Journal of Neurophysiology recent issues

Depression of Spinal Sensory Transmission During REM Sleep: Dopaminergic Involvement and Insights Into Restless Legs Syndrome. Focus on "State-Dependent Changes in Glutamate, Glycine, GABA, and Dopamine Levels in Cat Lumbar Spinal Cord"

Hochman, S. — 2008-08-12

Natural Whisking. Focus on "Variability in Velocity Profiles During Free-Air Whisking Behavior of Unrestrained Rats"

Moxon, K. A. — 2008-08-12

Inhibitory Interactions Among Olfactory Glomeruli Do Not Necessarily Reflect Spatial Proximity

Reisenman, C. E., Heinbockel, T., Hildebrand, J. G. — 2008-08-12

Inhibitory interactions shape the activity of output neurons in primary olfactory centers and promote contrast enhancement of odor representations. Patterns of interglomerular connectivity, however, are largely unknown. To test whether the proximity of glomeruli to one another is correlated with interglomerular inhibitory interactions, we used intracellular recording and staining methods to record the responses of projection (output) neurons (PNs) associated with glomeruli of known olfactory tuning in the primary olfactory center of the moth Manduca sexta. We focused on Toroid I, a glomerulus in the male-specific macroglomerular complex (MGC) specialized to one of the two key components of the conspecific females' sex pheromone, and the adjacent, sexually isomorphic glomerulus 35, which is highly sensitive to Z-3-hexenyl acetate (Z3-6:OAc). We used the two odorants to activate these reference glomeruli and tested the effects of olfactory activation in other glomeruli. We found that Toroid-I PNs were not inhibited by input to G35, whereas G35 PNs were inhibited by input to Toroid-I PNs. We also recorded the responses of PNs arborizing in other sexually isomorphic glomeruli to stimulation with the sex pheromone and Z3-6:OAc. We found that inhibitory responses were not related to proximity to the MGC and G35: both distant and adjacent PNs were inhibited by stimulation with the sex pheromone, some others were affected by only one odorant, and yet others by neither. Similar results were obtained in female PNs recorded in proximity to female-specific glomeruli. Our findings indicate that inhibitory interactions among glomeruli are widespread and independent of their spatial proximity.

Differentiating Between Two Models of Motor Lateralization

Shabbott, B. A., Sainburg, R. L. — 2008-08-12

This study was designed to differentiate between two models of motor lateralization: "feedback corrections" and dynamic dominance. Whereas the feedback correction hypothesis suggests that handedness reflects a dominant hemisphere advantage for visual-mediated correction processes, dynamic dominance proposes that each hemisphere has become specialized for distinct aspects of control. This model suggests that the dominant hemisphere is specialized for controlling task dynamics, as required for coordinating efficient trajectories, and the nondominant hemisphere is specialized for controlling limb impedance, as required for maintaining stable postures. To differentiate between these two models, we examined whether visuomotor corrections are mediated differently for the nondominant and dominant arms. Participants performed targeted reaches in a virtual reality environment in which visuomotor rotations occurred in two directions that elicited corrections with different coordination requirements. The feedback correction model predicts a dominant arm advantage for the timing and accuracy of corrections in both directions. Dynamic dominance predicts that correction timing and accuracy will be similar for both arms, but that interlimb differences in the quality of corrections will depend on the coordination requirements, and thus, direction of corrections. Our results indicated that correction time and accuracy did not depend on arm. However, correction quality, as reflected by trajectory curvature, depended on both arm and rotation direction. Nondominant trajectories were systematically more curvilinear than dominant trajectories for corrections with the highest coordination requirement. These results support the dynamic dominance hypothesis.

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in Mouse Vomeronasal Sensory Neurons

Dibattista, M., Mazzatenta, A., Grassi, F., Tirindelli, R., Menini, A. — 2008-08-12

Hyperpolarization-activated currents (I_h) are present in several neurons of the central and peripheral nervous system. However, I_h in neurons of the vomeronasal organ (VNO) is not well characterized. We studied the properties of I_h in sensory neurons from acute slices of mouse VNO. In voltage-clamp studies, I_h was identified by the characteristic kinetics of activation, voltage dependence, and blockage by Cs⁺ or ZD-7288, two blockers of the I_h. Forskolin, an activator of adenylyl cyclase, shifted the activation curve for I_h to less negative potentials. A comparison of I_h properties in VNO neurons with those of heterologously expressed hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, together with RT-PCR experiments in VNO, indicate that I_h is caused by HCN2 and/or HCN4 subunits. In current-clamp recordings, blocking I_h with ZD-7288 induced a hyperpolarization of 5.1 mV, an increase in input resistance, a decrease in the sensitivity to elicit action potentials in response to small current injections, and did not modify the frequency of action potentials elicited by a large current injection. It has been shown that in VNO neurons some pheromones induce a decrease in cAMP concentration, but the physiological role of cAMP is unknown. After application of blockers of adenylyl cyclase, we measured a hyperpolarization of 5.1 mV in 11 of 14 neurons, suggesting that basal levels of cAMP could modulate the resting potential. In conclusion, these results show that mouse VNO neurons express HCN2 and/or HCN4 subunits and that I_h contributes to setting the resting membrane potential and to increase excitability at stimulus threshold.

The "Diagonal Effect": a Systematic Error in Oblique Antisaccades

Koehn, J. D., Roy, E., Barton, J. J. S. — 2008-08-12

Antisaccades are known to show greater variable error and also a systematic hypometria in their amplitude compared with visually guided prosaccades. In this study, we examined whether their accuracy in direction (as opposed to amplitude) also showed a systematic error. We had human subjects perform prosaccades and antisaccades to goals located at a variety of polar angles. In the first experiment, subjects made prosaccades or antisaccades to one of eight equidistant locations in each block, whereas in the second, they made saccades to one of two equidistant locations per block. In the third, they made antisaccades to one of two locations at different distances but with the same polar angle in each block. Regardless of block design, the results consistently showed a saccadic systematic error, in that oblique antisaccades (but not prosaccades) requiring unequal vertical and horizontal vector components were deviated toward the 45° diagonal meridians. This finding could not be attributed to range effects in either Cartesian or polar coordinates. A perceptual origin of the diagonal effect is suggested by similar systematic errors in other studies of memory-guided manual reaching or perceptual estimation of direction, and may indicate a common spatial bias when there is uncertain information about spatial location.

State-Dependent Changes in Glutamate, Glycine, GABA, and Dopamine Levels in Cat Lumbar Spinal Cord

2008-08-12

Recent studies have indicated that the glycine receptor antagonist strychnine and the -aminobutyric acid type A (GABA_A) receptor antagonist bicuculline reduced the rapid-eye-movement (REM) sleep-specific inhibition of sensory inflow via the dorsal spinocerebellar tract (DSCT). These findings imply that the spinal release of glycine and GABA may be due directly to the REM sleep-specific activation of reticulospinal neurons and/or glutamate-activated last-order spinal interneurons. This study used in vivo microdialysis and high-performance liquid chromatography analysis techniques to provide evidence for these possibilities. Microdialysis probes were stereotaxically positioned in the L₃ spinal cord gray matter corresponding to sites where maximal cerebellar-evoked field potentials or individual DSCT and nearby spinoreticular tract (SRT) neurons could be recorded. Glutamate, glycine, and GABA levels significantly increased during REM sleep by approximately 48, 48, and 14%, respectively, compared with the control state of wakefulness. In contrast, dopamine levels significantly decreased by about 28% during REM sleep compared with wakefulness. During the state of wakefulness, electrical stimulation of the nucleus reticularis gigantocellularis (NRGc) at intensities sufficient to inhibit DSCT neuron activity, also significantly increased glutamate and glycine levels by about 69 and 45%, respectively, but not GABA or dopamine levels. We suggest that the reciprocal changes in the release of glutamate, glycine, and GABA versus dopamine during REM sleep contribute to the reduction of sensory inflow to higher brain centers via the DSCT and nearby SRT during this behavioral state. The neural pathways involved in this process likely include reticulo- and diencephalospinal and spinal interneurons.

Excitatory GABA in Rodent Developing Neocortex In Vitro

2008-08-12

GABA depolarizes immature cortical neurons. However, whether GABA excites immature neocortical neurons and drives network oscillations as in other brain structures remains controversial. Excitatory actions of GABA depend on three fundamental parameters: the resting membrane potential (E_m), reversal potential of GABA (E_GABA), and threshold of action potential generation (V_thr). We have shown recently that conventional invasive recording techniques provide an erroneous estimation of these parameters in immature neurons. In this study, we used noninvasive single N-methyl-d-aspartate and GABA channel recordings in rodent brain slices to measure both E_m and E_GABA in the same neuron. We show that GABA strongly depolarizes pyramidal neurons and interneurons in both deep and superficial layers of the immature neocortex (P2–P10). However, GABA generates action potentials in layer 5/6 (L5/6) but not L2/3 pyramidal cells, since L5/6 pyramidal cells have more depolarized resting potentials and more hyperpolarized V_thr. The excitatory GABA transiently drives oscillations generated by L5/6 pyramidal cells and interneurons during development (P5–P12). The NKCC1 co-transporter antagonist bumetanide strongly reduces [Cl^–]_i, GABA-induced depolarization, and network oscillations, confirming the importance of GABA signaling. Thus a strong GABA excitatory drive coupled with high intrinsic excitability of L5/6 pyramidal neurons and interneurons provide a powerful mechanism of synapse-driven oscillatory activity in the rodent neocortex in vitro. In the companion paper, we show that the excitatory GABA drives layer-specific seizures in the immature neocortex.

Layer-Specific Generation and Propagation of Seizures in Slices of Developing Neocortex: Role of Excitatory GABAergic Synapses

Rheims, S., Represa, A., Ben-Ari, Y., Zilberter, Y. — 2008-08-12

The neonatal period is critical for seizure susceptibility, and neocortical networks are central in infantile epilepsies. We report that application of 4-aminopyridine (4-AP) to immature (P6–P9) neocortical slices generates layer-specific interictal seizures (IISs) that transform after recurrent seizures to ictal seizures (ISs). During IISs, cell-attached recordings show action potentials in interneurons and pyramidal cells in L5/6 and interneurons but not pyramidal neurons in L2/3. However, L2/3 pyramidal neurons also fire during ISs. Using single N-methyl-d-aspartate (NMDA) channel recordings for measuring the cell resting potential (E_m), we show that transition from IISs to ISs is associated with a gradual E_m depolarization of L2/3 and L5/6 pyramidal neurons that enhances their excitability. Bumetanide, a NKCC1 co-transporter antagonist, inhibits generation of IISs and prevents their transformation to ISs, indicating the role excitatory GABA in epilepsies. Therefore deep layer neurons are more susceptible to seizures than superficial ones. The initiating phase of seizures is characterized by IISs generated in L5/6 and supported by activation of both L5/6 interneurons and pyramidal cells. IISs propagate to L2/3 via activation of L2/3 interneurons but not pyramidal cells, which are mostly quiescent at this phase. In superficial layers, a persistent increase in excitability of pyramidal neurons caused by E_m depolarization is associated with a transition from largely confined GABAergic IIS to ictal events that entrain the entire neocortex.

Intracellular Recordings From Combination-Sensitive Neurons in the Inferior Colliculus

Peterson, D. C., Voytenko, S., Gans, D., Galazyuk, A., Wenstrup, J. — 2008-08-12

In vertebrate auditory systems, specialized combination-sensitive neurons analyze complex vocal signals by integrating information across multiple frequency bands. We studied combination-sensitive interactions in neurons of the inferior colliculus (IC) of awake mustached bats, using intracellular somatic recording with sharp electrodes. Facilitated combinatorial neurons are coincidence detectors, showing maximum facilitation when excitation from low- and high-frequency stimuli coincide. Previous work showed that facilitatory interactions originate in the IC, require both low and high frequency–tuned glycinergic inputs, and are independent of glutamatergic inputs. These results suggest that glycinergic inputs evoke facilitation through either postinhibitory rebound or direct depolarizing mechanisms. However, in 35 of 36 facilitated neurons, we observed no evidence of low frequency–evoked transient hyperpolarization or depolarization that was closely related to response facilitation. Furthermore, we observed no evidence of shunting inhibition that might conceal inhibitory inputs. Since these facilitatory interactions originate in IC neurons, the results suggest that inputs underlying facilitation are electrically segregated from the soma. We also recorded inhibitory combinatorial interactions, in which low frequency sounds suppress responses to higher frequency signals. In 43% of 118 neurons, we observed low frequency–evoked hyperpolarizations associated with combinatorial inhibition. For these neurons, we conclude that low frequency–tuned inhibitory inputs terminate on neurons primarily excited by high-frequency signals; these inhibitory inputs may create or enhance inhibitory combinatorial interactions. In the remainder of inhibited combinatorial neurons (57%), we observed no evidence of low frequency–evoked hyperpolarizations, consistent with observations that inhibitory combinatorial responses may originate in lateral lemniscal nuclei.

Disruption of Balanced Cortical Excitation and Inhibition by Acoustic Trauma

Scholl, B., Wehr, M. — 2008-08-12

Sensory deafferentation results in rapid shifts in the receptive fields of cortical neurons, but the synaptic mechanisms underlying these changes remain unknown. The rapidity of these shifts has led to the suggestion that subthreshold inputs may be unmasked by a selective loss of inhibition. To study this, we used in vivo whole cell recordings to directly measure tone-evoked excitatory and inhibitory synaptic inputs in auditory cortical neurons before and after acoustic trauma. Here we report that acute acoustic trauma disrupted the balance of excitation and inhibition by selectively increasing and reducing the strength of inhibition at different positions within the receptive field. Inhibition was abolished for frequencies far below the trauma-tone frequency but was markedly enhanced near the edges of the region of elevated peripheral threshold. These changes occurred for relatively high-level tones. These changes in inhibition led to an expansion of receptive fields but not by a simple unmasking process. Rather, membrane potential responses were delayed and prolonged throughout the receptive field by distinct interactions between synaptic excitation and inhibition. Far below the trauma-tone frequency, decreased inhibition combined with prolonged excitation led to increased responses. Near the edges of the region of elevated peripheral threshold, increased inhibition served to delay rather than abolish responses, which were driven by prolonged excitation. These results show that the rapid receptive field shifts caused by acoustic trauma are caused by distinct mechanisms at different positions within the receptive field, which depend on differential disruption of excitation and inhibition.

Dynamic Effects on the Subjective Visual Vertical After Roll Rotation

Lorincz, E. N., Hess, B. J. M. — 2008-08-12

We investigated in normal human subjects how semicircular canal and otolith signals interact in the estimation of the subjective visual vertical after constant velocity or constant acceleration roll tilt. In the constant velocity paradigm, subjects were rotated in darkness at ±60°/s for five complete cycles before being stopped in one of seven orientations ranging from 0 to ±90° (right/left ear down). In the constant acceleration paradigm, subjects were rotated with an acceleration of +30 or –30°/s² to the same seven end positions between –90 and +90°, by way of passing once through the upside-down position. The subjective visual vertical was assessed by measuring the setting of a luminous line that appeared at different test delays after stop rotation in otherwise complete darkness. The data suggest that gravitational jerk signals generated by otolith–semicircular canal interactions and/or carried by phasic otolith signals are responsible for the observed transient bias in the estimation of the subjective visual vertical. This transient bias depended on both rotation and tilt direction after constant velocity rotations, but was almost abolished following constant acceleration rotations.

Arousal Facilitates Collision Avoidance Mediated by a Looming Sensitive Visual Neuron in a Flying Locust

Rind, F. C., Santer, R. D., Wright, G. A. — 2008-08-12

Locusts have two large collision-detecting neurons, the descending contralateral movement detectors (DCMDs) that signal object approach and trigger evasive glides during flight. We sought to investigate whether vision for action, when the locust is in an aroused state rather than a passive viewer, significantly alters visual processing in this collision-detecting pathway. To do this we used two different approaches to determine how the arousal state of a locust affects the prolonged periods of high-frequency spikes typical of the DCMD response to approaching objects that trigger evasive glides. First, we manipulated arousal state in the locust by applying a brief mechanical stimulation to the hind leg; this type of change of state occurs when gregarious locusts accumulate in high-density swarms. Second, we examined DCMD responses during flight because flight produces a heightened physiological state of arousal in locusts. When arousal was induced by either method we found that the DCMD response recovered from a previously habituated state; that it followed object motion throughout approach; and—most important—that it was significantly more likely to generate the maintained spike frequencies capable of evoking gliding dives even with extremely short intervals (1.8 s) between approaches. Overall, tethered flying locusts responded to 41% of simulated approaching objects (sets of 6 with 1.8 s ISI). When we injected epinastine, the neuronal octopamine receptor antagonist, into the hemolymph responsiveness declined to 12%, suggesting that octopamine plays a significant role in maintaining responsiveness of the DCMD and the locust to visual stimuli during flight.

Encoding of Stimulus Frequency and Sensor Motion in the Posterior Medial Thalamic Nucleus

Masri, R., Bezdudnaya, T., Trageser, J. C., Keller, A. — 2008-08-12

In all sensory systems, information is processed along several parallel streams. In the vibrissa-to-barrel cortex system, these include the lemniscal system and the lesser-known paralemniscal system. The posterior medial nucleus (POm) is the thalamic structure associated with the latter pathway. Previous studies suggested that POm response latencies are positively correlated with stimulation frequency and negatively correlated with response duration, providing a basis for a phase locked loop-temporal decoding of stimulus frequency. We tested this hypothesis by analyzing response latencies of POm neurons, in both awake and anesthetized rats, to vibrissae deflections at frequencies between 0.3 and 11 Hz. We found no significant, systematic correlation between stimulation frequency and the latency or duration of POm responses. We obtained similar findings from recording in awake rats, in rats under different anesthetics, and in anesthetized rats in which the reticular activating system was stimulated. These findings suggest that stimulus frequency is not reliably reflected in response latency of POm neurons. We also tested the hypothesis that POm neurons respond preferentially to sensor motion, that is, they respond to whisking in air, without contacts. We recorded from awake, head-restrained rats while monitoring vibrissae movements. All POm neurons responded to passive whisker deflections, but none responded to noncontact whisking. Thus like their counterparts in the trigeminal ganglion, POm neurons may not reliably encode whisking kinematics. These observations suggest that POm neurons might not faithfully encode vibrissae inputs to provide reliable information on vibrissae movements or contacts.

Silencing-Induced Metaplasticity in Hippocampal Cultured Neurons

Sokolova, I. V., Mody, I. — 2008-08-12

Silencing-induced homeostatic plasticity is usually expressed as a change in the amplitude or the frequency of miniature postsynaptic currents. Here we report that, prolonged (~24 h) silencing of mature (20–22 days in vitro) cultured hippocampal neurons using the voltage-gated sodium channel blocker tetrodotoxin (TTX) produced no effects on the amplitude or frequency of the miniature excitatory postsynaptic currents (mEPSCs). However, the silencing changed the intrinsic membrane properties of the neurons, resulting in an increased excitability and rate of action potentials firing upon TTX washout. Allowing neurons to recover in TTX-free recording solution for a short period of time after the silencing resulted in potentiation of mEPSC amplitudes. This form of activity-dependent potentiation is different from classical long-term potentiation, as similar potentiation was not seen in nonsilenced neurons treated with bicuculline to raise their spiking activity to the same level displayed by the silenced neurons during TTX washout. Also, the potentiation of mEPSC amplitudes after the recovery period was not affected by the N-methyl-d-aspartate receptor blocker d-2-amino-5-phosponopentanoic acid or by the calcium/calmodulin-dependent kinase II (CaMKII) inhibitor KN-62 but was abolished by the L-type calcium channel blocker nifedipine. We thus conclude that the potentiation of mEPSC amplitudes following brief recovery of spiking activity in chronically silenced neurons represents a novel form of metaplasticity that differs from the conventional models of homeostatic synaptic plasticity.

Glycine Receptors Mediate Excitation of Subplate Neurons in Neonatal Rat Cerebral Cortex

2008-08-12

The development of the cerebral cortex depends on genetic factors and early electrical activity patterns that form immature neuronal networks. Subplate neurons (SPn) are involved in the construction of thalamocortical innervation, generation of oscillatory network activity, and in the proper formation of the cortical columnar architecture. Because glycine receptors play an important role during early corticogenesis, we analyzed the functional consequences of glycine receptor activation in visually identified SPn in neocortical slices from postnatal day 0 (P0) to P4 rats using whole cell and perforated patch-clamp recordings. In all SPn the glycinergic agonists glycine, β-alanine, and taurine induced dose-dependent inward currents with the affinity for glycine being higher than that for β-alanine and taurine. Glycine-induced responses were blocked by the glycinergic antagonist strychnine, but were unaffected by either the GABAergic antagonist gabazine, the N-methyl-d-aspartate–receptor antagonist d-2-amino-5-phosphonopentanoic acid, or picrotoxin and cyanotriphenylborate, antagonists of -homomeric and ₁-subunit–containing glycine receptors, respectively. Under perforated-patch conditions, glycine induced membrane depolarizations that were sufficient to trigger action potentials (APs) in most cells. Furthermore, glycine and taurine decreased the injection currents as well as the synaptic stimulation strength required to elicit APs, indicating that glycine receptors have a consistent excitatory effect on SPn. Inhibition of taurine transport and application of hypoosmolar solutions induced strychnine-sensitive inward currents, suggesting that taurine can act as a possible endogenous agonist on SPn. In summary, these results demonstrate that SPn express glycine receptors that mediate robust excitatory membrane responses during early postnatal development.

Variability Reduction in Interaural Time Difference Tuning in the Barn Owl

Fischer, B. J., Konishi, M. — 2008-08-12

The interaural time difference (ITD) is the primary auditory cue used by the barn owl for localization in the horizontal direction. ITD is initially computed by circuits consisting of axonal delay lines from one of the cochlear nuclei and coincidence detector neurons in the nucleus laminaris (NL). NL projects directly to the anterior part of the dorsal lateral lemniscal nucleus (LLDa), and this area projects to the core of the central nucleus of the inferior colliculus (ICcc) in the midbrain. To show the selectivity of an NL neuron for ITD requires averaging of responses over several stimulus presentations for each ITD. In contrast, ICcc neurons detect their preferred ITD in a single burst of stimulus. We recorded extracellularly the responses of LLDa neurons to ITD in anesthetized barn owls and show that this ability is already present in LLDa, raising the possibility that ICcc inherits its noise reduction property from LLDa.

The Activity of Spinal Commissural Interneurons During Fictive Locomotion in the Lamprey

Biro, Z., Hill, R. H., Grillner, S. — 2008-08-12

Commissural interneurons in the lamprey coordinate activity of the hemisegmental oscillators to ensure proper left–right alternation during swimming. The activity of interneuronal axons at the ventral commissure was studied together with potential target motoneurons during fictive locomotion in the isolated lamprey spinal cord. To estimate the unperturbed activity of the interneurons, axonal recordings were chosen because soma recordings inevitably will affect the level of membrane depolarization and thereby spike initiation. Of 227 commissural axons recorded during locomotor activity, 14 produced inhibitory and 3 produced excitatory postsynaptic potentials (PSPs) in target motoneurons. The axons typically fired multiple spikes per locomotor cycle, with ~10 Hz sustained frequency. The average shortest spike interval in a burst corresponded to an instantaneous frequency of ~50 Hz for both the excitatory and inhibitory axons. The maximum number of spikes per locomotor cycle was inversely related to the locomotor frequency, in accordance with previous observations in the spinal hemicord preparation. In axons that fired multiple spikes per cycle, the mean interspike intervals were in the range in which the amplitude of the slow afterhyperpolarization (sAHP) is large, providing further support for the role of the sAHP in spike timing. One hundred ninety-five axons (86%) fired rhythmically during fictive locomotion, with preferred phase of firing distributed over either the segmental locomotor burst phase (40% of axons) or the transitional phase (between bursts; 60%). Thus in lamprey commissural interneurons, we found a broad distribution of firing rates and phases during fictive locomotion.

Effect of Intrathecal Administration of Serotoninergic and Noradrenergic Drugs on Postural Performance in Rabbits With Spinal Cord Lesions

Lyalka, V. F., Musienko, P. E., Orlovsky, G. N., Grillner, S., Deliagina, T. G. — 2008-08-12

Our previous studies have shown that extensive spinal lesions at T₁₂ in the rabbit [ventral hemisection (VHS) or 3/4-section that spares one ventral quadrant (VQ)] severely damaged the postural system. When tested on the platform periodically tilted in the frontal plane, VHS and VQ animals typically were not able to perform postural corrective movements by their hindlimbs, although EMG responses (correctly or incorrectly phased) could be observed. We attempted to restore postural control in VHS and VQ rabbits by applying serotoninergic and noradrenergic drugs to the spinal cord below the lesion through the intrathecal cannula. It was found that serotonin and quipazine (5-HT_1,2,3 agonist) did not re-establish postural corrective movements. However, when applied during a 10-day period after lesion, these drugs produced a twofold increase of the proportion of correct EMG responses to tilts. It was also found that methoxamine (₁ noradrenergic agonist), as well as the mixture of methoxamine and quipazine, did not re-establish postural corrective movements and did not increase the proportion of correct EMG responses. Serotonin (at later stages) and methoxamine induced periodical bursting in EMGs, suggesting activation of spinal rhythm-generating networks. Appearance of bursting seems to perturb normal operation of postural mechanisms, as suggested by methoxamine-induced abolishment of postural effects of quipazine. When applied in an intact animal, none of the tested drugs affected the value of postural corrections or evoked periodical bursting. We conclude that activation of the serotoninergic system (but not the noradrenergic one) causes selective enhancement of spinal postural reflexes during the earlier postlesion period.

Implicit and Explicit Learning of Temporal Sequences Studied With the Process Dissociation Procedure

Karabanov, A., Ullen, F. — 2008-08-12

We studied whether temporal sequences can be learned implicitly using a process dissociation procedure (PDP). Participants performed repeated serial recalls of sequential stimuli with a random ordinal structure and fixed temporal structure. Explicit knowledge was evaluated through verbal questions and PDP analysis of two generation tasks (inclusion and exclusion). Participants were divided into two groups: in the Ordinal group, stimulus presentation was visual and the participants were instructed to repeat the ordinal structure; in the Temporal+Ordinal group, stimulus presentation was audio-visual and the participants were instructed to repeat temporal and ordinal structure. We expected predominantly implicit learning in the Ordinal group and explicit learning in the Temporal+Ordinal group. This was supported by two findings. First, a significant difference between inclusion and exclusion performance was seen only in the Temporal+Ordinal group. Second, in both groups, a negative relation was found between the degree of improvement during serial recall and a measure of explicit knowledge in the generation tasks. This relation was independent of the final level of performance during serial recall. These findings suggest that distinct implicit and explicit systems may exist for learning of temporal sequences: implicit learning is gradual and gives rise to knowledge that is inaccessible to conscious control while the explicit system is fast and results in representations that can be used to control performance in inclusion and exclusion tasks.

Variability in Velocity Profiles During Free-Air Whisking Behavior of Unrestrained Rats

Towal, R. B., Hartmann, M. J. Z. — 2008-08-12

During exploratory behaviors, the velocity of an organism's sensory surfaces can have a pronounced effect on the incoming flow of sensory information. In this study, we quantified variability in the velocity profiles of rat whisking during natural exploratory behavior that included head rotations. A wide continuum of profiles was observed, including monotonic, delayed, and reversing velocities during protractions and retractions. Three alternative hypotheses for the function of the variable velocity profiles were tested: 1) that they produce bilateral asymmetry specifically correlated with rotational head velocity, 2) that they serve to generate bilaterally asymmetric and/or asynchronous whisker movements independent of head velocity, and 3) that the different profiles—despite increasing variability in instantaneous velocity—reduce variability in the average whisking velocity. Our results favor the third hypothesis and do not support the first two. Specifically, the velocity variability within a whisk can be observed as a shift in the phase of the maximum velocity. We discuss the implications of these results for the control of whisker motion, horizontal object localization, and processing in the thalamus and cortex of the rat vibrissal system.

Privileged Coding of Convex Shapes in Human Object-Selective Cortex

Haushofer, J., Baker, C. I., Livingstone, M. S., Kanwisher, N. — 2008-08-12

What is the neural code for object shape? Despite intensive research, the precise nature of object representations in high-level visual cortex remains elusive. Here we use functional magnetic resonance imaging (fMRI) to show that convex shapes are encoded in a privileged fashion by human lateral occipital complex (LOC), a region that has been implicated in object recognition. On each trial, two convex or two concave shapes that were either identical or different were presented sequentially. Critically, the convex and concave stimuli were the same except for a binocular disparity change that reversed the figure–ground assignment. The fMRI response in LOC for convex stimuli was higher for different than that for identical shape pairs, indicating sensitivity to differences in convex shape. However, when the same stimuli were seen as concave, the response for different and identical pairs was the same, indicating lower sensitivity to changes in concave shape than convex shape. This pattern was more pronounced in the anterior than that in the posterior portion of LOC. These results suggest that convex contours could be important elements in cortical object representations.

Head Stabilization by Vestibulocollic Reflexes During Quadrupedal Locomotion in Monkey

Xiang, Y., Yakushin, S. B., Kunin, M., Raphan, T., Cohen, B. — 2008-08-12

Little is known about the three-dimensional characteristics of vestibulocollic reflexes during natural locomotion. Here we determined how well head stability is maintained by the angular and linear vestibulocollic reflexes (aVCR, lVCR) during quadrupedal locomotion in rhesus and cynomolgus monkeys. Animals walked on a treadmill at velocities of 0.4–1.25 m/s. Head rotations were represented by Euler angles (Fick convention). The head oscillated in yaw and roll at stride frequencies (1–2 Hz) and pitched at step frequencies (2–4 Hz). Head angular accelerations (100–2,500°/s²) were sufficient to have excited the aVOR to stabilize gaze. Pitch and roll head movements were <7°, peak to peak, and the amplitude was unrelated to stride frequency. Yaw movements were larger due to spontaneous voluntary head shifts and were smaller at higher walking velocities. Head translations were small (≤4 cm). Cynomolgus monkeys positioned their heads more forward in pitch than the rhesus monkeys. None of the animals maintained a forward head fixation point, indicating that the lVCR contributed little to compensatory head movements in these experiments. Significantly, aVCR gains in roll and pitch were close to unity and phases were 180° over the full frequency range of natural walking, which is in contrast to previous findings using anesthesia or passive trunk rotation with body restraint. We conclude that the behavioral state associated with active body motion is necessary to maintain head stability in pitch and roll over the full range of stride/step frequencies encountered during walking.

Kinetic Isolation of a Slowly Recovering Component of Short-Term Depression During Exhaustive Use at Excitatory Hippocampal Synapses

Garcia-Perez, E., Lo, D. C., Wesseling, J. F. — 2008-08-12

This study examines the kinetics of the longest lasting form of short-term depression at excitatory hippocampal synapses. After initial depletion of the readily releasable pool (RRP), continued 20-Hz stimulation was found to be fast enough to maximally drive presynaptic neurotransmitter exocytosis; maximal is defined here as the rate needed to maintain the RRP in a nearly empty steady state. Induction of depression proceeded in two distinct phases. The first was caused by RRP depletion, whereas the second is shown to reflect the progressive reduction of the overall rate at which new vesicles are supplied to the RRP and is termed "supply-rate depression." Supply-rate depression is identified further with the emergence, during heavy use, of a rate-limiting vesicle trafficking step that slows the timing of RRP replenishment by switching from a fast ( 7 s) to a slow ( 1 min) vesicle supply mechanism. Both mechanisms apparently follow first-order kinetics. After the induction of the maximum amount of depression, individual synapses were able to output only <1 quantum of neurotransmitter per synapse per second, matching previous predictions based on cell biological measurements of synaptic vesicle cycling. Surprisingly, the onset of supply-rate depression occurred with a marked delay, not having a detectable impact on synaptic function until after several seconds of continuous use. The delayed onset is not consistent with traditional vesicle trafficking models, but may be important for limiting the impact of supply-rate depression to pathological episodes and might function as a native antiepilepsy device.

Shape Selectivity in Primate Frontal Eye Field

Peng, X., Sereno, M. E., Silva, A. K., Lehky, S. R., Sereno, A. B. — 2008-08-12

Previous neurophysiological studies of the frontal eye field (FEF) in monkeys have focused on its role in saccade target selection and gaze shift control. It has been argued that FEF neurons indicate the locations of behaviorally significant visual stimuli and are not inherently sensitive to specific features of the visual stimuli per se. Here, for the first time, we directly examined single cell responses to simple, two-dimensional shapes and found that shape selectivity exists in a substantial number of FEF cells during a passive fixation task or during the sample, delay (memory), and eye movement periods in a delayed match to sample (DMTS) task. Our data demonstrate that FEF neurons show sensory and mnemonic selectivity for stimulus shape features whether or not they are behaviorally significant for the task at hand. We also investigated the extent and localization of activation in the FEF using a variety of shape stimuli defined by static or dynamic cues employing functional magentic resonance imaging (fMRI) in anesthetized and paralyzed monkeys. Our fMRI results support the electrophysiological findings by showing significant FEF activation for a variety of shape stimuli and cues in the absence of attentional and motor processing. This shape selectivity in FEF is comparable to previous reports in the ventral pathway, inviting a reconsideration of the functional organization of the visual system.

Determinants of Laser-Evoked EEG Responses: Pain Perception or Stimulus Saliency?

Iannetti, G. D., Hughes, N. P., Lee, M. C., Mouraux, A. — 2008-08-12

Although laser-evoked electroencephalographic (EEG) responses are increasingly used to investigate nociceptive pathways, their functional significance remains unclear. The reproducible observation of a robust correlation between the intensity of pain perception and the magnitude of the laser-evoked N1, N2, and P2 responses has led some investigators to consider these responses a direct correlate of the neural activity responsible for pain intensity coding in the human cortex. Here, we provide compelling evidence to the contrary. By delivering trains of three identical laser pulses at four different energies, we explored the modulation exerted by the temporal expectancy of the stimulus on the relationship between intensity of pain perception and magnitude of the following laser-evoked brain responses: the phase-locked N1, N2, and P2 waves, and the non-phase-locked laser-induced synchronization (ERS) and desynchronization (ERD). We showed that increasing the temporal expectancy of the stimulus through stimulus repetition at a constant interstimulus interval 1) significantly reduces the magnitudes of the laser-evoked N1, N2, P2, and ERS; and 2) disrupts the relationship between the intensity of pain perception and the magnitude of these responses. Taken together, our results indicate that laser-evoked EEG responses are not determined by the perception of pain per se, but are mainly determined by the saliency of the eliciting nociceptive stimulus (i.e., its ability to capture attention). Therefore laser-evoked EEG responses represent an indirect readout of the function of the nociceptive system.

Independence of Anticipatory Signals for Spatial Attention From Number of Nontarget Stimuli in the Visual Field

2008-08-12

Covertly attending to a location modulates the activity of visual areas even in the absence of visual stimulation. These effects are widespread, being found in the cortical representations of both attended and unattended portions of the visual field. It is not clear, however, whether preparatory modulations depend on subjects' expectation regarding the presence of additional nontarget stimuli in the visual field. Here, we asked subjects to endogenously direct attention to a peripheral location in the upper visual field, to identify the orientation of a low-contrast target stimulus, and we manipulated the number and behavioral relevance of other low-contrast nontarget stimuli in the visual field. Anticipatory (i.e., prestimulus) blood oxygenation level–dependent (BOLD) signal increments in visual cortex were strongest at the contralateral attended location, whereas signal decrements were strongest at the unattended mirror-opposite ipsilateral location/region of visual cortex. Importantly, these strong anticipatory decrements were not related to the presence/absence of nontarget low-contrast stimuli and did not correlate with either weaker target-evoked responses or worse performance. Second, the presence of other low-contrast stimuli in the visual field, even when potential targets, did not modify the anticipatory signal modulation either at target or nontarget locations. We conclude that the topography of spatial attention–related anticipatory BOLD signal modulation across visual cortex, specifically decrements at unattended locations, is mainly determined by processes at the cued location and not by the number or behavioral relevance of distant low-contrast nontarget stimuli elsewhere in the visual field.

Trunk Sensorimotor Cortex Is Essential for Autonomous Weight-Supported Locomotion in Adult Rats Spinalized as P1/P2 Neonates

Giszter, S., Davies, M. R., Ramakrishnan, A., Udoekwere, U. I., Kargo, W. J. — 2008-08-12

Unlike adult spinalized rats, approximately 20% of rats spinalized as postnatal day 1 or 2 (P1/P2) neonates achieve autonomous hindlimb weight support. Cortical representations of mid/low trunk occur only in such rats with high weight support. However, the importance of hindlimb/trunk motor cortex in function of spinalized rats remains unclear. We tested the importance of trunk sensorimotor cortex in their locomotion using lesions guided by cortical microstimulation in P1/P2 weight-supporting neonatal spinalized rats and controls. In four intact control rats, lesions of hindlimb/trunk cortex caused no treadmill deficits. All spinalized rats lesioned in trunk cortex (n = 16: 4 transplant, 6 transect, 6 transect + fibrin glue) lost an average of about 40% of their weight support. Intact trunk cortex was essential to their level of function. Lesion of trunk cortex substantially increased roll of the hindquarters, which correlated to diminished weight support, but other kinematic stepping parameters showed little change. Embryonic day 14 (E14) transplants support development of the trunk motor representations in their normal location. We tested the role of novel relay circuits arising from the grafts in such cortical representations in E14 transplants using the rats that received (noncellular) fibrin glue grafting at P1/P2 (8 allografts and 32 xenografts). Fibrin-repaired rats with autonomous weight support also had trunk cortical representations similar to those of E14 transplant rats. Thus acellular repair and intrinsic plasticity were sufficient to support the observed features. Our data show that effective cortical mechanisms for trunk control are essential for autonomous weight support in P1/P2 spinalized rats and these can be achieved by intrinsic plasticity.

Temporal Processing Across Multiple Topographic Maps in the Electrosensory System

Krahe, R., Bastian, J., Chacron, M. J. — 2008-08-12

Multiple topographic representations of sensory space are common in the nervous system and presumably allow organisms to separately process particular features of incoming sensory stimuli that vary widely in their attributes. We compared the response properties of sensory neurons within three maps of the body surface that are arranged strictly in parallel to two classes of stimuli that mimic prey and conspecifics, respectively. We used information-theoretic approaches and measures of phase locking to quantify neuronal responses. Our results show that frequency tuning in one of the three maps does not depend on stimulus class. This map acts as a low-pass filter under both conditions. A previously described stimulus-class-dependent switch in frequency tuning is shown to occur in the other two maps. Only a fraction of the information encoded by all neurons could be recovered through a linear decoder. Particularly striking were low-pass neurons the information of which in the high-frequency range could not be decoded linearly. We then explored whether intrinsic cellular mechanisms could partially account for the differences in frequency tuning across maps. Injection of a Ca²⁺ chelator had no effect in the map with low-pass characteristics. However, injection of the same Ca²⁺ chelator in the other two maps switched the tuning of neurons from band-pass/high-pass to low-pass. These results show that Ca²⁺-dependent processes play an important part in determining the functional roles of different sensory maps and thus shed light on the evolution of this important feature of the vertebrate brain.

Characterization of Voltage-Dependent Ca2+ Currents in Identified Drosophila Motoneurons In Situ

Worrell, J. W., Levine, R. B. — 2008-08-12

Voltage-dependent Ca²⁺ channels contribute to neurotransmitter release, integration of synaptic information, and gene regulation within neurons. Thus understanding where diverse Ca²⁺ channels are expressed is an important step toward understanding neuronal function within a network. Drosophila provides a useful model for exploring the function of voltage-dependent Ca²⁺ channels in an intact system, but Ca²⁺ currents within the central processes of Drosophila neurons in situ have not been well described. The aim of this study was to characterize voltage-dependent Ca²⁺ currents in situ from identified larval motoneurons. Whole cell recordings from the somata of identified motoneurons revealed a significant influence of extracellular Ca²⁺ on spike shape and firing rate. Using whole cell voltage clamp, along with blockers of Na⁺ and K⁺ channels, a Ca²⁺-dependent inward current was isolated. The Drosophila genome contains three genes with homology to vertebrate voltage-dependent Ca²⁺ channels: Dmca1A, Dmca1D, and Dm1G. We used mutants of Dmca1A and Dmca1D as well as targeted expression of an RNAi transgene to Dmca1D to determine the genes responsible for the voltage-dependent Ca²⁺ current recorded from two identified motoneurons. Our results implicate Dmca1D as the major contributor to the voltage-dependent Ca²⁺ current recorded from the somatodendritic processes of motoneurons, whereas Dmca1A has previously been localized to the presynaptic terminal where it is essential for neurotransmitter release. Altered firing properties in cells from both Dmca1D and Dmca1A mutants indicate a role for both genes in shaping firing properties.

Active Learning: Learning a Motor Skill Without a Coach

Huang, V. S., Shadmehr, R., Diedrichsen, J. — 2008-08-12

When we learn a new skill (e.g., golf) without a coach, we are "active learners": we have to choose the specific components of the task on which to train (e.g., iron, driver, putter, etc.). What guides our selection of the training sequence? How do choices that people make compare with choices made by machine learning algorithms that attempt to optimize performance? We asked subjects to learn the novel dynamics of a robotic tool while moving it in four directions. They were instructed to choose their practice directions to maximize their performance in subsequent tests. We found that their choices were strongly influenced by motor errors: subjects tended to immediately repeat an action if that action had produced a large error. This strategy was correlated with better performance on test trials. However, even when participants performed perfectly on a movement, they did not avoid repeating that movement. The probability of repeating an action did not drop below chance even when no errors were observed. This behavior led to suboptimal performance. It also violated a strong prediction of current machine learning algorithms, which solve the active learning problem by choosing a training sequence that will maximally reduce the learner's uncertainty about the task. While we show that these algorithms do not provide an adequate description of human behavior, our results suggest ways to improve human motor learning by helping people choose an optimal training sequence.

Neural Response Properties of Primary, Rostral, and Rostrotemporal Core Fields in the Auditory Cortex of Marmoset Monkeys

Bendor, D., Wang, X. — 2008-08-12

The core region of primate auditory cortex contains a primary and two primary-like fields (AI, primary auditory cortex; R, rostral field; RT, rostrotemporal field). Although it is reasonable to assume that multiple core fields provide an advantage for auditory processing over a single primary field, the differential roles these fields play and whether they form a functional pathway collectively such as for the processing of spectral or temporal information are unknown. In this report we compare the response properties of neurons in the three core fields to pure tones and sinusoidally amplitude modulated tones in awake marmoset monkeys (Callithrix jacchus). The main observations are as follows. (1) All three fields are responsive to spectrally narrowband sounds and are tonotopically organized. (2) Field AI responds more strongly to pure tones than fields R and RT. (3) Field RT neurons have lower best sound levels than those of neurons in fields AI and R. In addition, rate-level functions in field RT are more commonly nonmonotonic than in fields AI and R. (4) Neurons in fields RT and R have longer minimum latencies than those of field AI neurons. (5) Fields RT and R have poorer stimulus synchronization than that of field AI to amplitude-modulated tones. (6) Between the three core fields the more rostral regions (R and RT) have narrower firing-rate–based modulation transfer functions than that of AI. This effect was seen only for the nonsynchronized neurons. Synchronized neurons showed no such trend.

Effects of Localized Intraspinal Injections of a Noradrenergic Blocker on Locomotion of High Decerebrate Cats

Delivet-Mongrain, H., Leblond, H., Rossignol, S. — 2008-08-12

Previous studies demonstrated that neuronal networks located in midlumbar segments (L3–L4) are critical for the expression of locomotion in cats following complete spinalization. In the present study the importance of several thoracolumbar segments (T8–L7) for the generation of spontaneous hindlimb locomotion in decerebrate cats was evaluated. Experiments were performed in high decerebrate cats (n = 18) walking spontaneously. Yohimbine, an alpha2-noradrenergic antagonist, was microinjected intraspinally in various thoracolumbar segments. Locomotor performance was evaluated with kinematics and electromyographic (EMG) recordings before and after each injection. When and if spontaneous locomotion (SL) was abolished, skin or perineal stimuli (exteroceptive stimuli) were used to trigger locomotion (exteroceptive-induced locomotion [EL]). Yohimbine injections at L3 or L4 completely inhibited SL and EL. In contrast, injections at T8 did not interfere with SL or EL. Injections at T10, T11, T12, L5, L6, and L7 inhibited SL but EL could still be evoked. Injections at T13, L1, and L2 had similar effects except that the quality of locomotion evoked by exteroceptive stimulation declined. Combined injections at T13, L1, and L2 abolished SL and EL, in contrast to injections restricted to the same individual segments. Simultaneous injections at L5, L6, and L7 also abolished SL but EL could still be induced. These results suggest that noradrenergic mechanisms in L3–L4 segments are involved in the expression of locomotion in decerebrate cats, whereas antagonizing noradrenergic inputs in individual rostral or caudal segments may alter the expression and overall quality of the locomotor pattern without abolishing locomotion.

Resting States Affect Spontaneous BOLD Oscillations in Sensory and Paralimbic Cortex

2008-08-12

The brain exhibits spontaneous neural activity that depends on the behavioral state of the organism. We asked whether the blood oxygenation level-dependent (BOLD) signal reflects these modulations. BOLD was measured under three steady-state conditions: while subjects kept their eyes closed, kept their eyes open, or while fixating. The BOLD spectral density was calculated across brain voxels and subjects. Visual, sensory-motor, auditory, and retrosplenial cortex showed modulations of the BOLD spectral density by resting state type. All modulated regions showed greater spontaneous BOLD oscillations in the eyes closed than the eyes open or fixation conditions, suggesting that the differences were endogenously driven. Next, we examined the pattern of correlations between regions whose ongoing BOLD signal was modulated by resting state type. Regional neuronal correlations were estimated using an analytic procedure from the comparison of BOLD–BOLD covariances in the fixation and eyes closed conditions. Most regions were highly correlated with one another, with the exception of the primary visual cortices, which showed low correlations with the other regions. In conclusion, changes in resting state were associated with synchronous modulations of spontaneous BOLD oscillations in cortical sensory areas driven by two spatially overlapping, but temporally uncorrelated signals.

Tonically Active Inhibition Selectively Controls Feedforward Circuits in Mouse Barrel Cortex

Krook-Magnuson, E. I., Li, P., Paluszkiewicz, S. M., Huntsman, M. M. — 2008-08-12

Tonic inhibition mediated by extrasynaptic -aminobutyric acid type A (GABA_A) receptors is a powerful conductance that controls cell excitability. Throughout the CNS, tonic inhibition is expressed at varying degrees across different cell types. Despite a rich history of cortical interneuron diversity, little is known about tonic inhibition in the different classes of cells in the cerebral cortex. We therefore examined the cell-type specificity and functional significance of tonic inhibition in layer 4 of the mouse somatosensory barrel cortex. In situ hybridization and immunocytochemistry showed moderate -subunit expression across the barrel structures. Whole cell patch-clamp recordings additionally indicated that significant levels of tonic inhibition can be found across cell types, with differences in the magnitude of inhibition between cell types. To activate tonic currents, we used 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, a superagonist at -subunit–containing GABA_A receptors) at a concentration that did not affect synaptic decay kinetics. THIP produced greater shifts in baseline holding current in inhibitory cells (low-threshold spiking [LTS], 109 ± 17 pA; fast spiking [FS], 111 ± 15 pA) than in excitatory cells (39 ± 10 pA; P < 0.001). In addition to these differences across cell types, there was also variability within inhibitory cells. FS cells with faster action potentials had larger baseline shifts. Because FS cells are known mediators of feedforward inhibition, we tested whether THIP-induced tonic conductance selectively controls feedforward circuits. THIP application resulted in the abolishment of the inhibitory postsynaptic potential in thalamic-evoked disynaptic responses in a subset of excitatory neurons. These data suggest multiple feedforward circuits can be differentiated by the inhibitory control of the presynaptic inhibitory neuron.

Asymmetric Recovery in Cerebellar-Deficient Mice Following Unilateral Labyrinthectomy

Beraneck, M., McKee, J. L., Aleisa, M., Cullen, K. E. — 2008-08-12

The term "vestibular compensation" refers to the resolution of motor deficits resulting from a peripheral vestibular lesion. We investigated the role of the cerebellum in the compensation process by characterizing the vestibuloocular reflex (VOR) evoked by head rotations at frequencies and velocities similar to those in natural behaviors in wild-type (WT) versus cerebellar-deficient Lurcher (Lc/+) mice. We found that during exploratory activity, normal mice produce head rotations largely consisting of frequencies ≤4 Hz and velocities and accelerations as large as 400°/s and 5,000°/s², respectively. Accordingly, the VOR was characterized using sinusoidal rotations (0.2–4 Hz) as well as transient impulses (~400°/s; ~2,000°/s²). Before lesions, WT and Lc/+ mice produced similar VOR responses to sinusoidal rotation. Lc/+ mice, however, had significantly reduced gains for transient stimuli. After unilateral labyrinthectomy, VOR recovery followed a similar course for WT and Lc/+ groups during the first week: gain was reduced by 80% for ipsilesionally directed head rotations on day 1 and improved for both strains to values of ~0.4 by day 5. Moreover, responses evoked by contralesionally directed rotations returned to prelesion in both strains within this period. However, unlike WT, which showed improving responses to ipsilesionally directed rotations, recovery plateaued after first week for Lc/+ mice. Our results show that despite nearly normal recovery in the acute phase, long-term compensation is compromised in Lc/+. We conclude that cerebellar pathways are critical for long-term restoration of VOR during head rotation toward the lesioned side, while noncerebellar pathways are sufficient to restore proper gaze stabilization during contralesionally directed movements.

Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex

Zhang, Y., Behrens, M. M., Lisman, J. E. — 2008-08-12

Postmortem studies have shown that schizophrenia produces a reduction in the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), a key enzyme for -aminobutyric acid (GABA) synthesis. N-methyl-d-aspartate receptor (NMDAR) antagonists have been extensively used to study schizophrenia because they can induce many aspects of the disease, including the decrease in GAD67. It is generally thought that this reduction in GAD implies a reduction in functional inhibition, but direct evidence had been lacking. We have therefore performed physiological studies in slices of prefrontal cortex taken from rats treated with the NMDAR antagonist ketamine. Both frequency and amplitude of miniature inhibitory postsynaptic currents were reduced. Consistent with a reduction of inhibition, we observed an increase in postsynaptic excitability. The increased excitability is likely to result from disinhibition because miniature excitatory postsynaptic current properties and intrinsic excitability were not changed. Ketamine did not affect inhibition or GAD levels in young rats, indicating a developmental regulation that may be related to the developmental increase in ketamine sensitivity that occurs in humans. Our results show that NMDAR antagonist produces biochemical changes in the GABA system that lead to a functional disinhibition. Such disinhibition would be expected to decrease gamma oscillations, which are reduced in schizophrenia.

Neural Selectivity in Anterior Inferotemporal Cortex for Morphed Photographic Images During Behavioral Classification or Fixation

Liu, Y., Jagadeesh, B. — 2008-08-12

Anterior inferotemporal cortex (aIT) contributes to the ability to discriminate and classify complex images. To determine whether and what proportion of single neurons in aIT cortex can yield enough information to classify complex images, we recorded from aIT neurons during the presentation of morphed photographic images in sessions in which monkeys classified images in a two alternative forced-choice—delayed-match-to-sample (2AFC-DMS) task or in sessions in which they performed a fixation task. The sample stimuli were chosen from a sequence in which one image was gradually morphed into another in a pair, while the original pair of images served as choices. Responses of many individual neurons in aIT cortex during the behavioral classification of the images, decoded using an ideal observer analysis, were sufficiently selective to account for the observed behavioral classification of the images. The responses of a separate population of neurons in aIT cortex recorded in subsequent sessions while the monkeys viewed the same images, were less selective than neural responses measured during sessions in which the 2AFC-DMS task was performed. Our findings show that many neurons in aIT could provide sensory information sufficient for the classification of images when a 2AFC-DMS task was performed.

A Biophysical Model of Synaptic Plasticity and Metaplasticity Can Account for the Dynamics of the Backward Shift of Hippocampal Place Fields

Yu, X., Shouval, H. Z., Knierim, J. J. — 2008-08-12

Hippocampal place cells in the rat undergo experience-dependent changes when the rat runs stereotyped routes. One such change, the backward shift of the place field center of mass, has been linked by previous modeling efforts to spike-timing–dependent plasticity (STDP). However, these models did not account for the termination of the place field shift and they were based on an abstract implementation of STDP that ignores many of the features found in cortical plasticity. Here, instead of the abstract STDP model, we use a calcium-dependent plasticity (CaDP) learning rule that can account for many of the observed properties of cortical plasticity. We use the CaDP learning rule in combination with a model of metaplasticity to simulate place field dynamics. Without any major changes to the parameters of the original model, the present simulations account both for the initial rapid place field shift and for the subsequent slowing down of this shift. These results suggest that the CaDP model captures the essence of a general cortical mechanism of synaptic plasticity, which may underlie numerous forms of synaptic plasticity observed both in vivo and in vitro.

Synaptic Regulation of the Light-Dependent Oscillatory Currents in Starburst Amacrine Cells of the Mouse Retina

Petit-Jacques, J., Bloomfield, S. A. — 2008-08-12

Responses of on-center starburst amacrine cells to steady light stimuli were recorded in the dark-adapted mouse retina. The response to spots of dim white light appear to show two components, an initial peak that correspond to the onset of the light stimulus and a series of oscillations that ride on top of the initial peak relaxation. The frequency of oscillations during light stimulation was three time higher than the frequency of spontaneous oscillations recorded in the dark. The light-evoked responses in starburst cells were exclusively dependent on the release of glutamate likely from presynaptic bipolar axon terminals and the binding of glutamate to AMPA/kainate receptors because they were blocked by 6-cyano-7-nitroquinoxalene-2,3-dione. The synaptic pathway responsible for the light responses was blocked by AP4, an agonist of metabotropic glutamate receptors that hyperpolarize on-center bipolar cells on activation. Light responses were inhibited by the calcium channel blockers cadmium ions and nifedipine, suggesting that the release of glutamate was calcium dependent. The oscillatory component of the response was specifically inhibited by blocking the glutamate transporter with d-threo-β-benzyloxyaspartic acid, suggesting that glutamate reuptake is necessary for the oscillatory release. GABAergic antagonists bicuculline, SR 95531, and picrotoxin increased the amplitude of the initial peak while they inhibit the frequency of oscillations. TTX had a similar effect. Strychnine, the blocker of glycine receptors did not affect the initial peak but strongly decreased the oscillations frequency. These inhibitory inputs onto the bipolar axon terminals shape and synchronize the oscillatory component.

Gustatory Neural Circuitry in the Hamster Brain Stem

Cho, Y. K., Li, C.-S. — 2008-08-12

The nucleus of the solitary tract (NST) and the parabrachial nuclei (PbN) are the first and second central relays for the taste pathway, respectively. Taste neurons in the NST project to the PbN, which further transmits taste information to the rostral taste centers. Nevertheless, details of the neural connections among the brain stem gustatory nuclei are obscure. Here, we investigated these relationships in the hamster brain stem. Three electrode assemblies were used to record the activity of taste neurons extracellularly and then to electrically stimulate these same areas in the order: left PbN, right PbN, and right NST. A fourth electrode, a glass micropipette, was used to record from gustatory cells in the left NST. Results showed extensive bilateral communication between brain stem nuclei at the same level: 1) 10% of 96 NST neurons projected to the contralateral NST and 58% received synaptic input from the contralateral NST; and 2) 12% of 43 PbN neurons projected to the contralateral PbN and 21% received synaptic input from the contralateral PbN. Results also showed extensive communication between levels: 1) as expected, the majority of 119 NST neurons, 82%, projected to the ipsilateral PbN, but 85% of the 20 NST neurons tested received synaptic input from the ipsilateral PbN, as did 59% of 22 NST neurons that did not project to the PbN; and 2) although few, 3%, of 119 NST cells projected to the contralateral PbN and 38% received synaptic input from the contralateral PbN. These results demonstrated that taste neurons in the NST not only project to, but also receive descending input from the bilateral PbN and that gustatory neurons in the NST and PbN also communicate with the corresponding nucleus on the contralateral side.

Cellular and Synaptic Actions of Acetylcholine in the Lamprey Spinal Cord

Quinlan, K. A., Buchanan, J. T. — 2008-08-12

This study investigated cellular and synaptic mechanisms of cholinergic neuromodulation in the in vitro lamprey spinal cord. Most spinal neurons tested responded to local application of acetylcholine (ACh) with depolarization and decreased input resistance. The depolarization persisted in the presence of either tetrodotoxin or muscarinic antagonist scopolamine and was abolished with nicotinic antagonist mecamylamine, indicating a direct depolarization through nicotinic ACh receptors. Local application of muscarinic ACh agonists modulated synaptic strength in the spinal cord by decreasing the amplitude of unitary excitatory and inhibitory postsynaptic potentials. The postsynaptic response to direct application of glutamate was unchanged by muscarinic agonists, suggesting a presynaptic mechanism. Cholinergic feedback from motoneurons was assessed using stimulation of a ventral root in the quiescent spinal cord while recording intracellularly from spinal motoneurons or interneurons. Mainly depolarizing potentials were observed, a portion of which was insensitive to removal of extracellular Ca²⁺, indicating electrotonic coupling. Hyperpolarizing potentials were also observed and were attenuated by the glycinergic antagonist strychnine, whereas depolarizing responses were potentiated by strychnine. Mecamylamine also reduced hyperpolarizing responses. The pharmacology of these responses suggests a Renshaw-like feedback pathway in lamprey. Immunohistochemistry for choline acetyltransferase, performed in combination with retrograde filling of motoneurons, demonstrated a population of nonmotoneuron cholinergic cells in the lamprey spinal cord. Thus endogenous cholinergic modulation of the lamprey spinal locomotor network is likely produced by both motoneurons and cholinergic interneurons acting via combined postsynaptic and presynaptic actions.

Time and Frequency Characteristics of Purkinje Cell Complex Spikes in the Awake Monkey Performing a Nonperiodic Task

2008-08-12

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

Endocannabinoid- and mGluR5-Dependent Short-Term Synaptic Depression in an Isolated Neuron/Bouton Preparation From the Hippocampal CA1 Region

Sheinin, A., Talani, G., Davis, M. I., Lovinger, D. M. — 2008-08-12

Endocannabinoids released from the postsynaptic neuronal membrane can activate presynaptic CB₁ receptors and inhibit neurotransmitter release. In hippocampal slices, depolarization of the CA1 pyramidal neurons elicits an endocannabinoid-mediated inhibition of -aminobutyric acid release known as depolarization-induced suppression of inhibition (DSI). Using the highly reduced neuron/synaptic bouton preparation from the CA1 region of hippocampus, we have begun to examine endocannabinoid-dependent short-term depression (STD) of inhibitory synaptic transmission under well-controlled physiological and pharmacological conditions in an environment free of other cells. Application of the CB₁ synthetic agonist WIN55212-2 and endogenous cannabinoids 2-AG and anandamide produced a decrease in spontaneous inhibitory postsynaptic current (sIPSC) frequency and amplitude, indicating the presence of CB₁ receptors at synapses in this preparation. Endocannabinoid-dependent STD is different from DSI found in hippocampal slices and the neuron/bouton preparation from basolateral amygdala (BLA) since depolarization alone was not sufficient to induce suppression of sIPSCs. However, concurrent application of the metabotropic glutamate receptor (mGluR) agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) and postsynaptic depolarization resulted in a transient (30–50 s) decrease in sIPSC frequency and amplitude. Application of DHPG alone had no effect on sIPSCs. The depolarization/DHPG-induced STD was blocked by the CB₁ antagonist SR141716A and the mGluR5 antagonist MPEP and was sensitive to intracellular calcium concentration. Comparing the present findings with earlier work in hippocampal slices and BLA, it appears that endocannabinoid release is less robust in isolated hippocampal neurons.

Pre- and Postsynaptic Serotoninergic Excitation of Globus Pallidus Neurons

Rav-Acha, M., Bergman, H., Yarom, Y. — 2008-08-12

The basal ganglia (BG) play a critical role in the pathogenesis and pathophysiology of Parkinson's disease (PD). Recent studies indicate that serotoninergic systems modulate BG activity and may be implicated in the pathophysiology and treatment of PD. The globus pallidus (GP), the rodent homologue of the primate GPe, is the main central nucleus of the basal ganglia, affecting the striatum, the subthalamic nucleus (STN), and BG output structures. We therefore studied the effect of serotonin (5-HT) and specific 5-HT agonists and antagonists on GP neurons from rat brain slices. Using intra- and extracellular recordings of GP neurons we found that serotonin increases the firing rate of GP neurons. Analyzing the effects of specific 5-HT agonists and antagonists on the firing rate of GP neurons showed that the increase in firing rate is due to the activation of 5-HT_1B and 5-HT_1A receptors. Intracellular recordings in both voltage- and current-clamp modes revealed that serotonin mediates its effect via pre- and postsynaptic mechanisms. The presynaptic effect is mediated by attenuation of -aminobutyric acid release, probably through activation of 5-HT_1B receptors. Postsynaptically, serotonin activates a hyperpolarization-activated cation channel, probably via 5-HT1_A receptors. Furthermore, serotonin decreases the fast synaptic depression characteristic of the striatal afferent input. The decreased serotonin concentrations in the BG nuclei in PD may contribute to depressed GP activity and enhance the emergence of BG pathological synchronous oscillations. We therefore suggest that future therapeutics of PD should be directed toward restoration of normal serotonin levels in BG nuclei.

A Hebbian Learning Rule Mediates Asymmetric Plasticity in Aligning Sensory Representations

Witten, I. B., Knudsen, E. I., Sompolinsky, H. — 2008-08-12

In the brain, mutual spatial alignment across different sensory representations can be shaped and maintained through plasticity. Here, we use a Hebbian model to account for the synaptic plasticity that results from a displacement of the space representation for one input channel relative to that of another, when the synapses from both channels are equally plastic. Surprisingly, although the synaptic weights for the two channels obeyed the same Hebbian learning rule, the amount of plasticity exhibited by the respective channels was highly asymmetric and depended on the relative strength and width of the receptive fields (RFs): the channel with the weaker or broader RFs always exhibited most or all of the plasticity. A fundamental difference between our Hebbian model and most previous models is that in our model synaptic weights were normalized separately for each input channel, ensuring that the circuit would respond to both sensory inputs. The model produced three distinct regimes of plasticity dynamics (winner-take-all, mixed-shift, and no-shift), with the transition between the regimes depending on the size of the spatial displacement and the degree of correlation between the sensory channels. In agreement with experimental observations, plasticity was enhanced by the accumulation of incremental adaptive adjustments to a sequence of small displacements. These same principles would apply not only to the maintenance of spatial registry across input channels, but also to the experience-dependent emergence of aligned representations in developing circuits.

Noninvasive Stimulation of Human Corticospinal Axons Innervating Leg Muscles

Martin, P. G., Butler, J. E., Gandevia, S. C., Taylor, J. L. — 2008-08-12

These studies investigated whether a single electrical stimulus over the thoracic spine activates corticospinal axons projecting to human leg muscles. Transcranial magnetic stimulation of the motor cortex and electrical stimulation over the thoracic spine were paired at seven interstimulus intervals, and surface electromyographic responses were recorded from rectus femoris, tibialis anterior, and soleus. The interstimulus intervals (ISIs) were set so that the first descending volley evoked by cortical stimulation had not arrived at (positive ISIs), was at the same level as (0 ISI) or had passed (negative ISIs) the site of activation of descending axons by the thoracic stimulation at the moment of its delivery. Compared with the responses to motor cortical stimulation alone, responses to paired stimuli were larger at negative ISIs but reduced at positive ISIs in all three leg muscles. This depression of responses at positive ISIs is consistent with an occlusive interaction in which an antidromic volley evoked by the thoracic stimulation collides with descending volleys evoked by cortical stimulation. The cortical and spinal stimuli activate some of the same corticospinal axons. Thus it is possible to examine the excitability of lower limb motoneuron pools to corticospinal inputs without the confounding effects of changes occurring within the motor cortex.

Complex Temporal Response Patterns With a Simple Retinal Circuit

Werner, B., Cook, P. B., Passaglia, C. L. — 2008-08-12

The retina can respond to a wide array of features in the visual input. It was recently reported that the retina can even recognize complicated temporal input patterns and signal violations in the patterns. When a sequence of flashes was presented, ganglion cells exhibited a variety of firing profiles and many cells showed an "omitted stimulus response" (OSR), in which they fired strongly if a flash in the sequence was omitted. We examined the synaptic origins of the OSR by recording excitatory synaptic currents from ganglion cells in the salamander retina in response to periodic flash sequences. Consistent with previous spike recordings, ganglion cells exhibited an OSR in their current response and the OSR shifted in time with a change in flash frequency such that it could predict when the next flash should have occurred. Although the behavior may seem sophisticated, we show that a simple linear–nonlinear model with a spike threshold can account for the OSR in on ganglion cells and that the variety of complex firing profiles seen in other ganglion cells can be explained by adding contributions from the off pathway. We discuss the physiological and simulation results and their implications for understanding retinal mechanisms of visual information processing.