Journal of Neurophysiology current issue

Dynamical Foundations of the Neural Circuit for Bayesian Decision Making

Morita, K. — 2009-06-29

On the basis of accumulating behavioral and neural evidences, it has recently been proposed that the brain neural circuits of humans and animals are equipped with several specific properties, which ensure that perceptual decision making implemented by the circuits can be nearly optimal in terms of Bayesian inference. Here, I introduce the basic ideas of such a proposal and discuss its implications from the standpoint of biophysical modeling developed in the framework of dynamical systems.

Touching Sounds: Thalamocortical Plasticity and the Neural Basis of Multisensory Integration

Naumer, M. J., van den Bosch, J. J. F. — 2009-06-29

To date, noninvasive neuroimaging research on multisensory perception has focused on cortical activations. In a series of elegant functional magnetic resonance imaging experiments, Beauchamp and Ro recently investigated altered cortical activations associated with acquired sound–touch synesthesia resulting from a thalamic lesion. Their findings highlight the important role of intact thalamocortical projections for preventing illusory crossmodal perception and for underlying reliable multisensory integration.

Identifying the Functional Role of Martinotti Cells in Cortical Sensory Processing

Cottam, J. C. H. — 2009-06-29

Inhibitory interneurons are highly diverse, although the functional significance of their diversity is not yet well understood. This presents a barrier to understanding neural computation at the local circuit level. This review focuses on a recent study by Murayama et al. who used a novel in vivo technique in neocortex to demonstrate a specific sensory processing function of dendritic-targeting Martinotti interneurons. The function of Martinotti cells arises from their interaction with layer 5 pyramidal cell dendrites.

Impaired Perception of Gravity Leads to Altered Head Direction Signals: What Can We Learn From Vestibular-Deficient Mice?

Beraneck, M., Lambert, F. M. — 2009-06-29

Many mutant mouse strains display pathological behaviors, such as head tilts, head bobbing, or circling and waltzing, strongly suggesting that their vestibular system is impaired. Recently, Yoder and Taube studied head direction signals in tilted mutant mice, which have an impaired gravitation sensitivity in the vestibular periphery. Here we summarize their findings and discuss a caveat related to the general use of mutant mouse strains in systems physiology.

Organization of Color-Selective Neurons in Macaque Visual Area V4

Kotake, Y., Morimoto, H., Okazaki, Y., Fujita, I., Tamura, H. — 2009-06-29

Cortical area V4 in monkeys contains neurons that respond selectively to particular colors. It has been controversial how these color-selective neurons are spatially organized in V4. One view asserts that color-selective neurons are organized in columns with different colors orderly mapped across the cortex, whereas other studies have found no evidence for columnar organization or any other clustered structure. In the present study, we reexamined the functional organization of color-selective neurons in area V4 by quantitatively evaluating and comparing the color selectivity of nearby neurons as well as those encountered along electrode penetrations. Using a multiple single-unit recording technique, we recorded extracellular activities simultaneously from groups of nearby V4 neurons. Color discrimination and color preferences exhibited a moderate correlation between nearby neurons, consistent with neurons in a local region of V4 sharing similar responses to stimulus color. However, the degree of clustering was variable across recording sites. Some regions contained neurons with similar color preferences, whereas others contained neurons with diverse color preferences. Neurons in penetrations normal to the cortical surface responded to an overlapping range of colors and maintained a moderate correlation. Neurons in penetrations tangential to the cortical surface differed dramatically in their preferred color and exhibited a negative correlation. We conclude that neurons in area V4 are moderately clustered according to their color selectivity and that this weak clustering is columnar in structure.

Dynamic Characterization of Agonist and Antagonist Oculomotoneurons During Conjugate and Disconjugate Eye Movements

Van Horn, M. R., Cullen, K. E. — 2009-06-29

In this report, we provide the first quantitative characterization of the relationship between the spike train dynamics of medial rectus oculomotoneurons (OMNs) and eye movements during conjugate and disconjugate saccades. We show that a simple, first-order model (i.e., containing eye position and velocity terms) provided an adequate model of neural discharges during both on and off-directed conjugate saccades, while a second-order model, which included a decaying slide term, significantly improved the ability to fit neuronal responses by ~10% (P < 0.05). To understand how the same neurons drove disconjugate eye movements, we evaluated whether sensitivities estimated during conjugate saccades could be used to predict responses during disconjugate saccades. For the majority of neurons (68%), a conjugate-based model failed, and instead neurons preferentially encoded the position and velocity of the ipsilateral eye. Similar to our previous results with abducens motoneurons, we also found that position and velocity sensitivities of OMNs decreased with increasing velocity, and the simulated population drive of OMNs during disconjugate saccades was less (~10%) than during conjugate saccades. Taken together, our results provide evidence that the activation of the antagonist, as well as agonist, motoneuron pools must be considered to understand the neural control of horizontal eye movements across different oculomotor behaviors. Moreover, we propose that the undersampling of smaller motoneurons (e.g., nontwitch) was likely to account for the missing drive observed during disconjugate saccades; these cells are thought to be more specialized for vergence movements and thus could provide the additional input required to command disconjugate eye movements.

Developmental Changes in Dendritic Shape and Synapse Location Tune Single-Neuron Computations to Changing Behavioral Functions

Meseke, M., Evers, J. F., Duch, C. — 2009-06-29

During nervous system development, different classes of neurons obtain different dendritic architectures, each of which receives a large number of input synapses. However, it is not clear whether synaptic inputs are targeted to specific regions within a dendritic tree and whether dendritic tree geometry and subdendritic synapse distributions might be optimized to support proper neuronal input-output computations. This study uses an insect model where structure and function of an individually identifiable neuron, motoneuron 5 (MN5), are changed while it develops from a slow larval crawling into a fast adult flight motoneuron during metamorphosis. This allows for relating postembryonic dendritic remodeling of an individual motoneuron to developmental changes in behavioral function. Dendritic architecture of MN5 is analyzed by three-dimensional geometric reconstructions and quantitative co-localization analysis to address the distribution of synaptic terminals. Postembryonic development of MN5 comprises distinct changes in dendritic shape and in the subdendritic distribution of GABAergic input synapses onto MN5. Subdendritic synapse targeting is not a consequence of neuropil structure but must rely on specific subdendritic recognition mechanisms. Passive multicompartment simulations indicate that postembryonic changes in dendritic architecture and in subdendritic input synapse distributions may tune the passive computational properties of MN5 toward stage-specific behavioral requirements.

Structured Variability of Muscle Activations Supports the Minimal Intervention Principle of Motor Control

Valero-Cuevas, F. J., Venkadesan, M., Todorov, E. — 2009-06-29

Numerous observations of structured motor variability indicate that the sensorimotor system preferentially controls task-relevant parameters while allowing task-irrelevant ones to fluctuate. Optimality models show that controlling a redundant musculo-skeletal system in this manner meets task demands while minimizing control effort. Although this line of inquiry has been very productive, the data are mostly behavioral with no direct physiological evidence on the level of muscle or neural activity. Furthermore, biomechanical coupling, signal-dependent noise, and alternative causes of trial-to-trial variability confound behavioral studies. Here we address those confounds and present evidence that the nervous system preferentially controls task-relevant parameters on the muscle level. We asked subjects to produce vertical fingertip force vectors of prescribed constant or time-varying magnitudes while maintaining a constant finger posture. We recorded intramuscular electromyograms (EMGs) simultaneously from all seven index finger muscles during this task. The experiment design and selective fine-wire muscle recordings allowed us to account for a median of 91% of the variance of fingertip forces given the EMG signals. By analyzing muscle coordination in the seven-dimensional EMG signal space, we find that variance-per-dimension is consistently smaller in the task-relevant subspace than in the task-irrelevant subspace. This first direct physiological evidence on the muscle level for preferential control of task-relevant parameters strongly suggest the use of a neural control strategy compatible with the principle of minimal intervention. Additionally, variance is nonnegligible in all seven dimensions, which is at odds with the view that muscle activation patterns are composed from a small number of synergies.

Predictions of Phase-Locking in Excitatory Hybrid Networks: Excitation Does Not Promote Phase-Locking in Pattern-Generating Networks as Reliably as Inhibition

Sieling, F. H., Canavier, C. C., Prinz, A. A. — 2009-06-29

Phase-locked activity is thought to underlie many high-level functions of the nervous system, the simplest of which are produced by central pattern generators (CPGs). It is not known whether we can define a theoretical framework that is sufficiently general to predict phase-locking in actual biological CPGs, nor is it known why the CPGs that have been characterized are dominated by inhibition. Previously, we applied a method based on phase response curves measured using inputs of biologically realistic amplitude and duration to predict the existence and stability of 1:1 phase-locked modes in hybrid networks of one biological and one model bursting neuron reciprocally connected with artificial inhibitory synapses. Here we extend this analysis to excitatory coupling. Using the pyloric dilator neuron from the stomatogastric ganglion of the American lobster as our biological cell, we experimentally prepared 86 networks using five biological neurons, four model neurons, and heterogeneous synapse strengths between 1 and 10,000 nS. In 77% of networks, our method was robust to biological noise and accurately predicted the phasic relationships. In 3%, our method was inaccurate. The remaining 20% were not amenable to analysis because our theoretical assumptions were violated. The high failure rate for excitation compared with inhibition was due to differential effects of noise and feedback on excitatory versus inhibitory coupling and suggests that CPGs dominated by excitatory synapses would require precise tuning to function, which may explain why CPGs rely primarily on inhibitory synapses.

Task-Dependent Modulation of Primary Afferent Depolarization in Cervical Spinal Cord of Monkeys Performing an Instructed Delay Task

Seki, K., Perlmutter, S. I., Fetz, E. E. — 2009-06-29

Task-dependent modulation of primary afferent depolarization (PAD) was studied in the cervical spinal cord of two monkeys performing a wrist flexion and extension task with an instructed delay period. We implanted two nerve cuff electrodes on proximal and distal parts of the superficial radial nerve (SR) and a recording chamber over a hemi-laminectomy in the lower cervical vertebrae. Antidromic volleys (ADVs) in the SR were evoked by intraspinal microstimuli (ISMS, 3–10 Hz, 3–30 µA) applied through a tungsten microelectrode, and the area of each ADV was measured. In total, 434 ADVs were evoked by ISMS in two monkeys, with onset latency consistently shorter in the proximal than distal cuffs. Estimated conduction velocity suggest that most ADVs were caused by action potentials in cutaneous fibers originating from low-threshold tactile receptors. Modulation of the size of ADVs as a function of the task was examined in 281 ADVs induced by ISMS applied at 78 different intraspinal sites. The ADVs were significantly facilitated during active movement in both flexion and extension (P < 0.05), suggesting an epoch-dependent modulation of PAD. This facilitation started 400–900 ms before the onset of EMG activity. Such pre-EMG modulation is hard to explain by movement-induced reafference and probably is associated with descending motor commands.

Dynamics of Input Patterns Modulate the Behavior of a Model of Olfactory Bulb Function

Kunsting, T., Spors, H. — 2009-06-29

Input patterns to the olfactory bulb are dynamic and change in an odor-specific manner as measured by selective calcium imaging of olfactory bulb input. To our knowledge, none of the published models of olfactory bulb function uses dynamic input patterns. Therefore we tested how dynamic input alters the behavior of a simple model consisting of two layers. The membrane potential of the first-layer neurons, integrate-and-fire neurons corresponding to mitral cells, was modulated with a subthreshold oscillation at respiration frequency. The membrane potential of the second-layer neurons was used to discriminate input patterns. We implemented oscillating input with amplitudes and latencies different for each mitral cell. Not only varying the input amplitudes but also de-synchronizing the input, and varying the relation between latency and input amplitude, individually changed the model's performance significantly. The discrimination time was affected more easily than the number of second-layer neurons that can differentiate an odor pair. Increasing the de-synchronization, i.e., the spread of latency values, reduced the differences in response time between strong and weak stimulus pairs without reducing the number of reacting cells. Input phase relative to the subthreshold oscillation altered the effect of de-synchronization. Thus dynamic input changes performance parameters of models of olfactory information processing that can be verified experimentally.

Dynamics of Smooth Pursuit Maintenance

Tavassoli, A., Ringach, D. L. — 2009-06-29

Smooth pursuit eye movements allow the approximate stabilization of a moving visual target on the retina. To study the dynamics of smooth pursuit, we measured eye velocity during the visual tracking of a Gabor target moving at a constant velocity plus a noisy perturbation term. The optimal linear filter linking fluctuations in target velocity to evoked fluctuations in eye velocity was computed. These filters predicted eye velocity to novel stimuli in the 0- to 15-Hz band with good accuracy, showing that pursuit maintenance is approximately linear under these conditions. The shape of the filters were indicative of fast dynamics, with pure delays of merely ~67 ms, times-to-peak of ~115 ms, and effective integration times of ~45 ms. The gain of the system, reflected in the amplitude of the filters, was inversely proportional to the size of the velocity fluctuations and independent of the target mean speed. A modest slow-down of the dynamics was observed as the contrast of the target decreased. Finally, the temporal filters recovered during fixation and pursuit were similar in shape, supporting the notion that they might share a common underlying circuitry. These findings show that the visual tracking of moving objects by the human eye includes a reflexive-like pathway with high contrast sensitivity and fast dynamics.

Impact of Persistent Cortical Activity (Up States) on Intracortical and Thalamocortical Synaptic Inputs

Rigas, P., Castro-Alamancos, M. A. — 2009-06-29

The neocortex generates short epochs of persistent activity called up states, which are associated with changes in cellular and network excitability. Using somatosensory thalamocortical slices, we studied the impact of persistent cortical activity during spontaneous up states on intrinsic cellular excitability (input resistance) and on excitatory synaptic inputs of cortical cells. At the intrinsic excitability level, we found that the expected decrease in input resistance (high conductance) resulting from synaptic barrages during up states is counteracted by an increase in input resistance due to depolarization per se. The result is a variable but on average relatively small reduction in input resistance during up states. At the synaptic level, up states enhanced a late synaptic component of short-latency thalamocortical field potential responses but suppressed intracortical field potential responses. The thalamocortical enhancement did not reflect an increase in synaptic strength, as determined by measuring the evoked postsynaptic current, but instead an increase in evoked action potential (spike) probability due to depolarization during up states. In contrast, the intracortical suppression was associated with a reduction in synaptic strength, apparently driven by increased presynaptic intracortical activity during up states. In addition, intracortical suppression also reflected a reduction in evoked spike latency caused by depolarization and the abolishment of longer-latency spikes caused by stronger inhibitory drive during up states. In conclusion, depolarization during up states increases the success of excitatory synaptic inputs to reach firing. However, activity-dependent synaptic depression caused by increased presynaptic firing during up states and the enhancement of evoked inhibitory drive caused by depolarization suppress excitatory intracortical synaptic inputs.

Signaling of Grasp Dimension and Grasp Force in Dorsal Premotor Cortex and Primary Motor Cortex Neurons During Reach to Grasp in the Monkey

Hendrix, C. M., Mason, C. R., Ebner, T. J. — 2009-06-29

A fundamental question is how the CNS controls the hand with its many degrees of freedom. Several motor cortical areas, including the dorsal premotor cortex (PMd) and primary motor cortex (M1), are involved in reach to grasp. Although neurons in PMd are known to modulate in relation to the type of grasp and neurons in M1 in relation to grasp force and finger movements, whether specific parameters of whole hand shaping are encoded in the discharge of these cells has not been studied. In this study, two monkeys were trained to reach and grasp 16 objects varying in shape, size, and orientation. Grasp force was explicitly controlled, requiring the monkeys to exert either three or five levels of grasp force on each object. The animals were unable to see the objects or their hands. Single PMd and M1 neurons were recorded during the task, and cell firing was examined for modulation with object properties and grasp force. The firing of the vast majority of PMd and M1 neurons varied significantly as a function of the object presented as well as the object grasp dimension. Grasp dimension of the object was an important determinant of the firing of cells in both PMd and M1. A smaller percentage of PMd and M1 neurons were modulated by grasp force. Linear encoding was prominent with grasp force but less so with grasp dimension. The correlations with grasp dimension and grasp force were stronger in the firing of M1 than PMd neurons and across both regions the modulation with these parameters increased as reach to grasp proceeded. All PMd and M1 neurons that signaled grasp force also signaled grasp dimension, yet the two signals showed limited interactions, providing a neural substrate for the independent control of these two parameters at the behavioral level.

Extrasynaptic Release of GABA by Retinal Dopaminergic Neurons

Hirasawa, H., Puopolo, M., Raviola, E. — 2009-06-29

GABA release by dopaminergic amacrine (DA) cells of the mouse retina was detected by measuring Cl^– currents generated by isolated perikarya in response to their own neurotransmitter. The possibility that the Cl^– currents were caused by GABA release from synaptic endings that had survived the dissociation of the retina was ruled out by examining confocal Z series of the surface of dissociated tyrosine hydroxylase-positive perikarya after staining with antibodies to preand postsynaptic markers. GABA release was caused by exocytosis because 1) the current events were transient on the millisecond time scale and thus resembled miniature synaptic currents; 2) they were abolished by treatment with a blocker of the vesicular proton pump, bafilomycin A1; and 3) their frequency was controlled by the intracellular Ca²⁺ concentration. Because DA cell perikarya do not contain presynaptic active zones, release was by necessity extrasynaptic. A range of depolarizing stimuli caused GABA exocytosis, showing that extrasynaptic release of GABA is controlled by DA cell electrical activity. With all modalities of stimulation, including long-lasting square pulses, segments of pacemaker activity delivered by the action-potential-clamp method and high-frequency trains of ramps, discharge of GABAergic currents exhibited considerable variability in latency and duration, suggesting that coupling between Ca²⁺ influx and transmitter exocytosis is extremely loose in comparison with the synapse. Paracrine signaling based on extrasynaptic release of GABA by DA cells and other GABAergic amacrines may participate in controlling the excitability of the neuronal processes that interact synaptically in the inner plexiform layer.

Asymmetric Activation of Motor Cortex Controlling Human Anterior Digastric Muscles During Speech and Target-Directed Jaw Movements

2009-06-29

Like most of the cranial muscles involved in speech, the trigeminally innervated anterior digastric muscles are controlled by descending corticobulbar projections from the primary motor cortex (M1) of each hemisphere. We hypothesized that changes in corticobulbar M1 excitability during speech production would show a hemispheric asymmetry favoring the left side, which is the dominant hemisphere for language processing in most strongly right handed subjects. Fifteen volunteers aged 24.5 ± 5.3 (SD) yr participated. All subjects were strongly right handed as reported by questionnaire. A surface electromyograph (EMG) was recorded bilaterally from digastrics and jaw movement detected by an accelerometer attached to a lower incisor. Focal transcranial magnetic stimulation (TMS) was used to assess corticomotor excitability of the digastric representation in M1 of both hemispheres during four tasks: 1) static isometric contraction of digastrics; 2) speaking a single word; 3) visually guided, nonspeech jaw movement that matched the jaw kinematics recorded during task 2; and 4) reciting a sentence. Background EMG was well matched in all tasks and jaw kinematics were similar around the time of the TMS pulse for tasks 2–4. TMS resting thresholds and digastric muscle-evoked potential (MEP) size during isometric contraction did not differ for TMS over left versus right M1. MEPs elicited by TMS over left, but not right M1 increased in size during speech and nonspeech jaw movement compared with isometric contraction. We conclude that left corticobulbar M1 is preferentially engaged for descending control of digastric muscles during speech and the performance of a rapid jaw movement to match a target kinematic profile.

Temporal Features of Spectral Integration in the Inferior Colliculus: Effects of Stimulus Duration and Rise Time

Gans, D., Sheykholeslami, K., Peterson, D. C., Wenstrup, J. — 2009-06-29

This report examines temporal features of facilitation and suppression that underlie spectrally integrative responses to complex vocal signals. Auditory responses were recorded from 160 neurons in the inferior colliculus (IC) of awake mustached bats. Sixty-two neurons showed combination-sensitive facilitation: responses to best frequency (BF) signals were facilitated by well-timed signals at least an octave lower in frequency, in the range 16–31 kHz. Temporal features and strength of facilitation were generally unaffected by changes in duration of facilitating signals from 4 to 31 ms. Changes in stimulus rise time from 0.5 to 5.0 ms had little effect on facilitatory strength. These results suggest that low frequency facilitating inputs to high BF neurons have phasic-on temporal patterns and are responsive to stimulus rise times over the tested range. We also recorded from 98 neurons showing low-frequency (11–32 kHz) suppression of higher BF responses. Effects of changing duration were related to the frequency of suppressive signals. Signals <23 kHz usually evoked suppression sustained throughout signal duration. This and other features of such suppression are consistent with a cochlear origin that results in masking of responses to higher, near-BF signal frequencies. Signals in the 23- to 30-kHz range—frequencies in the first sonar harmonic—generally evoked phasic suppression of BF responses. This may result from neural inhibitory interactions within and below IC. In many neurons, we observed two or more forms of the spectral interactions described here. Thus IC neurons display temporally and spectrally complex responses to sound that result from multiple spectral interactions at different levels of the ascending auditory pathway.

Zona Incerta: A Role in Central Pain

2009-06-29

Central pain syndrome (CPS) is a debilitating condition that affects a large number of patients with a primary lesion or dysfunction in the CNS. Despite its discovery over a century ago, the pathophysiological processes underlying the development and maintenance of CPS are poorly understood. We recently demonstrated that activity in the posterior thalamus (PO) is tightly regulated by inhibitory inputs from zona incerta (ZI). Here we test the hypothesis that CPS is associated with abnormal inhibitory regulation of PO by ZI. We recorded single units from ZI and PO in animals with CPS resulting from spinal cord lesions. Consistent with our hypothesis, the spontaneous firing rate and somatosensory evoked responses of ZI neurons were lower in lesioned animals compared with sham-operated controls. In PO, neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses to noxious and innocuous stimuli applied to the hindpaw and to the face. These changes were not associated with increased afferent drive from the spinal trigeminal nucleus or changes in the ventroposterior thalamus. Thus CPS can result from suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus.

Group III Metabotropic Glutamate Receptors (mGluRs) Modulate Transmission of Gustatory Inputs in the Brain Stem

Hallock, R. M., Martyniuk, C. J., Finger, T. E. — 2009-06-29

Glutamate is the principal neurotransmitter at the primary sensory afferent synapse in the medulla for the taste system. At this synapse, glutamate activates N-methyl-d-aspartate (NMDA) and non-NMDA (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and kainate) ionotropic receptors to effect a response in the second-order neurons. The current experiment is the first to examine the role of metabotropic glutamate receptors (mGluRs) in the transmission of taste information. In an in vitro slice preparation of the primary vagal gustatory nucleus in goldfish, primary gustatory afferent fibers were stimulated electrically, whereas evoked dendritic field potentials were recorded in the sensory layers. Recordings were made before, during, and after bath application of mGluR agonists for various mGluR groups and subtypes. Whereas l-AP4, a group III agonist, reduced the field potential, group I and group II agonists had no effect. Furthermore, the selective mGluR4 agonist ACPT-III and mGluR8 agonist PPG were effective at reducing the field potential, whereas agonists selective for mGluR6 and 7 were not. MAP4, a group III mGluR antagonist, attenuated frequency-dependent depression, indicating that endogenous glutamate binds to presynaptic mGluRs under normal conditions. Furthermore, polymerase chain reaction showed that mRNA for mGluR4 and 8 is expressed in the vagal ganglia, a prerequisite if those receptors are expressed presynaptically in the vagal lobe. Collectively, these experiments indicate that mGluR4 and 8 are presynaptic at the primary gustatory afferent synapse and that their activation inhibits glutamatergic release.

Synergistic Roles of GABAA Receptors and SK Channels in Regulating Thalamocortical Oscillations

Kleiman-Weiner, M., Beenhakker, M. P., Segal, W. A., Huguenard, J. R. — 2009-06-29

Rhythmic oscillations throughout the cortex are observed during physiological and pathological states of the brain. The thalamus generates sleep spindle oscillations and spike-wave discharges characteristic of absence epilepsy. Much has been learned regarding the mechanisms underlying these oscillations from in vitro brain slice preparations. One widely used model to understand the epileptiform oscillations underlying absence epilepsy involves application of bicuculline methiodide (BMI) to brain slices containing the thalamus. BMI is a well-known GABA_A receptor blocker that has previously been discovered to also block small-conductance, calcium-activated potassium (SK) channels. Here we report that the robust epileptiform oscillations observed during BMI application rely synergistically on both GABA_A receptor and SK channel antagonism. Neither application of picrotoxin, a selective GABA_A receptor antagonist, nor application of apamin, a selective SK channel antagonist, alone yielded the highly synchronized, long-lasting oscillations comparable to those observed during BMI application. However, partial blockade of SK channels by subnanomolar concentrations of apamin combined with picrotoxin sufficiently replicated BMI oscillations. We found that, at the cellular level, apamin enhanced the intrinsic excitability of reticular nucleus (RT) neurons but had no effect on relay neurons. This work suggests that regulation of RT excitability by SK channels can influence the excitability of thalamocortical networks and may illuminate possible pharmacological treatments for absence epilepsy. Finally, our results suggest that changes in the intrinsic properties of individual neurons and changes at the circuit level can robustly modulate these oscillations.

Two Interacting Olfactory Transduction Mechanisms Have Linked Polarities and Dynamics in Drosophila melanogaster Antennal Basiconic Sensilla Neurons

Schuckel, J., Torkkeli, P. H., French, A. S. — 2009-06-29

We measured frequency response functions between concentrations of fruit odorants and individual action potentials in large basiconic sensilla of the Drosophila melanogaster antenna. A new method of randomly varying odorant concentration was combined with rapid, continuous measurement of concentration at the antenna by a miniature photoionization detector. All frequency responses decreased progressively at frequencies approaching 100 Hz, providing an upper limit for the dynamics of Drosophila olfaction. We found two distinct response patterns: excitatory band-pass frequency responses were seen with ethyl acetate, ethyl butyrate, and hexanol, whereas inhibitory low-pass responses were seen with methyl salicylate and phenylethyl acetate. Band-pass responses peaked at 1–10 Hz. Frequency responses could be well fitted by simple linear filter equations, and the fitted parameters were consistent within each of the two types of responses. Experiments with equal mixtures of excitatory and inhibitory odorants gave responses that were characteristic of the inhibitory components, indicating that interaction during transduction causes inhibitory odorants to suppress the responses to excitatory odorants. Plots of response amplitude versus odorant concentration indicated that the odorant concentrations used were within approximately linear regions of the dose response relationships. We also estimated linear information capacity from the coherence function of each recording. Although coherence was relatively high, indicating a large signal-to-noise ratio, information capacity for olfaction was much lower than comparable estimates for mechanotransduction or visual transduction because of the limited bandwidth of olfaction. These data offer new insights into transduction by primary chemoreceptors and place temporal constraints on Drosophila olfactory behavior.

Tolerance to Sedative/Hypnotic Actions of GABAergic Drugs Correlates With Tolerance to Potentiation of Extrasynaptic Tonic Currents of Alcohol-Dependent Rats

Liang, J., Spigelman, I., Olsen, R. W. — 2009-06-29

Alcohol tolerance resulting from chronic administration is well known to be accompanied by cross-tolerance to sedative/anesthetic drugs, especially those acting on the -aminobutyric acid type A receptors (GABA_ARs). Rats treated with chronic intermittent ethanol (CIE) show decreased function and altered pharmacology of GABA_ARs in hippocampal neurons, consistent with cell- and location-specific changes in GABA_AR subunit composition. We previously observed variably altered sensitivity to GABAergic drugs in vivo and in hippocampal neurons using whole cell patch-clamp recording in brain slices. Here, we examined additional clinical GABAergic drugs to correlate CIE-induced tolerance to potentiation of neuronal GABA_AR-mediated currents with tolerance of these agents to sedative/anesthetic effects in vivo. Typical of several drug classes and two cell types, in CA1 pyramidal neurons, the benzodiazepine diazepam doubled the total charge transfer (TCT) of miniature postsynaptic inhibitory currents (mIPSCs), whereas it quadrupled the TCT of tonic currents. CIE treatment altered these responses to variable extent, as it did to loss of righting reflex (LORR) induced by these same drugs: 90–95% tolerance to flurazepam, the neuroactive steroid alphaxalone, and ethanol; 30–40% to pentobarbital, etomidate, and the GABA agonist gaboxadol; and no tolerance to propofol. There was a strong correlation between tolerance in the LORR assay and tolerance to enhancement of tonic currents, but not mIPSCs. The striking correlation suggests that the sedative/anesthetic actions of GABAergic drugs may be mediated primarily via the potentiation of extrasynaptic GABA_ARs. This requires the reasonable assumption that the same types of GABA_ARs in other brain regions involved directly in hypnotic drug actions show similar tolerance.

The Role of The TRPV1 Endogenous Agonist N-Oleoyldopamine in Modulation of Nociceptive Signaling at the Spinal Cord Level

Spicarova, D., Palecek, J. — 2009-06-29

Transient receptor potential vanilloid (TRPV1) receptors are abundant in a subpopulation of primary sensory neurons that convey nociceptive information from the periphery to the spinal cord dorsal horn. The TRPV1 receptors are expressed on both the peripheral and central branches of these dorsal root ganglion (DRG) neurons and can be activated by capsaicin, heat, low pH, and also by recently described endogenous lipids. Using patch-clamp recordings from superficial dorsal horn (DH) neurons in acute spinal cord slices, the effect of application of the endogenous TRPV1 agonist N-oleoyldopamine (OLDA) on the frequency of miniature excitatory postsynaptic currents (mEPSCs) was evaluated. A high concentration OLDA (10 µM) solution was needed to increase the mEPSC frequency, whereas low concentration OLDA (0.2 µM) did not evoke any change under control conditions. The increase was blocked by the TRPV1 antagonists SB366791 or BCTC. Application of a low concentration of OLDA evoked an increase in mEPSC frequency after activation of protein kinase C by phorbol ester (PMA) and bradykinin or in slices from animals with peripheral inflammation. Increasing the bath temperature from 24 to 34°C enhanced the basal mEPSC frequency, but the magnitude of changes in the mEPSC frequency induced by OLDA administration was similar at both temperatures. Our results suggest that presumed endogenous agonists of TRPV1 receptors, like OLDA, could have a considerable impact on synaptic transmission in the spinal cord, especially when TRPV1 receptors are sensitized. Spinal TRPV1 receptors could play a pivotal role in modulation of nociceptive signaling in inflammatory pain.

Central Lateral Thalamic Neurons Receive Noxious Visceral Mechanical and Chemical Input in Rats

Ren, Y., Zhang, L., Lu, Y., Yang, H., Westlund, K. N. — 2009-06-29

Thalamic intralaminar and medial nuclei participate mainly in affective and motivational aspects of pain processing. Unique to the present study were identification and characterization of spontaneously active neurons in the central lateral nucleus (CL) of the intralaminar thalamus, which were found to respond only to viscerally evoked noxious stimuli in animals under pentobarbital anesthesia. Responses to noxious colorectal distention, intrapancreatic bradykinin, intraperitoneal dilute acetic acid, and greater splanchnic nerve electrical stimulation were characterized. Electrophysiological recordings revealed activity in most CL neurons (93%) was excited (69%) or inhibited (31%) in response to noxious visceral stimulation of visceral nerves. Expression of c-Fos observed in CL nucleus after intensive visceral stimulation confirmed the activation. However, excited CL neurons did not have somatic fields, except in 3 of 43 (7%) CL neurons tested for responses to somatic stimulation (innocuous brush and noxious pinch). Intrathecal administration of morphine significantly reduced the increased responses of CL neurons to colorectal and pancreatic stimuli and was naloxone reversible. High-level thoracic midline dorsal column (DC) myelotomy also dramatically reduced responses, identifying the DC as a major route of travel from the spinal cord for CL input, in addition to input traveling ventromedially in the spinothalamic tract identified anatomically in a previous study. Spinal cord and lower brain stem cells providing input to medial thalamus were mapped after stereotaxic injections of a retrograde dye. These data combined with our previous data suggest that the CL nucleus is an important component of a medial visceral nociceptive system that may mediate attentional, affective, endocrine, motor, and autonomic responses to noxious visceral stimuli.

Regulation of Cation Channel Voltage and Ca2+ Dependence by Multiple Modulators

Gardam, K. E., Magoski, N. S. — 2009-06-29

Ion channel regulation is key to controlling neuronal excitability. However, the extent that modulators and gating factors interact to regulate channels is less clear. For Aplysia, a nonselective cation channel plays an essential role in reproduction by driving an afterdischarge in the bag cell neurons to elicit egg-laying hormone secretion. We examined the regulation of cation channel voltage and Ca²⁺ dependence by protein kinase C (PKC) and inositol trisphosphate (IP₃)—two prominent afterdischarge signals. In excised, inside-out patches, the channel remained open longer and reopened more often with depolarization from –90 to +30 mV. As previously reported, PKC could closely associate with the channel and increase activity at –60 mV. We now show that, following the effects of PKC, voltage dependence was shifted to the left (essentially enhanced), particularly at more negative voltages. Conversely, the voltage dependence of channels lacking PKC was shifted to the right (essentially suppressed). Predictably, activity was increased at all Ca²⁺ concentrations following the effects of PKC; nevertheless, Ca²⁺ dependence was actually shifted to the right. Moreover, whereas IP₃ did not alter activity at –60 mV, it drastically shifted Ca²⁺ dependence to the right—an outcome largely reversed by PKC. With respect to the afterdischarge, these data suggest PKC initially upregulates the channel by direct gating and shifting voltage dependence to the left. Subsequently, PKC and IP₃ attenuate the channel by suppressing Ca²⁺ dependence. This ensures hormone delivery by allowing afterdischarge initiation and maintenance but also prevents interminable bursting. Similar regulatory interactions may be used by other neurons to achieve diverse outputs.

Cholecystokinin Excites Interneurons in Rat Basolateral Amygdala

Chung, L., Moore, S. D. — 2009-06-29

The amygdala formation is implicated in generation of emotional states such as anxiety and fear. Many substances that modulate neuronal activity in the amygdala alter anxiety. Cholecystokinin (CCK) is an endogenous neuropeptide that induces anxiety states in behavioral studies in both animals and humans. Using a brain slice preparation, we found that application of CCK increases inhibitory synaptic transmission measured in projection neurons of the basolateral amygdala. To determine the source of the increased inhibition we examined the direct effect of CCK on local interneurons in this region. CCK most strongly depolarized fast-spiking interneurons. Burst-firing and regular-firing interneurons were also depolarized, although to a lesser degree. However, another distinct group of interneurons was unaffected by CCK. These effects were mediated by the CCK_B receptor subtype. The excitatory effect of CCK appeared to be mediated by both a nonselective cation and a K⁺ current.

Loss of Potassium Homeostasis Underlies Hyperthermic Conduction Failure in Control and Preconditioned Locusts

Money, T. G. A., Rodgers, C. I., McGregor, S. M. K., Robertson, R. M. — 2009-06-29

At extreme temperature, neurons cease to function appropriately. Prior exposure to a heat stress (heat shock [HS]) can extend the temperature range for action potential conduction in the axon, but how this occurs is not well understood. Here we use electrophysiological recordings from the axon of a locust visual interneuron, the descending contralateral movement detector (DCMD), to examine what physiological changes result in conduction failure and what modifications allow for the observed plasticity following HS. We show that at high temperature, conduction failure in the DCMD occurred preferentially where the axon passes through the thoracic ganglia rather than in the connective. Although the membrane potential hyperpolarized with increasing temperature, we observed a modest depolarization (3–6 mV) in the period preceding the failure. Prior to the conduction block, action potential amplitude decreased and half-width increased. Both of these failure-associated effects were attenuated following HS. Extracellular potassium concentration ([K⁺]_o) increased sharply at failure and the failure event could be mimicked by the application of high [K⁺]_o. Surges in [K⁺]_o were muted following HS, suggesting that HS may act to stabilize ion distribution. Indeed, experimentally increased [K⁺]_o lowered failure temperature significantly more in control animals than in HS animals and experimentally maintained [K⁺]_o was found to be protective. We suggest that the more attenuated effects of failure on the membrane properties of the DCMD axon in HS animals is consistent with a decrease in the disruptive nature of the [K⁺]_o-dependent failure event following HS and thus represents an adaptive mechanism to cope with thermal stress.

Brain Polarization Enhances the Formation and Retention of Motor Memories

Galea, J. M., Celnik, P. — 2009-06-29

One of the first steps in the acquisition of a new motor skill is the formation of motor memories. Here we tested the capacity of transcranial DC stimulation (tDCS) applied over the motor cortex during motor practice to increase motor memory formation and retention. Nine healthy individuals underwent a crossover transcranial magnetic stimulation (TMS) study designed to test motor memory formation resulting from training. Anodal tDCS elicited an increase in the magnitude and duration of motor memories in a polarity-specific manner, as reflected by changes in the kinematic characteristics of TMS-evoked movements after anodal, but not cathodal or sham stimulation. This effect was present only when training and stimulation were associated and mediated by a differential modulation of corticomotor excitability of the involved muscles. These results indicate that anodal brain polarization can enhance the initial formation and retention of a new motor memory resulting from training. These processes may be the underlying mechanisms by which tDCS enhances motor learning.

Conceptual Binding: Integrated Visual Cues Reduce Processing Costs in Bimanual Movements

2009-06-29

In discrete reaction time (RT) tasks, it has been shown that nonsymmetric bimanual movements are initiated slower than symmetric movements in response to symbolic cues. By contrast, no such RT differences are found in response to direct cues ("direct cue effect"). Here, we report three experiments showing that the direct cue effect generalizes to rhythmical bimanual movements and that RT cost depends on different cue features: 1) symbolic versus direct or 2) integrated (i.e., action of both hands is indicated as one entity) versus dissociated (i.e., action of each hand is indicated separately). Our main finding was that dissociated symbolic cues were most likely processed serially, resulting in the longest RTs, which were substantially reduced with integrated symbolic cues. However, extra RT costs for switching to nonsymmetrical bimanual movements were overcome only when the integrated cues were direct. We conclude that computational resources might have been exceeded when the response needs to be determined for each hand separately, but not when a common response for both hands is selected. This supports the idea that bimanual control benefits from conceptual binding.

Proteinase-Activated Receptor-1 Activation Presynaptically Enhances Spontaneous Glutamatergic Excitatory Transmission in Adult Rat Substantia Gelatinosa Neurons

Fujita, T., Liu, T., Nakatsuka, T., Kumamoto, E. — 2009-06-29

Proteinase-activated receptors (PARs) have a unique activation mechanism in that a proteolytically exposed N-terminal region acts as a tethered ligand. A potential impact of PAR on sensory processing has not been fully examined yet. Here we report that synthetic peptides with sequences corresponding to PAR ligands enhance glutamatergic excitatory transmission in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using the whole cell patch-clamp technique. The frequency of spontaneous excitatory postsynaptic current (EPSC) was increased by PAR-1 agonist SFLLRN-NH₂ (by 47% at 1 µM) with small increases by PAR-2 and -4 agonists (SLIGKV-NH₂ and GYPGQV-OH, respectively; at >3 µM); there was no change in its amplitude or in holding current at –70 mV. The PAR-1 peptide action was inhibited by PAR-1 antagonist YFLLRNP-OH. TFLLR-NH₂, an agonist which is more selective to PAR-1 than SFLLRN-NH₂, dose-dependently increased spontaneous EPSC frequency (EC₅₀ = 0.32 µM). A similar presynaptic effect was produced by PAR-1 activating proteinase thrombin in a manner sensitive to YFLLRNP-OH. The PAR-1 peptide action was resistant to tetrodotoxin and inhibited in Ca²⁺-free solution. Primary-afferent monosynaptically evoked EPSC amplitudes were unaffected by PAR-1 agonist. These results indicate that PAR-1 activation increases the spontaneous release of l-glutamate onto SG neurons from nerve terminals in a manner dependent on extracellular Ca²⁺. Considering that sensory processing within the SG plays a pivotal role in regulating nociceptive transmission to the spinal dorsal horn, the PAR-1-mediated glutamatergic transmission enhancement could be involved in a positive modulation of nociceptive transmission.

Electrical Microstimulation of the Fastigial Oculomotor Region in the Head-Unrestrained Monkey

Quinet, J., Goffart, L. — 2009-06-29

It has been shown that inactivation of the caudal fastigial nucleus (cFN) by local injection of muscimol leads to inaccurate gaze shifts in the head-unrestrained monkey and that the gaze dysmetria is primarily due to changes in the horizontal amplitude of eye saccades in the orbit. Moreover, changes in the relationship between amplitude and duration are observed for only the eye saccades and not for the head movements. These results suggest that the cFN output primarily influences a neural network involved in moving the eyes in the orbit. The present study further tested this hypothesis by examining whether head movements could be evoked by electrical microstimulation of the saccade-related region in the cFN. Long stimulation trains (200–300 ms) evoked staircase gaze shifts that were ipsi- or contralateral, depending on the stimulated site. These gaze shifts were small in amplitude and were essentially accomplished by saccadic movements of the eyes. Head movements were observed in some sites but their amplitudes were very small (mean = 2.4°). The occurrence of head movements and their amplitude were not enhanced by increasing stimulation frequency or intensity. In several cases, electrically evoked gaze shifts exhibited an eye-head coupling that was different from that observed in visually triggered gaze shifts. This study provides additional observations suggesting that the saccade-related region in the cFN modulates the generation of eye movements and that the deep cerebellar output region involved in influencing head movements is located elsewhere.

Spinal 5-HT7 Receptors Are Critical for Alternating Activity During Locomotion: In Vitro Neonatal and In Vivo Adult Studies Using 5-HT7 Receptor Knockout Mice

Liu, J., Akay, T., Hedlund, P. B., Pearson, K. G., Jordan, L. M. — 2009-06-29

5-HT₇ receptors have been implicated in the control of locomotion. Here we use 5-HT₇ receptor knockout mice to rigorously test whether 5-HT acts at the 5-HT₇ receptor to control locomotor-like activity in the neonatal mouse spinal cord in vitro and voluntary locomotion in adult mice. We found that 5-HT applied onto in vitro spinal cords of 5-HT₇^+/+ mice produced locomotor-like activity that was disrupted and subsequently blocked by the 5-HT₇ receptor antagonist SB-269970. In spinal cords isolated from 5-HT₇^–/– mice, 5-HT produced either uncoordinated rhythmic activity or resulted in synchronous discharges of the ventral roots. SB-269970 had no effect on 5-HT-induced rhythmic activity in the 5-HT₇^–/– mice. In adult in vivo experiments, SB-269970 applied directly to the spinal cord consistently disrupted locomotion and produced prolonged-extension of the hindlimbs in 5-HT₇^+/+ but not 5-HT₇^–/– mice. Disrupted EMG activity produced by SB-269970 in vivo was similar to the uncoordinated rhythmic activity produced by the drug in vitro. Moreover, 5-HT₇^–/– mice displayed greater maximal extension at the hip and ankle joints than 5-HT₇^+/+ animals during voluntary locomotion. These results suggest that spinal 5-HT₇ receptors are required for the production and coordination of 5-HT-induced locomotor-like activity in the neonatal mouse and are important for the coordination of voluntary locomotion in adult mice. We conclude that spinal 5-HT₇ receptors are critical for alternating activity during locomotion.

Resolving Precise Temporal Processing Properties of the Auditory System Using Continuous Stimuli

Lalor, E. C., Power, A. J., Reilly, R. B., Foxe, J. J. — 2009-06-29

In natural environments complex and continuous auditory stimulation is virtually ubiquitous. The human auditory system has evolved to efficiently process an infinitude of everyday sounds, which range from short, simple bursts of noise to signals with a much higher order of information such as speech. Investigation of temporal processing in this system using the event-related potential (ERP) technique has led to great advances in our knowledge. However, this method is restricted by the need to present simple, discrete, repeated stimuli to obtain a useful response. Alternatively the continuous auditory steady-state response is used, although this method reduces the evoked response to its fundamental frequency component at the expense of useful information on the timing of response transmission through the auditory system. In this report, we describe a method for eliciting a novel ERP, which circumvents these limitations, known as the AESPA (auditory-evoked spread spectrum analysis). This method uses rapid amplitude modulation of audio carrier signals to estimate the impulse response of the auditory system. We show AESPA responses with high signal-to-noise ratios obtained using two types of carrier wave: a 1-kHz tone and broadband noise. To characterize these responses, they are compared with auditory-evoked potentials elicited using standard techniques. A number of similarities and differences between the responses are noted and these are discussed in light of the differing stimulation and analysis methods used. Data are presented that demonstrate the generalizability of the AESPA method and a number of applications are proposed.

What Response Properties Do Individual Neurons Need to Underlie Position and Clutter "Invariant" Object Recognition?

Li, N., Cox, D. D., Zoccolan, D., DiCarlo, J. J. — 2009-06-29

Primates can easily identify visual objects over large changes in retinal position—a property commonly referred to as position "invariance." This ability is widely assumed to depend on neurons in inferior temporal cortex (IT) that can respond selectively to isolated visual objects over similarly large ranges of retinal position. However, in the real world, objects rarely appear in isolation, and the interplay between position invariance and the representation of multiple objects (i.e., clutter) remains unresolved. At the heart of this issue is the intuition that the representations of nearby objects can interfere with one another and that the large receptive fields needed for position invariance can exacerbate this problem by increasing the range over which interference acts. Indeed, most IT neurons' responses are strongly affected by the presence of clutter. While external mechanisms (such as attention) are often invoked as a way out of the problem, we show (using recorded neuronal data and simulations) that the intrinsic properties of IT population responses, by themselves, can support object recognition in the face of limited clutter. Furthermore, we carried out extensive simulations of hypothetical neuronal populations to identify the essential individual-neuron ingredients of a good population representation. These simulations show that the crucial neuronal property to support recognition in clutter is not preservation of response magnitude, but preservation of each neuron's rank-order object preference under identity-preserving image transformations (e.g., clutter). Because IT neuronal responses often exhibit that response property, while neurons in earlier visual areas (e.g., V1) do not, we suggest that preserving the rank-order object preference regardless of clutter, rather than the response magnitude, more precisely describes the goal of individual neurons at the top of the ventral visual stream.

Comparison of Time-Frequency Responses and the Event-Related Potential to Auditory Speech Stimuli in Human Cortex

2009-06-29

We recorded the electrocorticogram directly from the exposed cortical surface of awake neurosurgical patients during the presentation of auditory syllable stimuli. All patients were unanesthetized as part of a language-mapping procedure for subsequent left-hemisphere tumor resection. Time–frequency analyses showed significant high-gamma (_high: 70–160 Hz) responses from the left superior temporal gyrus, but no reliable response from the left inferior frontal gyrus. Alpha suppression (: 7–14 Hz) and event-related potential responses exhibited a more widespread topography. Across electrodes, the suppression from 200 to 450 ms correlated with the preceding (50–200 ms) _high increase. The results are discussed in terms of the different physiological origins of these electrocortical signals.

Functional Phase Response Curves: A Method for Understanding Synchronization of Adapting Neurons

Cui, J., Canavier, C. C., Butera, R. J. — 2009-06-29

Phase response curves (PRCs) for a single neuron are often used to predict the synchrony of mutually coupled neurons. Previous theoretical work on pulse-coupled oscillators used single-pulse perturbations. We propose an alternate method in which functional PRCs (fPRCs) are generated using a train of pulses applied at a fixed delay after each spike, with the PRC measured when the phasic relationship between the stimulus and the subsequent spike in the neuron has converged. The essential information is the dependence of the recovery time from pulse onset until the next spike as a function of the delay between the previous spike and the onset of the applied pulse. Experimental fPRCs in Aplysia pacemaker neurons were different from single-pulse PRCs, principally due to adaptation. In the biological neuron, convergence to the fully adapted recovery interval was slower at some phases than that at others because the change in the effective intrinsic period due to adaptation changes the effective phase resetting in a way that opposes and slows the effects of adaptation. The fPRCs for two isolated adapting model neurons were used to predict the existence and stability of 1:1 phase-locked network activity when the two neurons were coupled. A stability criterion was derived by linearizing a coupled map based on the fPRC and the existence and stability criteria were successfully tested in two-simulated-neuron networks with reciprocal inhibition or excitation. The fPRC is the first PRC-based tool that can account for adaptation in analyzing networks of neural oscillators.

Multisensory Integration in Mesencephalic Trigeminal Neurons in Xenopus Tadpoles

Pratt, K. G., Aizenman, C. D. — 2009-06-29

Mesencephalic trigeminal (M-V) neurons are primary somatosensory neurons with somata located within the CNS, instead of in peripheral sensory ganglia. In amphibians, these unipolar cells are found within the optic tectum and have a single axon that runs along the mandibular branch of the trigeminal nerve. The axon has collaterals in the brain stem and is believed to make synaptic contact with neurons in the trigeminal motor nucleus, forming part of a sensorimotor loop. The number of M-V neurons is known to increase until metamorphosis and then decrease, suggesting that at least some M-V neurons may play a transient role during tadpole development. It is not known whether their location in the optic tectum allows them to process both visual and somatosensory information. Here we compare the anatomical and electrophysiological properties of M-V neurons in the Xenopus tadpole to principal tectal neurons. We find that, unlike principal tectal cells, M-V neurons can sustain repetitive spiking when depolarized and express a significant H-type current. M-V neurons could also be driven synaptically by visual input both in vitro and in vivo, but visual responses were smaller and longer-lasting than those seen in principal tectal neurons. We also found that the axon of M-V neurons appears to directly innervate a tentacle found in the corner of the mouth of premetamorphic tadpoles. Electrical stimulation of this transient sensory organ results in antidromic spiking in M-V neurons in the tectum. Thus M-V neurons may play an integrative multisensory role during tadpole development.

Eccentric Muscle Damage Has Variable Effects on Motor Unit Recruitment Thresholds and Discharge Patterns in Elbow Flexor Muscles

Dartnall, T. J., Rogasch, N. C., Nordstrom, M. A., Semmler, J. G. — 2009-06-29

The purpose of this study was to determine the effect of eccentric muscle damage on recruitment threshold force and repetitive discharge properties of low-threshold motor units. Ten subjects performed four tasks involving isometric contraction of elbow flexors while electromyographic (EMG) data were recorded from human biceps brachii and brachialis muscles. Tasks were 1) maximum voluntary contraction (MVC); 2) constant-force contraction at various submaximal targets; 3) motor unit recruitment threshold task; and 4) minimum motor unit discharge rate task. These tasks were performed on three separate days before, immediately after, and 24 h after eccentric exercise of elbow flexor muscles. MVC force declined (42%) immediately after exercise and remained depressed (29%) 24 h later, indicative of muscle damage. Mean motor unit recruitment threshold for biceps brachii was 8.4 ± 4.2% MVC, (n = 34) before eccentric exercise, and was reduced by 41% (5.0 ± 3.0% MVC, n = 34) immediately after and by 39% (5.2 ± 2.5% MVC, n = 34) 24 h after exercise. No significant changes in motor unit recruitment threshold were observed in the brachialis muscle. However, for the minimum tonic discharge rate task, motor units in both muscles discharged 11% faster (10.8 ± 2.0 vs. 9.7 ± 1.7 Hz) immediately after (n = 29) exercise compared with that before (n = 32). The minimum discharge rate variability was greater in brachialis muscle immediately after exercise (13.8 ± 3.1%) compared with that before (11.9 ± 3.1%) and 24 h after exercise (11.7 ± 2.4%). No significant changes in minimum discharge rate variability were observed in the biceps brachii motor units after exercise. These results indicate that muscle damage from eccentric exercise alters motor unit recruitment thresholds for ≥24 h, but the effect is not the same in the different elbow flexor muscles.

Heat-Induced Action Potential Discharges in Nociceptive Primary Sensory Neurons of Rats

Greffrath, W., Schwarz, S. T., Busselberg, D., Treede, R.-D. — 2009-06-29

Although several transducer molecules for noxious stimuli have been identified, little is known about the transformation of the resulting generator currents into action potentials (APs). Therefore we investigated the transformation process for stepped noxious heat stimuli (42–47°C, 3-s duration) into membrane potential changes and subsequent AP discharges using the somata of acutely dissociated small dorsal root ganglion (DRG) neurons (diameter ≤32.5 µm) of adult rats as a model for their own peripheral terminals. Three types of heat-induced membrane potential changes were differentiated: type 1, heat-induced AP discharges (~37% of the neurons); type 2, heat-induced membrane depolarization (40%); and type 3, responses not exceeding those of switching the superfusion (23%). Warming neurons from room temperature to 35°C increased their background conductance, nearly doubled the AP threshold current, and led to smaller and narrower APs. Adaptation of heat-induced AP discharges was seen in about half of the type 1 neurons. The remaining half displayed accelerating discharges to both heat stimuli and depolarizing current injection. Repeated heat stimulation induced marked suppression of AP discharges. Under rapid calcium buffering using BAPTA, repolarization of heat-induced APs stopped at a plateau potential slowly decreasing from +16.5 ± 2.9 to –2.2 ± 5.5 mV, resulting in no further AP discharges. This study demonstrates that heat-induced AP discharges can be elicited in the soma of a subgroup of DRG neurons. These discharges display suppression on repetitive stimulation, but either adaptation or sensitization during prolonged stimuli. AP threshold and AP shape during these discharges suggest temperature dependence of background conductance and repolarizing currents.

Influence of Subcortical Inhibition on Barrel Cortex Receptive Fields

Hirata, A., Aguilar, J., Castro-Alamancos, M. A. — 2009-06-29

Influence of subcortical inhibition on barrel cortex receptive fields. By the time neural responses driven by vibrissa stimuli reach the barrel cortex, they have undergone significant spatial and temporal transformations within subcortical relays. A major regulator of these transformations is thought to be subcortical GABA-mediated inhibition, but the actual degree of this influence is unknown. We used disinhibition produced by GABA receptor antagonists to unmask the excitatory sensory responses that are normally suppressed by inhibition in the main subcortical sensory relays to barrel cortex; principal trigeminal (Pr5) and primary thalamic (VPM) nuclei. We found that, within subcortical relays, inhibition only slightly suppresses short-latency receptive field responses, but robustly suppresses long-latency center and surround receptive field responses. However, the long-latency subcortical effects of inhibition are mostly not reflected in the barrel cortex. The most robust effect of subcortical inhibition on barrel cortex responses is to transiently suppress the receptive field responses of high-frequency sensory stimuli. This transient adaptation caused by subcortical inhibition recovers within a few stimuli and gives way to a steady-state adaptation that is independent of subcortical inhibition.

Recovery of Thumb and Finger Extension and Its Relation to Grasp Performance After Stroke

Lang, C. E., DeJong, S. L., Beebe, J. A. — 2009-06-29

This study investigated how the ability to extend the fingers and thumb recovers early after stroke and how the ability to extend all of the digits affects grasping performance. We studied 24 hemiparetic patients at 3 and 13 wk post stroke. At each visit, we tested the subjects' ability to actively extend all five digits of their contralesional, affected hand against gravity and to perform a grasp movement with the same hand. Three-dimensional motion analysis captured: 1) maximal voluntary extension excursion of each digit and 2) grasp performance variables of movement time, peak aperture, peak aperture rate, and aperture path ratio. We found that finger and thumb extension improved from 3 to 13 wk, with average improvements ranging from 12 to 19° across the five digits. Grasp performance improved on two of the four variables measured. Peak apertures and peak aperture rates improved from 3 to 13 wk, but self-selected movement time and aperture path ratio did not. Stepwise multiple regression models showed that the majority of variance in grasp performance at 13 wk could be predicted by the ability to extend the index or middle finger at 3 wk, plus the change in the ability to extend the index finger from 3 to 13 wk. R² values ranged from 0.55 to 0.89. Our data indicate that the amount of recovery in finger and thumb extension and grasping is small from 3 to 13 wk post stroke. In people with relatively pure motor hemiparesis, one important factor underlying deficits in hand shaping during grasping is the inability to extend the fingers and thumb. Without sufficient volitional control of finger and thumb extension, successful grasping of objects will not occur.

The Consequences of Short-Range Stiffness and Fluctuating Muscle Activity for Proprioception of Postural Joint Rotations: The Relevance to Human Standing

Loram, I. D., Lakie, M., Di Giulio, I., Maganaris, C. N. — 2009-06-29

Proprioception comes from muscles and tendons. Tendon compliance, muscle stiffness, and fluctuating activity complicate transduction of joint rotation to a proprioceptive signal. These problems are acute in postural regulation because of tiny joint rotations and substantial short-range muscle stiffness. When studying locomotion or perturbed balance these problems are less applicable. We recently measured short-range stiffness in standing and considered the implications for load stability. Here, using an appropriately simplified model we analyze the conversion of joint rotation to spindle input and tendon tension while considering the effect of short-range stiffness, tendon compliance, fluctuating muscle activity, and fusimotor activity. Basic principles determine that when muscle stiffness and tendon compliance are high, fluctuating muscle activity is the greatest factor confounding registration of postural movements, such as ankle rotations during standing. Passive and isoactive muscle, uncomplicated by active length fluctuations, enable much better registration of joint rotation and require fewer spindles. Short-range muscle stiffness is a degrading factor for spindle input and enhancing factor for Golgi input. Constant fusimotor activity does not enhance spindle registration of postural joint rotations in actively modulated muscle: spindle input remains more strongly associated with muscle activity than joint rotation. A hypothesized rigid – linkage could remove this association with activity but would require large numbers of spindles in active postural muscles. Using microneurography, the existence of a rigid – linkage could be identified from the correlation between spindle output and muscle activity. Basic principles predict a proprioceptive "dead zone" in the active agonist muscle that is related to the short-range muscle stiffness.

Neuronal Correlates of Instrumental Learning in the Dorsal Striatum

Kimchi, E. Y., Torregrossa, M. M., Taylor, J. R., Laubach, M. — 2009-06-29

We recorded neuronal activity simultaneously in the medial and lateral regions of the dorsal striatum as rats learned an operant task. The task involved making head entries into a response port followed by movements to collect rewards at an adjacent reward port. The availability of sucrose reward was signaled by an acoustic stimulus. During training, animals showed increased rates of responding and came to move rapidly and selectively, following the stimulus, from the response port to the reward port. Behavioral "devaluation" studies, pairing sucrose with lithium chloride, established that entries into the response port were habitual (insensitive to devaluation of sucrose) from early in training and entries into the reward port remained goal-directed (sensitive to devaluation) throughout training. Learning-related changes in behavior were paralleled by changes in neuronal activity in the dorsal striatum, with an increasing number of neurons showing task-related firing over the training period. Throughout training, we observed more task-related neurons in the lateral striatum compared with those in the medial striatum. Many of these neurons fired at higher rates during initiation of movements in the presence of the stimulus, compared with similar movements in the absence of the stimulus. Learning was also accompanied by progressive increases in movement-related potentials and transiently increased theta-band oscillations (5–8 Hz) in simultaneously recorded field potentials. Together, these data suggest that representations of task-relevant stimuli and movements develop in the dorsal striatum during instrumental learning.

Temporal Information Can Influence Spatial Localization

Maij, F., Brenner, E., Smeets, J. B. J. — 2009-06-29

To localize objects relative to ourselves, we need to combine various sensory and motor signals. When these signals change abruptly, as information about eye orientation does during saccades, small differences in latency between the signals could introduce localization errors. We examine whether independent temporal information can influence such errors. We asked participants to follow a randomly jumping dot with their eyes and to point at flashes that occurred near the time they made saccades. Such flashes are mislocalized. We presented a tone at different times relative to the flash. We found that the flash was mislocalized as if it had occurred closer in time to the tone. This demonstrates that temporal information is taken into consideration when combining sensory information streams for localization.

Contribution of Sensorimotor Integration to Spinal Stabilization in Humans

Goodworth, A. D., Peterka, R. J. — 2009-06-29

The control of upper body (UB) orientation relative to the pelvis in the frontal plane was characterized by analyzing responses to external perturbations consisting of continuous pelvis tilts (eyes open [EO] and eyes closed [EC]) and visual surround tilts (EO) at various amplitudes. Lateral sway of the lower body was prevented on all tests. UB sway was analyzed by calculating impulse–response functions (IRFs) and frequency–response functions (FRFs) from 0.023 to 10.3 Hz for pelvis tilt tests and FRFs from 0.041 to 1.5 Hz for visual tests. For pelvis tilt tests, differences between FRFs were limited to frequencies <3 Hz and were dependent on stimulus amplitude. IRFs were nearly identical across all pelvis tilt tests for the first 0.2 s, but showed amplitude-dependent changes in their time course at longer time lags. The availability of visual orientation cues (EO vs. EC) had only a small effect on the UB sway during pelvis tilt tests. This small effect of vision was consistent with the small UB sway evoked on visual tilt tests. Experimental results were interpreted using a feedback model of UB orientation control that included time-delayed sensory integration, short-latency reflexive mechanisms, and intrinsic biomechanical properties of the UB. Variation in model parameters indicated that subjects shifted toward reliance on vestibular information and away from proprioceptive information as pelvis tilt amplitudes increased. For visual tilt stimuli, model parameters indicated that subjects shifted toward reliance on vestibular and proprioceptive information and away from visual information as the stimulus amplitude increased.

Effect of Vergence on Human Ocular Following Response (OFR)

Joshi, A. C., Thurtell, M. J., Walker, M. F., Serra, A., Leigh, R. J. — 2009-06-29

The human ocular following response (OFR) is a preattentive, short-latency visual-field–holding mechanism, which is enhanced if the moving stimulus is applied in the wake of a saccade. Since most natural gaze shifts incorporate both saccadic and vergence components, we asked whether the OFR was also enhanced during vergence. Ten subjects viewed vertically moving sine-wave gratings on a video monitor at 45 cm that had a temporal frequency of 16.7 Hz, contrast of 32%, and spatial frequency of 0.17, 0.27, or 0.44 cycle/deg. In Fixation/OFR experiments, subjects fixed on a white central dot on the video monitor, which disappeared at the beginning of each trial, just as the sinusoidal grating started moving up or down. We measured the change in eye position in the 70- to 150-ms open-loop interval following stimulus onset. Group mean downward responses were larger (0.14°) and made at shorter latency (85 ms) than upward responses (0.10° and 96 ms). The direction of eye drifts during control trials, when gratings remained stationary, was unrelated to the prior response. During vergence/OFR experiments, subjects switched their fixation point between the white dot at 45 cm and a red spot at 15 cm, cued by the disappearance of one target and appearance of the other. When horizontal vergence velocity exceeded 15°/s, motion of sinusoidal gratings commenced and elicited the vertical OFR. Subjects showed significantly (P < 0.001) larger OFR when the moving stimulus was presented during convergence (group mean increase of 46%) or divergence (group mean increase of 36%) compared with following fixation. Since gaze shifts between near and far are common during natural activities, we postulate that the increase of OFR during vergence movements reflects enhancement of early cortical motion processing, which serves to stabilize the visual field as the eyes approach their new fixation point.

Impedance Control and Its Relation to Precision in Orofacial Movement

Laboissiere, R., Lametti, D. R., Ostry, D. J. — 2009-06-29

Speech production involves some of the most precise and finely timed patterns of human movement. Here, in the context of jaw movement in speech, we show that spatial precision in speech production is systematically associated with the regulation of impedance and in particular, with jaw stiffness—a measure of resistance to displacement. We estimated stiffness and also variability during movement using a robotic device to apply brief force pulses to the jaw. Estimates of stiffness were obtained using the perturbed position and force trajectory and an estimate of what the trajectory would be in the absence of load. We estimated this "reference trajectory" using a new technique based on Fourier analysis. A moving-average (MA) procedure was used to estimate stiffness by modeling restoring force as the moving average of previous jaw displacements. The stiffness matrix was obtained from the steady state of the MA model. We applied this technique to data from 31 subjects whose jaw movements were perturbed during speech utterances and kinematically matched nonspeech movements. We observed systematic differences in stiffness over the course of jaw-lowering and jaw-raising movements that were correlated with measures of kinematic variability. Jaw stiffness was high and variability was low early and late in the movement when the jaw was elevated. Stiffness was low and variability was high in the middle of movement when the jaw was lowered. Similar patterns were observed for speech and nonspeech conditions. The systematic relationship between stiffness and variability points to the idea that stiffness regulation is integral to the control of orofacial movement variability.

Sparse but Selective and Potent Synaptic Transmission From the Globus Pallidus to the Subthalamic Nucleus

2009-06-29

The reciprocally connected GABAergic globus pallidus (GP)-glutamatergic subthalamic nucleus (STN) network is critical for voluntary movement and an important site of dysfunction in movement disorders such as Parkinson's disease. Although the GP is a key determinant of STN activity, correlated GP-STN activity is rare under normal conditions. Here we define fundamental features of the GP-STN connection that contribute to poorly correlated GP-STN activity. Juxtacellular labeling of single GP neurons in vivo and stereological estimation of the total number of GABAergic GP-STN synapses suggest that the GP-STN connection is surprisingly sparse: single GP neurons maximally contact only 2% of STN neurons and single STN neurons maximally receive input from 2% of GP neurons. However, GP-STN connectivity may be considerably more selective than even these estimates imply. Light and electron microscopic analyses revealed that single GP axons give rise to sparsely distributed terminal clusters, many of which correspond to multiple synapses with individual STN neurons. Application of the minimal stimulation technique in brain slices confirmed that STN neurons receive multisynaptic unitary inputs and that these inputs largely arise from different sets of GABAergic axons. Finally, the dynamic-clamp technique was applied to quantify the impact of GP-STN inputs on STN activity. Small fractions of GP-STN input were sufficiently powerful to inhibit and synchronize the autonomous activity of STN neurons. Together these data are consistent with the conclusion that the rarity of correlated GP-STN activity in vivo is due to the sparsity and selectivity, rather than the potency, of GP-STN synaptic connections.

Characteristics of Rostral Solitary Tract Nucleus Neurons With Identified Afferent Connections That Project to the Parabrachial Nucleus in Rats

Suwabe, T., Bradley, R. M. — 2009-06-29

Afferent information derived from oral chemoreceptors is transmitted to second-order neurons in the rostral solitary tract nucleus (rNST) and then relayed to other CNS locations responsible for complex sensory and motor behaviors. Here we investigate the characteristics of rNST neurons sending information rostrally to the parabrachial nucleus (PBN). Afferent connections to these rNST-PBN projection neurons were identified by anterograde labeling of the chorda tympani (CT), glossopharyngeal (IX), and lingual (LV) nerves. We used voltage- and current-clamp recordings in brain slices to characterize the expression of both the transient A-type potassium current, I_KA and the hyperpolarization-activated inward current, I_h, important determinants of neuronal repetitive discharge characteristics. The majority of rNST-PBN neurons express I_KA, and these I_KA-expressing neurons predominate in CT and IX terminal fields but were expressed in approximately half of the neurons in the LV field. rNST-PBN neurons expressing I_h were evenly distributed among CT, IX and LV terminal fields. However, expression patterns of I_KA and I_h differed among CT, IX, and LV fields. I_KA-expressing neurons frequently coexpress I_h in CT and IX terminal fields, whereas neurons in LV terminal field often express only I_h. After GABA_A receptor block all rNST-PBN neurons responded to afferent stimulation with all-or-none excitatory synaptic responses. rNST-PBN neurons had either multipolar or elongate morphologies and were distributed throughout the rNST, but multipolar neurons were more often encountered in CT and IX terminal fields. No correlation was found between the biophysical and morphological characteristics of the rNST-PBN projection neurons in each terminal field.

A Code for Spatial Alternation During Fixation in Rat Hippocampal CA1 Neurons

Takahashi, M., Lauwereyns, J., Sakurai, Y., Tsukada, M. — 2009-06-29

The classical notion of hippocampal CA1 "place cells," whose activity tracks physical locations, has undergone substantial revision in recent years. Here, we provide further evidence of an abstract spatial code in hippocampal CA1, which relies on memory and adds complexity to the basic "place cell." Using a nose-poking paradigm with four male Wistar rats, we specifically concentrated on activity during fixation, when the rat was immobile and waiting for the next task event in a memory-guided spatial alternation task. The rat had to alternate between choosing the right and left holes on a trial-by-trial basis, without any sensory cue, and relying on an internal representation of the sequence of trials. Twelve tetrodes were chronically implanted for single-unit recording in the right CA1 of each rat. We focus on 76 single neurons that showed significant activation during the fixation period compared with baseline activity between trials. Among these 76 fixation neurons, we observed 38 neurons that systematically changed their fixation activity as a function of the alternation sequence. That is, even though these rats were immobile during the fixation period, the neurons fired differently for trials in which the next spatial choice should be left (i.e., RIGHT-TO-LEFT trials) compared with trials in which the next spatial choice should be right (i.e., LEFT-TO-RIGHT trials), or vice versa. Our results imply that these neurons maintain a sequential code of the required spatial response during the alternation task and thus provide abstract information, derived from memory, that can be used for efficient navigation.

Timing-Specific Transfer of Adapted Muscle Activity After Walking in an Elastic Force Field

Blanchette, A., Bouyer, L. J. — 2009-06-29

Human locomotion results from interactions between feedforward (central commands from voluntary and automatic drive) and feedback (peripheral commands from sensory inputs) mechanisms. Recent studies have shown that locomotion can be adapted when an external force is applied to the lower limb. To better understand the neural control of this adaptation, the present study investigated gait modifications resulting from exposure to a position-dependent force field. Ten subjects walked on a treadmill before, during, and after exposure to a force field generated by elastic tubing that pulled the foot forward and up during swing. Lower limb kinematics and electromyographic (EMG) activity were recorded during each walking period. During force field exposure, peak foot velocity was initially increased by 38%. As subjects adapted, peak foot velocity gradually returned to baseline in ≤125 strides. In the adapted state, hamstring EMG activity started earlier (16% before toe off) and remained elevated throughout swing. After force field exposure, foot velocity was initially reduced by 22% and returned to baseline in 9–51 strides. Aftereffects in hamstring EMGs consisted of increased activity around toe off. Contrary to the adapted state, this increase was not maintained during the rest of swing. Together, these results suggest that while the neural control of human locomotion can adapt to force field exposure, the mechanisms underlying this adaptation may vary according to the timing in the gait cycle. Adapted hamstring EMG activity may rely more on feedforward mechanisms around toe off and more on feedback mechanisms during the rest of swing.

Glycine Site of NMDA Receptor Serves as a Spatiotemporal Detector of Synaptic Activity Patterns

Li, Y., Krupa, B., Kang, J.-S., Bolshakov, V. Y., Liu, G. — 2009-06-29

Calcium influx associated with the opening of N-methyl-d-aspartate (NMDA) receptor channels is the major signal triggering synaptic and developmental plasticity. Controlling the NMDA receptor function is therefore critical for many functions of the brain. We explored the mechanisms of synaptic activation of the NMDAR glycine site by endogenous coagonist using whole cell voltage-clamp recordings from hippocampal neurons in mixed cultures, containing both neurons and glial cells, and, under more physiological conditions, in hippocampal slices. Here we show that the glycine site of the NMDA receptor at hippocampal synapses, both in culture and acute brain slices, is not saturated by the ambient coagonist concentration and is modulated through activity-dependent coagonist release. Augmentation of the NMDA receptor-mediated synaptic responses by local glutamate-induced coagonist release is spatially restricted and determined by spatiotemporal summation of synaptic events at neighboring synaptic inputs on a single dendritic branch. Therefore different spatiotemporal patterns of presynaptic activity could be translated into different levels of the NMDAR activation in specific afferent projections. These results suggest that the NMDA receptor glycine site may serve as a detector of the spatiotemporal characteristics of presynaptic activity patterns.

Whole Cell Recordings From Visualized Neurons in the Inner Laminae of the Functionally Intact Spinal Cord

Dyck, J., Gosgnach, S. — 2009-06-29

The in vitro whole spinal cord preparation has been an invaluable tool for the study of the neural network that underlies walking because it provides a means of recording fictive locomotor activity following surgical and/or pharmacological manipulation. The recent use of molecular genetic techniques to identify discrete neuronal populations in the spinal cord and subsequent studies showing some of these populations to be involved in locomotor activity have been exciting developments that may lead to a better understanding of the structure and mechanism of function of this neural network. It would be of great benefit if the in vitro whole spinal cord preparation could be updated to allow for the direct targeting of genetically defined neuronal populations, allowing each to be characterized physiologically and anatomically. This report describes a new technique that enables the visualization of, and targeted whole cell patch-clamp recordings from, genetically defined populations of neurons while leaving connectivity largely intact. The key feature of this technique is a small notch cut in the lumbar spinal cord that reveals cells located in the intermediate laminae while leaving the ventral portion of the spinal cord—the region containing the locomotor neural network—untouched. Whole cell patch-clamp recordings demonstrate that these neurons are healthy and display large rhythmic depolarizations that are related to electroneurogram bursts recorded from ventral roots during fictive locomotion. Intracellular labeling demonstrates that this technique can also be used to map axonal projection patterns of neurons. We expect that this procedure will greatly facilitate electrophysiological and anatomical study of important neuronal populations that constitute neural networks throughout the CNS.

Wireless Neural Stimulation in Freely Behaving Small Animals

Arfin, S. K., Long, M. A., Fee, M. S., Sarpeshkar, R. — 2009-06-29

We introduce a novel wireless, low-power neural stimulation system for use in freely behaving animals. The system consists of an external transmitter and a miniature, implantable wireless receiver–stimulator. The implant uses a custom integrated chip to deliver biphasic current pulses to four addressable bipolar electrodes at 32 selectable current levels (10 µA to 1 mA). To achieve maximal battery life, the chip enters a sleep mode when not needed and can be awakened remotely when required. To test our device, we implanted bipolar stimulating electrodes into the songbird motor nucleus HVC (formerly called the high vocal center) of zebra finches. Single-neuron recordings revealed that wireless stimulation of HVC led to a strong increase of spiking activity in its downstream target, the robust nucleus of the arcopallium. When we used this device to deliver biphasic pulses of current randomly during singing, singing activity was prematurely terminated in all birds tested. Thus our device is highly effective for remotely modulating a neural circuit and its corresponding behavior in an untethered, freely behaving animal.

Reproducible Measurement of Human Motoneuron Excitability With Magnetic Stimulation of the Corticospinal Tract

Martin, P. G., Hudson, A. L., Gandevia, S. C., Taylor, J. L. — 2009-06-29

It is difficult to test responses of human motoneurons in a controlled way or to make longitudinal assessments of adaptive changes at the motoneuron level. These studies assessed the reliability of responses produced by magnetic stimulation of the corticospinal tract. Cervicomedullary motor evoked potentials (CMEPs) were recorded in the first dorsal interosseus (FDI) on 2 separate days. On each day, four sets of stimuli were delivered at the maximal output of the stimulator, with the final two sets ≥10 min after the initial sets. Sets of stimuli were also delivered at different stimulus intensities to obtain stimulus-response curves. In addition, on the second day, responses at different stimulus intensities were evoked during weak voluntary contractions. Responses were normalized to the maximal muscle compound action potential (M_max). CMEPs evoked in the relaxed FDI were small, even when stimulus intensity was maximal (3.6 ± 2.5% M_max) but much larger during a weak contraction (e.g., 26.2 ± 10.2% M_max). CMEPs evoked in the relaxed muscle at the maximal output of the stimulator were highly reproducible both within (ICC = 0.83, session 1; ICC = 0.87, session 2) and between sessions (ICC = 0.87). ICCs for parameters of the input-output curves, which included measures of motor threshold, slope, and maximal response size, ranged between 0.87 and 0.62. These results suggest that responses to magnetic stimulation of the corticospinal tract can be assessed in relaxation and contraction and can be reliably obtained for longitudinal studies of motoneuronal excitability.

Gaussian-Process Factor Analysis for Low-Dimensional Single-Trial Analysis of Neural Population Activity

2009-06-29

We consider the problem of extracting smooth, low-dimensional neural trajectories that summarize the activity recorded simultaneously from many neurons on individual experimental trials. Beyond the benefit of visualizing the high-dimensional, noisy spiking activity in a compact form, such trajectories can offer insight into the dynamics of the neural circuitry underlying the recorded activity. Current methods for extracting neural trajectories involve a two-stage process: the spike trains are first smoothed over time, then a static dimensionality-reduction technique is applied. We first describe extensions of the two-stage methods that allow the degree of smoothing to be chosen in a principled way and that account for spiking variability, which may vary both across neurons and across time. We then present a novel method for extracting neural trajectories—Gaussian-process factor analysis (GPFA)—which unifies the smoothing and dimensionality-reduction operations in a common probabilistic framework. We applied these methods to the activity of 61 neurons recorded simultaneously in macaque premotor and motor cortices during reach planning and execution. By adopting a goodness-of-fit metric that measures how well the activity of each neuron can be predicted by all other recorded neurons, we found that the proposed extensions improved the predictive ability of the two-stage methods. The predictive ability was further improved by going to GPFA. From the extracted trajectories, we directly observed a convergence in neural state during motor planning, an effect that was shown indirectly by previous studies. We then show how such methods can be a powerful tool for relating the spiking activity across a neural population to the subject's behavior on a single-trial basis. Finally, to assess how well the proposed methods characterize neural population activity when the underlying time course is known, we performed simulations that revealed that GPFA performed tens of percent better than the best two-stage method.

Reverse Optical Trawling for Synaptic Connections In Situ

Sasaki, T., Minamisawa, G., Takahashi, N., Matsuki, N., Ikegaya, Y. — 2009-06-29

We introduce a new method to unveil the network connectivity among dozens of neurons in brain slice preparations. While synaptic inputs were whole cell recorded from given postsynaptic neurons, the spatiotemporal firing patterns of presynaptic neuron candidates were monitored en masse with functional multineuron calcium imaging, an optical technique that records action potential–evoked somatic calcium transients with single-cell resolution. By statistically screening the neurons that exhibited calcium transients immediately before the postsynaptic inputs, we identified the presynaptic cells that made synaptic connections onto the patch-clamped neurons. To enhance the detection power, we devised the following points: 1) [K⁺]_e was lowered and [Ca²⁺]_e and [Mg²⁺]_e were elevated, to reduce background synaptic activity and minimize the failure rate of synaptic transmission; and 2) a small fraction of presynaptic neurons was specifically activated by glutamate applied iontophoretically through a glass pipette that was moved to survey the presynaptic network of interest ("trawling"). Then we could theoretically detect 96% of presynaptic neurons activated in the imaged regions with a 1% false-positive error rate. This on-line probing technique would be a promising tool in the study of the wiring topography of neuronal circuits.