Coupling Specificity of NOP Opioid Receptors to Pertussis-Toxin-Sensitive G{alpha} Proteins in Adult Rat Stellate Ganglion Neurons Using Small Interference RNA

Margas, W., Sedeek, K., Ruiz-Velasco, V. — 2008-09-08

The opioid receptor-like 1 (NOP or ORL1) receptor is a G-protein-coupled receptor the endogenous ligand of which is the heptadecapeptide, nociceptin (Noc). NOP receptors are known to modulate pain processing at spinal, supraspinal, and peripheral levels. Previous work has demonstrated that NOP receptors inhibit N-type Ca²⁺ channel currents in rat sympathetic stellate ganglion (SG) neurons via pertussis toxin (PTX)-sensitive G_i/o subunits. However, the identification of the specific G subunit that mediates the Ca²⁺ current modulation is unknown. The purpose of the present study was to examine coupling specificity of Noc-activated NOP receptors to N-type Ca²⁺ channels in SG neurons. Small interference RNA (siRNA) transfection was employed to block the expression of PTX-sensitive G subunits. RT-PCR results showed that siRNA specifically decreased the expression of the intended G subunit. Evaluation of cell surface protein expression and Ca²⁺ channel modulation were assessed by immunofluorescence staining and electrophysiological recordings, respectively. Furthermore, the presence of mRNA of the intended siRNA target G protein was examined by RT-PCR experiments. Fluorescence imaging showed that G_i1, G_i3, and G_o were expressed in SG neurons. The transfection of G_i1-specific siRNA resulted in a significant decrease in Noc-mediated Ca²⁺ current inhibition, while silencing of either G_i3 or G_o was without effect. Taken together, these results suggest that in SG neurons G_i1 subunits selectively couple NOP receptors to N-type Ca²⁺ channels.

Modulation of Phasic and Tonic Muscle Synergies With Reaching Direction and Speed

d'Avella, A., Fernandez, L., Portone, A., Lacquaniti, F. — 2008-09-08

How the CNS masters the many degrees of freedom of the musculoskeletal system to control goal-directed movements is a long-standing question. We have recently provided support to the hypothesis that the CNS relies on a modular control architecture by showing that the phasic muscle patterns for fast reaching movements in different directions are generated by combinations of a few time-varying muscle synergies: coordinated recruitment of groups of muscles with specific activation profiles. However, natural reaching movements occur at different speeds and require the control of both movement and posture. Thus we have investigated whether muscle synergies also underlie reaching at different speeds as well as the maintenance of stable arm postures. Hand kinematics and shoulder and elbow muscle surface EMGs were recorded in five subjects during reaches to eight targets in the frontal plane at different speeds. We found that the amplitude modulation of three time-invariant synergies captured the variations in the postural muscle patterns at the end of the movement. During movement, three phasic and three tonic time-varying synergies could reconstruct the time-normalized muscle pattern in all conditions. Phasic synergies were modulated in both amplitude and timing by direction and speed. Tonic synergies were modulated only in amplitude by direction. The directional tuning of both types of synergies was well described by a single or a double cosine function. These results suggest that muscle synergies are basic control modules that allow generating the appropriate muscle patterns through simple modulation and combination rules.

Reach Adaptation: What Determines Whether We Learn an Internal Model of the Tool or Adapt the Model of Our Arm?

Kluzik, J., Diedrichsen, J., Shadmehr, R., Bastian, A. J. — 2008-09-08

We make errors when learning to use a new tool. However, the cause of error may be ambiguous: is it because we misestimated properties of the tool or of our own arm? We considered a well-studied adaptation task in which people made goal-directed reaching movements while holding the handle of a robotic arm. The robot produced viscous forces that perturbed reach trajectories. As reaching improved with practice, did people recalibrate an internal model of their arm, or did they build an internal model of the novel tool (robot), or both? What factors influenced how the brain solved this credit assignment problem? To investigate these questions, we compared transfer of adaptation between three conditions: catch trials in which robot forces were turned off unannounced, robot-null trials in which subjects were told that forces were turned off, and free-space trials in which subjects still held the handle but watched as it was detached from the robot. Transfer to free space was 40% of that observed in unannounced catch trials. We next hypothesized that transfer to free space might increase if the training field changed gradually, rather than abruptly. Indeed, this method increased transfer to free space from 40 to 60%. Therefore although practice with a novel tool resulted in formation of an internal model of the tool, it also appeared to produce a transient change in the internal model of the subject's arm. Gradual changes in the tool's dynamics increased the extent to which the nervous system recalibrated the model of the subject's own arm.

Neuromusculoskeletal Torque-Generation Process Has a Large Destabilizing Effect on the Control Mechanism of Quiet Standing

Masani, K., Vette, A. H., Kawashima, N., Popovic, M. R. — 2008-09-08

The delay of the sensory-motor feedback loop is a destabilizing factor within the neural control mechanism of quiet standing. The purposes of this study were 1) to experimentally identify the neuromusculoskeletal torque-generation process during standing posture and 2) to investigate the effect of the delay induced by this system on the control mechanism of balance during quiet standing. Ten healthy adults participated in this study. The ankle torque, ankle angle, and electromyograms from the right lower leg muscles were measured. A ground-fixed support device was used to support the subject at his/her knees, without changing the natural ankle angle during quiet standing. Each subject was asked to mimic the ankle torque fluctuation by exerting voluntary ankle extension while keeping the supported standing posture. Using the rectified soleus electromyogram as the input and the ankle torque as the output, a critically damped, second-order system (twitch contraction time of 0.152 ± 0.027 s) successfully described the dynamics of the torque-generation process. According to the performed Bode analysis, the phase delay induced by this torque-generation process in the frequency region of spontaneous body sway during quiet standing was considerably large, corresponding to an effective time delay of about 200 to 380 ms. We compared the stability of the balance control system with and without the torque-generation process and demonstrated that a much smaller number of gain combinations can stabilize the model with the torque-generation process than without it. We concluded that the phase delay induced by the torque-generation process is a more destabilizing factor in the control mechanism of quiet standing than previously assumed, which restricts the control strategies that can stabilize the entire system.

Postnatal Development of Onset Transient Responses in Macaque V1 and V2 Neurons

Zhang, B., Smith, E. L., Chino, Y. M. — 2008-09-08

Vision of newborn infants is limited by immaturities in their visual brain. In adult primates, the transient onset discharges of visual cortical neurons are thought to be intimately involved with capturing the rapid succession of brief images in visual scenes. Here we sought to determine the responsiveness and quality of transient responses in individual neurons of the primary visual cortex (V1) and visual area 2 (V2) of infant monkeys. We show that the transient component of neuronal firing to 640-ms stationary gratings was as robust and as reliable as in adults only 2 wk after birth, whereas the sustained component was more sluggish in infants than in adults. Thus the cortical circuitry supporting onset transient responses is functionally mature near birth, and our findings predict that neonates, known for their "impoverished vision," are capable of initiating relatively mature fixating eye movements and of performing in detection of simple objects far better than traditionally thought.

Canal and Otolith Contributions to Compensatory Tilt Responses in Pigeons

McArthur, K. L., Dickman, J. D. — 2008-09-08

Gaze-stabilizing eye and head responses compensate more effectively for low-frequency rotational motion when such motion stimulates the otolith organs, as during earth-horizontal axis rotations. However, the nature of the otolith signal responsible for this improvement in performance has not been previously determined. In this study, we used combinations of earth-horizontal axis rotational and translational motion to manipulate the magnitude of net linear acceleration experienced by pigeons, under both head-fixed and head-free conditions. We show that phase enhancement of eye and head responses to low-frequency rotational motion was causally related to the magnitude of dynamic net linear acceleration and not the gravitational acceleration component. We also show that canal-driven and otolith-driven eye responses were both spatially and temporally appropriate to combine linearly, and that a simple linear model combining canal- and otolith-driven components predicted eye responses to complex motion that were consistent with our experimental observations. However, the same model did not predict the observed head responses, which were spatially but not temporally appropriate to combine according to the same linear scheme. These results suggest that distinct vestibular processing substrates exist for eye and head responses in pigeons and that these are likely different from the vestibular processing substrates observed in primates.

Early and Late Changes in the Distal Forelimb Representation of the Supplementary Motor Area After Injury to Frontal Motor Areas in the Squirrel Monkey

2008-09-08

Neuroimaging studies in stroke survivors have suggested that adaptive plasticity occurs following stroke. However, the complex temporal dynamics of neural reorganization after injury make the interpretation of functional imaging studies equivocal. In the present study in adult squirrel monkeys, intracortical microstimulation (ICMS) techniques were used to monitor changes in representational maps of the distal forelimb in the supplementary motor area (SMA) after a unilateral ischemic infarct of primary motor (M1) and premotor distal forelimb representations (DFLs). In each animal, ICMS maps were derived at early (3 wk) and late (13 wk) postinfarct stages. Lesions resulted in severe deficits in motor abilities on a reach and retrieval task. Limited behavioral recovery occurred and plateaued at 3 wk postinfarct. At both early and late postinfarct stages, distal forelimb movements could still be evoked by ICMS in SMA at low current levels. However, the size of the SMA DFL changed after the infarct. In particular, wrist-forearm representations enlarged significantly between early and late stages, attaining a size substantially larger than the preinfarct area. At the late postinfarct stage, the expansion in the SMA DFL area was directly proportional to the absolute size of the lesion. The motor performance scores were positively correlated to the absolute size of the SMA DFL at the late postinfarct stage. Together, these data suggest that, at least in squirrel monkeys, descending output from M1 and dorsal and ventral premotor cortices is not necessary for SMA representations to be maintained and that SMA motor output maps undergo delayed increases in representational area after damage to other motor areas. Finally, the role of SMA in recovery of function after such lesions remains unclear because behavioral recovery appears to precede neurophysiological map changes.

Locomotor and Reflex Adaptation After Partial Denervation of Ankle Extensors in Chronic Spinal Cats

Frigon, A., Rossignol, S. — 2008-09-08

This work investigates the capacity of the spinal cord to generate locomotion after a complete spinal section and its ability to adapt its locomotor pattern after a peripheral nerve lesion. To study this intrinsic adaptive capacity, the left lateral gastrocnemius-soleus (LGS) nerve was sectioned in three cats that expressed a stable locomotion following a complete spinal transection. The electromyograph (EMG) of multiple hindlimb muscles and reflexes, evoked by stimulating the left tibial (Tib) nerve at the ankle, were recorded before and after denervation during treadmill locomotion. Following denervation, the mean amplitude of EMG bursts of multiple hindlimb muscles increased during locomotion, similar to what is found after an identical denervation in otherwise intact cats. Reflex changes were noted in ipsilateral flexors, such as semitendinosus and tibialis anterior, but not in the ipsilateral knee extensor vastus lateralis following denervation. The present results demonstrate that the spinal cord possesses the circuitry necessary to mediate increased EMG activity in multiple hindlimb muscles and also to produce changes in reflex pathways after a muscle denervation. The similarity of changes following LGS denervation in cats with an intact and transected spinal cord suggests that spinal mechanisms play a major role in the locomotor adaptation.

Synchronization of Neuronal Responses in Primary Visual Cortex of Monkeys Viewing Natural Images

Maldonado, P., Babul, C., Singer, W., Rodriguez, E., Berger, D., Grun, S. — 2008-09-08

When inspecting visual scenes, primates perform on average four saccadic eye movements per second, which implies that scene segmentation, feature binding, and identification of image components is accomplished in <200 ms. Thus individual neurons can contribute only a small number of discharges for these complex computations, suggesting that information is encoded not only in the discharge rate but also in the timing of action potentials. While monkeys inspected natural scenes we registered, with multielectrodes from primary visual cortex, the discharges of simultaneously recorded neurons. Relating these signals to eye movements revealed that discharge rates peaked around 90 ms after fixation onset and then decreased to near baseline levels within 200 ms. Unitary event analysis revealed that preceding this increase in firing there was an episode of enhanced response synchronization during which discharges of spatially distributed cells coincided within 5-ms windows significantly more often than predicted by the discharge rates. This episode started 30 ms after fixation onset and ended by the time discharge rates had reached their maximum. When the animals scanned a blank screen a small change in firing rate, but no excess synchronization, was observed. The short latency of the stimulation-related synchronization phenomena suggests a fast-acting mechanism for the coordination of spike timing that may contribute to the basic operations of scene segmentation.

Gaze Behavior When Reaching to Remembered Targets

Flanagan, J. R., Terao, Y., Johansson, R. S. — 2008-09-08

People naturally direct their gaze to visible hand movement goals. Doing so improves reach accuracy through use of signals related to gaze position and visual feedback of the hand. Here, we studied where people naturally look when acting on remembered target locations. Four targets were presented on a screen, in peripheral vision, while participants fixed a central cross (encoding phase). Four seconds later, participants used a pen to mark the remembered locations while free to look wherever they wished (recall phase). Visual references, including the screen and the cross, were present throughout. During recall, participants neither looked at the marked locations nor prevented eye movements. Instead, gaze behavior was erratic and was comprised of gaze shifts loosely coupled in time and space with hand movements. To examine whether eye and hand movements during encoding affected gaze behavior during recall, in additional encoding conditions, participants marked the visible targets with either free gaze or with central cross fixation or just looked at the targets. All encoding conditions yielded similar erratic gaze behavior during recall. Furthermore, encoding mode did not influence recall performance, suggesting that participants, during recall, did not exploit sensorimotor memories related to hand and gaze movements during encoding. Finally, we recorded a similar lose coupling between hand and eye movements during an object manipulation task performed in darkness after participants had viewed the task environment. We conclude that acting on remembered versus visible targets can engage fundamentally different control strategies, with gaze largely decoupled from movement goals during memory-guided actions.

Neuronal Responses to Moving Targets in Monkey Frontal Eye Fields

Cassanello, C. R., Nihalani, A. T., Ferrera, V. P. — 2008-09-08

Due to delays in visuomotor processing, eye movements directed toward moving targets must integrate both target position and velocity to be accurate. It is unknown where and how target velocity information is incorporated into the planning of rapid (saccadic) eye movements. We recorded the activity of neurons in frontal eye fields (FEFs) while monkeys made saccades to stationary and moving targets. A substantial fraction of FEF neurons was found to encode not only the initial position of a moving target, but the metrics (amplitude and direction) of the saccade needed to intercept the target. Many neurons also encoded target velocity in a nearly linear manner. The quasi-linear dependence of firing rate on target velocity means that the neuronal response can be directly read out to compute the future position of a target moving with constant velocity. This is demonstrated using a quantitative model in which saccade amplitude is encoded in the population response of neurons tuned to retinal target position and modulated by target velocity.

Specificity of Inferior Olive Response to Stimulus Timing

Liu, T., Xu, D., Ashe, J., Bushara, K. — 2008-09-08

The inferior olive is the sole source of the climbing fiber system, one of the two major afferent systems of the cerebellum; however, its exact role remains unknown. A longstanding hypothesis is that the inferior olive with its unique intrinsic rhythmic firing properties mediates motor timing. However, direct evidence linking the inferior olive to timing behavior has been difficult to demonstrate in animal or human studies likely due to the inhibition of inferior olive responses by self-produced movement. Here we used event-related functional magnetic resonance imaging (fMRI) and a perceptual task that dissociates the temporal from nontemporal attributes of sensory input. Subjects were asked to attend to rhythmically occurring identical visual stimuli and to detect a change in their timing, spatial orientation, or color. Inferior olive activation was seen only when perceiving a change in stimulus timing. These results are consistent with animal studies demonstrating that the inferior olive is especially sensitive to "unexpected" sensory events and further provide evidence supporting the specificity of the inferior olive response to stimulus timing. The results are consistent with the view that the inferior olive and the climbing fiber system mediate the encoding of temporal information required for both motor and nonmotor cognitive processes.

Effect of Synaptic Connectivity on Long-Range Synchronization of Fast Cortical Oscillations

Bazhenov, M., Rulkov, N. F., Timofeev, I. — 2008-09-08

Cortical gamma oscillations in the 20- to 80-Hz range are associated with attentiveness and sensory perception and have strong connections to both cognitive processing and temporal binding of sensory stimuli. These gamma oscillations become synchronized within a few milliseconds over distances spanning a few millimeters in spite of synaptic delays. In this study using in vivo recordings and large-scale cortical network models, we reveal a critical role played by the network geometry in achieving precise long-range synchronization in the gamma frequency band. Our results indicate that the presence of many independent synaptic pathways in a two-dimensional network facilitate precise phase synchronization of fast gamma band oscillations with nearly zero phase delays between remote network sites. These findings predict a common mechanism of precise oscillatory synchronization in neuronal networks.

Subthreshold Membrane-Potential Resonances Shape Spike-Train Patterns in the Entorhinal Cortex

Engel, T. A., Schimansky-Geier, L., Herz, A.V.M., Schreiber, S., Erchova, I. — 2008-09-08

Many neurons exhibit subthreshold membrane-potential resonances, such that the largest voltage responses occur at preferred stimulation frequencies. Because subthreshold resonances are known to influence the rhythmic activity at the network level, it is vital to understand how they affect spike generation on the single-cell level. We therefore investigated both resonant and nonresonant neurons of rat entorhinal cortex. A minimal resonate-and-fire type model based on measured physiological parameters captures fundamental properties of neuronal firing statistics surprisingly well and helps to shed light on the mechanisms that shape spike patterns: 1) subthreshold resonance together with a spike-induced reset of subthreshold oscillations leads to spike clustering and 2) spike-induced dynamics influence the fine structure of interspike interval (ISI) distributions and are responsible for ISI correlations appearing at higher firing rates (≥3 Hz). Both mechanisms are likely to account for the specific discharge characteristics of various cell types.

AMPA Receptor-Dependent H2O2 Generation in Striatal Medium Spiny Neurons But Not Dopamine Axons: One Source of a Retrograde Signal That Can Inhibit Dopamine Release

Avshalumov, M. V., Patel, J. C., Rice, M. E. — 2008-09-08

Dopamine-glutamate interactions in the striatum are critical for normal basal ganglia-mediated control of movement. Although regulation of glutamatergic transmission by dopamine is increasingly well understood, regulation of dopaminergic transmission by glutamate remains uncertain given the apparent absence of ionotropic glutamate receptors on dopaminergic axons in dorsal striatum. Indirect evidence suggests glutamatergic regulation of striatal dopamine release is mediated by a diffusible messenger, hydrogen peroxide (H₂O₂), generated downstream from glutamatergic AMPA receptors (AMPARs). The mechanism of H₂O₂-dependent inhibition of dopamine release involves activation of ATP-sensitive K⁺ (K_ATP) channels. However, the source of modulatory H₂O₂ is unknown. Here, we used whole cell recording, fluorescence imaging of H₂O₂, and voltammetric detection of evoked dopamine release in guinea pig striatal slices to examine contributions from medium spiny neurons (MSNs), the principal neurons of striatum, and dopamine axons to AMPAR-dependent H₂O₂ generation. Imaging studies of H₂O₂ generation in MSNs provide the first demonstration of AMPAR-dependent H₂O₂ generation in neurons in the complex brain-cell microenvironment of brain slices. Stimulation-induced increases in H₂O₂ in MSNs were prevented by GYKI-52466, an AMPAR antagonist, or catalase, an H₂O₂ metabolizing enzyme, but amplified by mercaptosuccinate (MCS), a glutathione peroxidase inhibitor. By contrast, dopamine release evoked by selective stimulation of dopamine axons was unaffected by GYKI-52466 or MCS, arguing against dopamine axons as a significant source of modulatory H₂O₂. Together, these findings suggest that glutamatergic regulation of dopamine release via AMPARs is mediated through retrograde signaling by diffusible H₂O₂ generated in striatal cells, including medium spiny neurons, rather than in dopamine axons.

The Representation of Amplitude Modulations in the Mammalian Auditory Midbrain

Krebs, B., Lesica, N. A., Grothe, B. — 2008-09-08

Temporal modulations in stimulus amplitude are essential for recognizing and categorizing behaviorally relevant acoustic signals such as speech. Despite this behavioral importance, it remains unclear how amplitude modulations (AMs) are represented in the responses of neurons at higher levels of the auditory system. Studies using stimuli with sinusoidal amplitude modulations (SAMs) have shown that the responses of many neurons are strongly tuned to modulation frequency, leading to the hypothesis that AMs are represented by their periodicity in the auditory midbrain. However, AMs in general are defined not only by their modulation frequency, but also by a number of other parameters (duration, duty cycle, etc.), which covary with modulation frequency in SAM stimuli. Thus the relationship between modulation frequency and neural responses as characterized with SAM stimuli alone is ambiguous. In this study, we characterize the representation of AMs in the gerbil inferior colliculus by analyzing neural responses to a series of pulse trains in which duration and interpulse interval are systematically varied to quantify the importance of duration, interpulse interval, duty cycle, and modulation frequency independently. We find that, although modulation frequency is indeed an important parameter for some neurons, the responses of many neurons are also strongly influenced by other AM parameters, typically duration and duty cycle. These results suggest that AMs are represented in the auditory midbrain not only by their periodicity, but by a complex combination of several important parameters.

Subcortical Interactions Between Somatosensory Stimuli of Different Modalities and Their Temporal Profile

Costa, J., Valls-Sole, J., Valldeoriola, F., Rumia, J. — 2008-09-08

Interactions between inputs of different sensory modality occur along the sensory pathway, including the thalamus. However, the temporal profile of such interaction has not been fully studied. In eight patients who had been implanted an intrathalamic electrode for deep brain stimulation as symptomatic treatment of tremor, we investigated the interactions between mechanical taps and electrical nerve stimuli. Somatosensory evoked potentials (SEPs) were recorded from Erb's point, cervical spinal cord, nucleus ventrointermedialis of the thalamus, and parietal cortex. A handheld electronic reflex hammer was used to deliver a mechanical tap to the skin overlying the first dorsal interosseous muscle and to trigger an ipsilateral digital median nerve electrical stimulus time-locked to the mechanical tap with a variable delay of 0 to 50 ms. There were significant time-dependent interactions between the two sensory volleys at the subcortical level. Thalamic SEPs were decreased in amplitude at interstimulus intervals (ISIs) from 10 to 40 ms with maximum effect at 20 ms (–42.8 ± 10.5%; P < 0.001). A similar decrease was also seen in the number and frequency of the high-frequency components of thalamic SEPs (–25 ± 4%). A smaller reduction (–18.1 ± 5.8%; P < 0.001) was present in upper cervical response at ISI = 20 ms. There were no changes in peripheral responses. Cortical SEPs were almost completely absent in some subjects at ISIs from 20 to 50 ms. There were no changes in SEP latencies. Our results indicate that significant time-dependent interactions between sensory volleys occur at the subcortical level. These observations provide further insight into the physiological mechanisms underlying afferent gating between sensory volleys of different modality.

Heterogeneous Neuronal Responses to Frequency-Modulated Tones in the Primary Auditory Cortex of Awake Cats

Qin, L., Wang, J., Sato, Y. — 2008-09-08

Previous studies in anesthetized animals reported that the primary auditory cortex (A1) showed homogenous phasic responses to FM tones, namely a transient response to a particular instantaneous frequency when FM sweeps traversed a neuron's tone-evoked receptive field (TRF). Here, in awake cats, we report that A1 cells exhibit heterogeneous FM responses, consisting of three patterns. The first is continuous firing when a slow FM sweep traverses the receptive field of a cell with a sustained tonal response. The duration and amplitude of FM response decrease with increasing sweep speed. The second pattern is transient firing corresponding to the cell's phasic tonal response. This response could be evoked only by a fast FM sweep through the cell's TRF, suggesting a preference for fast FM. The third pattern was associated with the off response to pure tones and was composed of several discrete response peaks during slow FM stimulus. These peaks were not predictable from the cell's tonal response but reliably reflected the time when FM swept across specific frequencies. Our A1 samples often exhibited a complex response pattern, combining two or three of the basic patterns above, resulting in a heterogeneous response population. The diversity of FM responses suggests that A1 use multiple mechanisms to fully represent the whole range of FM parameters, including frequency extent, sweep speed, and direction.

Endogenous Dopamine Suppresses Initiation of Swimming in Prefeeding Zebrafish Larvae

Thirumalai, V., Cline, H. T. — 2008-09-08

Dopamine is a key neuromodulator of locomotory circuits, yet the role that dopamine plays during development of these circuits is less well understood. Here, we describe a suppressive effect of dopamine on swim circuits in larval zebrafish. Zebrafish larvae exhibit marked changes in swimming behavior between 3 days postfertilization (dpf) and 5dpf. We found that swim episodes were fewer and of longer durations at 3 than at 5dpf. At 3dpf, application of dopamine as well as bupropion, a dopamine reuptake blocker, abolished spontaneous fictive swim episodes. Blocking D2 receptors increased frequency of occurrence of episodes and activation of adenylyl cyclase, a downstream target inhibited by D2-receptor signaling, blocked the inhibitory effect of dopamine. Dopamine had no effect on motor neuron firing properties, input impedance, resting membrane potential, or the amplitude of spike afterhyperpolarization. Application of dopamine either to the isolated spinal cord or locally within the cord does not decrease episode frequency, whereas dopamine application to the brain silences episodes, suggesting a supraspinal locus of dopaminergic action. Treating larvae with 10 µM MPTP reduced catecholaminergic innervation in the brain and increased episode frequency. These data indicate that dopamine inhibits the initiation of fictive swimming episodes at 3dpf. We found that at 5dpf, exogenously applied dopamine inhibits swim episodes, yet the dopamine reuptake blocker or the D2-receptor antagonist have no effect on episode frequency. These results led us to propose that endogenous dopamine release transiently suppresses swim circuits in developing zebrafish.

Neural Modulation by Regularity and Passage of Time

Correa, A., Nobre, A. C. — 2008-09-08

The current study tested whether multiple rhythms could flexibly induce temporal expectations (temporal orienting) and whether these expectations interact with temporal expectations associated with the passage of time (foreperiod effects). A visual stimulus that moved following a regular rhythm was temporarily occluded for a variable duration (occlusion foreperiod). The task involved making a speeded perceptual discrimination about the target stimulus that reappeared after the occlusion. Temporal-orienting effects were measured by comparing performance and event-related potentials on conditions in which the timing for target reappearance was predictable (valid) versus unpredictable (invalid) according to the rhythm. Foreperiod effects were measured by comparing conditions in which the target was occluded for progressively longer periods of time (short, medium, and long foreperiods) and hence were increasingly predictable. The results showed strong interactions between temporal orienting and foreperiod effects during the facilitation of behavior and neural activity associated with late perceptual and response selection processes. Temporal orienting attenuated the N2 amplitude and decreased the P3 latency only at short foreperiods. Temporal preparation related to foreperiod effects abolished temporal orienting effects at medium and long foreperiods. Likewise, foreperiod effects attenuated the N1 and N2 amplitudes and decreased the P3 latency only in the invalid orienting condition as preparation related to temporal orienting abolished foreperiod effects in the valid condition. This high degree of neural overlap between the effects of temporal orienting driven by rhythms and foreperiod effects associated with the passage of time suggests the involvement of a common mechanism for temporal preparation.

Serotonin 1B Receptor Modulates Frequency Response Curves and Spectral Integration in the Inferior Colliculus by Reducing GABAergic Inhibition

Hurley, L. M., Tracy, J. A., Bohorquez, A. — 2008-09-08

The selectivity of sensory neurons for stimuli is often shaped by a balance between excitatory and inhibitory inputs, making this balance an effective target for regulation. In the inferior colliculus (IC), an auditory midbrain nucleus, the amplitude and selectivity of frequency response curves are altered by the neuromodulator serotonin, but the changes in excitatory-inhibitory balance that mediate this plasticity are not well understood. Previous findings suggest that the presynaptic 5-HT1B receptor may act to decrease the release of GABA onto IC neurons. Here, in vivo extracellular recording and iontophoresis of the selective 5-HT1B agonist CP93129 were used to characterize inhibition within and surrounding frequency response curves using two-tone protocols to indirectly measure inhibition as a decrease in spikes relative to an excitatory tone alone. The 5-HT1B agonist attenuated such two-tone spike reduction in a varied pattern among neurons, suggesting that the function of 5-HT1B modulation also varies. The hypothesis that the 5-HT1B receptor reduces inhibition was tested by comparing the effects of CP93129 and the GABA_A antagonists bicuculline and gabazine in the same neurons. The effects of GABA_A antagonists on spike count, tuning bandwidth, two-tone ratio, and temporal response characteristics mimicked those of CP93129 across the neuron population. GABA_A antagonists also blocked or reduced the facilitation of evoked responses by CP93129. These results are all consistent with the reduction of GABA_A-mediated inhibition by 5-HT1B receptors in the IC, resulting in an increase in the level of evoked responses in some neurons, and a decrease in spectral selectivity in others.

Fast and Accurate Detection of Action Potentials From Somatic Calcium Fluctuations

Sasaki, T., Takahashi, N., Matsuki, N., Ikegaya, Y. — 2008-09-08

Large-scale recording from a population of neurons is a promising strategy for approaching the study of complex brain functions. Taking advantage of the fact that action potentials reliably evoke transient calcium fluctuations in the cell body, functional multineuron calcium imaging (fMCI) monitors the suprathreshold activity of hundreds of neurons. However, a limitation of fMCI is its semi-manual procedure of spike extraction from somatic calcium fluctuations, which is not only time consuming but is also associated with human errors. Here we describe a novel automatic method that combines principal-component analysis and support vector machine. This simple algorithm determines the timings of the spikes in calcium fluorescence traces more rapidly and reliably than human operators.

Neck Muscle Synergies During Stimulation and Inactivation of the Interstitial Nucleus of Cajal (INC)

Farshadmanesh, F., Chang, P., Wang, H., Yan, X., Corneil, B. D., Crawford, J. D. — 2008-09-08

The interstitial nucleus of Cajal (INC) is thought to control torsional and vertical head posture. Unilateral microstimulation of the INC evokes torsional head rotation to positions that are maintained until stimulation offset. Unilateral INC inactivation evokes head position-holding deficits with the head tilted in the opposite direction. However, the underlying muscle synergies for these opposite behavioral effects are unknown. Here, we examined neck muscle activity in head-unrestrained monkeys before and during stimulation (50 µA, 200 ms, 300 Hz) and inactivation (injection of 0.3 µl of 0.05% muscimol) of the same INC sites. Three-dimensional eye and head movements were recorded simultaneously with electromyographic (EMG) activity in six bilateral neck muscles: sternocleidomastoid (SCM), splenius capitis (SP), rectus capitis posterior major (RCPmaj.), occipital capitis inferior (OCI), complexus (COM), and biventer cervicis (BC). INC stimulation evoked a phasic, short-latency (~5–10 ms) facilitation and later (~100–200 ms) a more tonic facilitation in the activity of ipsi-SCM, ipsi-SP, ipsi-COM, ipsi-BC, contra-RCPmaj., and contra-OCI. Unilateral INC inactivation led to an increase in the activity of contra-SCM, ipsi-SP, ipsi-RCPmaj., and ipsi-OCI and a decrease in the activity of contra-RCPmaj. and contra-OCI. Thus the influence of INC stimulation and inactivation were opposite on some muscles (i.e., contra-OCI and contra-RCPmaj.), but the comparative influences on other neck muscles were more variable. These results show that the relationship between the neck muscle responses during INC stimulation and inactivation is much more complex than the relationship between the overt behaviors.

Adaptation of Orientation Vectors of Otolith-Related Central Vestibular Neurons to Gravity

Eron, J. N., Cohen, B., Raphan, T., Yakushin, S. B. — 2008-09-08

Behavioral experiments indicate that central pathways that process otolith-ocular and perceptual information have adaptive capabilities. Because polarization vectors of otolith afferents are directly related to the electro-mechanical properties of the hair cell bundle, it is unlikely that they change their direction of excitation. This indicates that the adaptation must take place in central pathways. Here we demonstrate for the first time that otolith polarization vectors of canal-otolith convergent neurons in the vestibular nuclei have adaptive capability. A total of 10 vestibular-only and vestibular-plus-saccade neurons were recorded extracellularly in two monkeys before and after they were in side-down positions for 2 h. The spatial characteristics of the otolith input were determined from the response vector orientation (RVO), which is the projection of the otolith polarization vector, onto the head horizontal plane. The RVOs had no specific orientation before animals were in side-down positions but moved toward the gravitational axis after the animals were tilted for extended periods. Vector reorientations varied from 0 to 109° and were linearly related to the original deviation of the RVOs from gravity in the position of adaptation. Such reorientation of central polarization vectors could provide the basis for changes in perception and eye movements related to prolonged head tilts relative to gravity or in microgravity.

Corrigendum

2008-09-08