Journal of Neurophysiology current issue

The Hemo-Neural Hypothesis: On The Role of Blood Flow in Information Processing

Moore, C. I., Cao, R. — 2008-05-13

Brain vasculature is a complex and interconnected network under tight regulatory control that exists in intimate communication with neurons and glia. Typically, hemodynamics are considered to exclusively serve as a metabolic support system. In contrast to this canonical view, we propose that hemodynamics also play a role in information processing through modulation of neural activity. Functional hyperemia, the basis of the functional MRI (fMRI) BOLD signal, is a localized influx of blood correlated with neural activity levels. Functional hyperemia is considered by many to be excessive from a metabolic standpoint, but may be appropriate if interpreted as having an activity-dependent neuro-modulatory function. Hemodynamics may impact neural activity through direct and indirect mechanisms. Direct mechanisms include delivery of diffusible blood-borne messengers and mechanical and thermal modulation of neural activity. Indirect mechanisms are proposed to act through hemodynamic modulation of astrocytes, which can in turn regulate neural activity. These hemo-neural mechanisms should alter the information processing capacity of active local neural networks. Here, we focus on analysis of neocortical sensory processing. We predict that hemodynamics alter the gain of local cortical circuits, modulating the detection and discrimination of sensory stimuli. This novel view of information processing—that includes hemodynamics as an active and significant participant—has implications for understanding neural representation and the construction of accurate brain models. There are also potential medical benefits of an improved understanding of the role of hemodynamics in neural processing, as it directly bears on interpretation of and potential treatment for stroke, dementia, and epilepsy.

Recording Temperature Affects the Excitability of Mouse Superficial Dorsal Horn Neurons, In Vitro

Graham, B. A., Brichta, A. M., Callister, R. J. — 2008-05-13

Superficial dorsal horn (SDH) neurons in laminae I–II of the spinal cord play an important role in processing noxious stimuli. These neurons represent a heterogeneous population and are divided into various categories according to their action potential (AP) discharge during depolarizing current injection. We recently developed an in vivo mouse preparation to examine functional aspects of nociceptive processing and AP discharge in SDH neurons and to extend investigation of pain mechanisms to the genetic level of analysis. Not surprisingly, some in vivo data obtained at body temperature (37°C) differed from those generated at room temperature (22°C) in spinal cord slices. In the current study we examine how temperature influences SDH neuron properties by making recordings at 22 and 32°C in transverse spinal cord slices prepared from L3–L5 segments of adult mice (C57Bl/6). Patch-clamp recordings (KCH₃SO₄ internal) were made from visualized SDH neurons. At elevated temperature all SDH neurons had reduced input resistance and smaller, briefer APs. Resting membrane potential and AP afterhyperpolarization amplitude were temperature sensitive only in subsets of the SDH population. Notably, elevated temperature increased the prevalence of neurons that did not discharge APs during current injection. These reluctant firing neurons expressed a rapid A-type potassium current, which is enhanced at higher temperatures and thus restrains AP discharge. When compared with previously published whole cell recordings obtained in vivo (37°C) our results suggest that, on balance, in vitro data collected at elevated temperature more closely resemble data collected under in vivo conditions.

Similar Properties of Transient, Persistent, and Resurgent Na Currents in GABAergic and Non-GABAergic Vestibular Nucleus Neurons

Gittis, A. H., du Lac, S. — 2008-05-13

Sodium currents in fast firing neurons are tuned to support sustained firing rates >50–60 Hz. This is typically accomplished with fast channel kinetics and the ability to minimize the accumulation of Na channels into inactivated states. Neurons in the medial vestibular nuclei (MVN) can fire at exceptionally high rates, but their Na currents have never been characterized. In this study, Na current kinetics and voltage-dependent properties were compared in two classes of MVN neurons with distinct firing properties. Non-GABAergic neurons (fluorescently labeled in YFP-16 transgenic mice) have action potentials with faster rise and fall kinetics and sustain higher firing rates than GABAergic neurons (fluorescently labeled in GIN transgenic mice). A previous study showed that these neurons express a differential balance of K currents. To determine whether the Na currents in these two populations were different, their kinetics and voltage-dependent properties were measured in acutely dissociated neurons from 24- to 40-day-old mice. All neurons expressed persistent Na currents and large transient Na currents with resurgent kinetics tuned for fast firing. No differences were found between the Na currents expressed in GABAergic and non-GABAergic MVN neurons, suggesting that differences in properties of these neurons are tuned by their K currents.

Dendritic Ih Ensures High-Fidelity Dendritic Spike Responses of Motion-Sensitive Neurons in Rat Superior Colliculus

2008-05-13

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that generate I_h currents are widely distributed in the brain and have been shown to contribute to various neuronal functions. In the present study, we investigated the functions of I_h in the motion-sensitive projection neurons [wide field vertical (WFV) cells] of the superior colliculus, a pivotal visual center for detection of and orientating to salient objects. Combination of whole cell recordings and immunohistochemical investigations suggested that HCN1 channels dominantly contribute to the I_h in WFV cells among HCN isoforms expressed in the superficial superior colliculus and mainly located on their expansive dendritic trees. We found that blocking I_h suppressed the initiation of short- and fixed-latency dendritic spike responses and led instead to long- and fluctuating-latency somatic spike responses to optic fiber stimulations. These results suggest that the dendritic I_h facilitates the dendritic initiation and/or propagation of action potentials and ensures that WFV cells generate spike responses to distal synaptic inputs in a sensitive and robustly time-locked manner, probably by acting as continuous depolarizing drive and fixing dendritic membrane potentials close to the spike threshold. These functions are different from known functions of dendritic I_h revealed in hippocampal and neocortical pyramidal cells, where they spatiotemporally limit the propagations of synaptic inputs along the apical dendrites by reducing dendritic membrane resistance. Thus we have revealed new functional aspects of I_h, and these dendritic properties are likely critical for visual motion processing in these neurons.

Modulation of Olfactory Information Processing in the Antennal Lobe of Manduca sexta by Serotonin

Dacks, A. M., Christensen, T. A., Hildebrand, J. G. — 2008-05-13

The nervous system copes with variability in the external and internal environment by using neuromodulators to adjust the efficacy of neural circuits. The role of serotonin (5HT) as a neuromodulator of olfactory information processing in the antennal lobe (AL) of Manduca sexta was examined using multichannel extracellular electrodes to record the responses of ensembles of AL neurons to olfactory stimuli. In one experiment, the effects of 5HT on the concentration-response functions for two essential plant oils across a range of stimulus intensities were examined. In a second experiment, the effect of 5HT on the ability of ensembles to discriminate odorants from different chemical classes was examined. Bath application of 5HT enhanced AL unit responses by increasing response duration and firing rate, which in turn increased the amount of spike time cross-correlation and -covariance between pairs of units. 5HT had the greatest effect on overall ensemble activation at higher odorant concentrations, resulting in an increase in the gain of the dose-response function of individual units. Additionally, response thresholds shifted to lower odorant concentrations for some units, suggesting that 5HT increased their sensitivity. Serotonin enhanced ensemble discrimination of different concentrations of individual odorants as well as discrimination of structurally dissimilar odors at the same concentration. Given the known circadian fluctuations of 5HT in the AL of this species, these findings support the hypothesis that 5HT periodically enhances sensitivity and responsiveness in the AL of Manduca to maximize efficiency when the requirement for olfactory acuity is the greatest.

A Computational Model of Perceptual Fill-in Following Retinal Degeneration

McManus, J. N. J., Ullman, S., Gilbert, C. D. — 2008-05-13

The ablation of afferent input results in the reorganization of sensory and motor cortices. In the primary visual cortex (V1), binocular retinal lesions deprive a corresponding cortical region [lesion projection zone (LPZ)] of visual input. Nevertheless, neurons in the LPZ regain responsiveness by shifting their receptive fields (RFs) outside the retinal lesions; this re-emergence of neural activity is paralleled by the perceptual completion of disrupted visual input in human subjects with retinal damage. To determine whether V1 reorganization can account for perceptual fill-in, we developed a neural network model that simulates the cortical remapping in V1. The model shows that RF shifts mediated by the plexus of spatial- and orientation-dependent horizontal connections in V1 can engender filling-in that is both robust and consistent with psychophysical reports of perceptual completion. Our model suggests that V1 reorganization may underlie perceptual fill-in, and it predicts spatial relationships between the original and remapped RFs that can be tested experimentally. More generally, it provides a general explanation for adaptive functional changes following CNS lesions, based on the recruitment of existing cortical connections that are involved in normal integrative mechanisms.

Interactions With Compliant Loads Alter Stretch Reflex Gains But Not Intermuscular Coordination

Perreault, E. J., Chen, K., Trumbower, R. D., Lewis, G. — 2008-05-13

The human motor system regulates arm mechanics to produce stable postures during interactions with different physical environments. This occurs partly via involuntary mechanisms, including stretch reflexes. Previous single-joint studies demonstrated enhanced reflex sensitivity during interactions with compliant environments, suggesting reflex gain increases to enhance limb stability when that stability is not provided by the environment. This study examined whether similar changes in reflex gain are present throughout the limb following perturbations that simultaneously influence multiple joints. Furthermore, we investigated whether any observed modulation was accompanied by task-specific changes in reflex coordination across muscles, a question that cannot be addressed using single-joint perturbations. Reflexes were elicited during the maintenance of posture by perturbing the arm with a three degrees of freedom robot, configured to have isotropic stiffness of either 10 N/m (compliant) or 10 kN/m (stiff). Perturbation characteristics were matched in both environments. Reflex magnitude was quantified by the average rectified electromyogram, recorded from eight muscles crossing the elbow and shoulder. Reflex coordination was assessed using independent components analysis to compare reflex activation patterns during interactions with stiff and compliant environments. Stretch reflex sensitivity increased significantly in all muscles during interactions with the compliant environment and these changes were not due to changes in background muscle activity. However, there was no significant difference in the reflex coordination patterns observed during interactions with the stiff and compliant environments. These results suggest that reflex modulation occurred through altered use of fixed muscle coordination patterns rather than through a change in reflex coordination.

Differential Modulation of Neural Network and Pacemaker Activity Underlying Eupnea and Sigh-Breathing Activities

2008-05-13

Many networks generate distinct rhythms with multiple frequency and amplitude characteristics. The respiratory network in the pre-Bötzinger complex (pre-Böt) generates both the low-frequency, large-amplitude sigh rhythm and a faster, smaller-amplitude eupneic rhythm. Could the same set of pacemakers generate both rhythms? Here we used an in vitro respiratory brainslice preparation. We describe a subset of synaptically isolated pacemakers that spontaneously generate two distinct bursting patterns. These two patterns resemble network activity including sigh-like bursts that occur at low frequencies and have large amplitudes and eupneic-like bursts with higher frequency and smaller amplitudes. Cholinergic neuromodulation altered the network and pacemaker bursting: fictive sigh frequency is increased dramatically, whereas fictive eupneic frequency is drastically lowered. The data suggest that timing and amplitude characteristics of fictive eupneic and sigh rhythms are set by the same set of pacemakers that are tuned by changes in the neuromodulatory state.

cGMP Activates a pH-Sensitive Leak K+ Current in the Presumed Cholinergic Neuron of Basal Forebrain

2008-05-13

In an earlier study, we demonstrated that nitric oxide (NO) causes the long-lasting membrane hyperpolarization in the presumed basal forebrain cholinergic (BFC) neurons by cGMP–PKG-dependent activation of leak K⁺ currents in slice preparations. In the present study, we investigated the ionic mechanisms underlying the long-lasting membrane hyperpolarization with special interest in the pH sensitivity because 8-Br-cGMP–induced K⁺ current displayed Goldman–Hodgkin–Katz rectification characteristic of TWIK-related acid-sensitive K⁺ (TASK) channels. When examined with the ramp command pulse depolarizing from –130 to –40 mV, the presumed BFC neurons displayed a pH-sensitive leak K⁺ current that was larger in response to pH decrease from 8.3 to 7.3 than in response to pH decrease from 7.3 to 6.3. This K⁺ current was similar to TASK1 current in its pH sensitivity, whereas it was highly sensitive to Ba²⁺, unlike TASK1 current. The 8-Br-cGMP–induced K⁺ currents in the presumed BFC neurons were almost completely inhibited by lowering external pH to 6.3 as well as by bath application of 100 µM Ba²⁺, consistent with the nature of the leak K⁺ current expressed in the presumed BFC neurons. After 8-Br-cGMP application, the K⁺ current obtained by pH decrease from 7.3 to 6.3 was larger than that obtained by pH decrease from pH 8.3 to 7.3, contrary to the case seen in the control condition. These observations strongly suggest that 8-Br-cGMP activates a pH- and Ba²⁺-sensitive leak K⁺ current expressed in the presumed BFC neurons by modulating its pH sensitivity.

Neurotensin Enhances GABAergic Activity in Rat Hippocampus CA1 Region by Modulating L-Type Calcium Channels

Li, S., Geiger, J. D., Lei, S. — 2008-05-13

Neurotensin (NT) is a tridecapeptide that interacts with three NT receptors; NTS1, NTS2, and NTS3. Although NT has been reported to modulate GABAergic activity in the brain, the underlying cellular and molecular mechanisms of NT are elusive. Here, we examined the effects of NT on GABAergic transmission and the involved cellular and signaling mechanisms of NT in the hippocampus. Application of NT dose-dependently increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from CA1 pyramidal neurons with no effects on the amplitude of sIPSCs. NT did not change either the frequency or the amplitude of miniature (m)IPSCs recorded in the presence of tetrodotoxin. Triple immunofluorescent staining of recorded interneurons demonstrated the expression of NTS1 on GABAergic interneurons. NT increased the action potential firing rate but decreased the afterhyperpolarization (AHP) amplitude in identified CA1 interneurons. Application of L-type calcium channel blockers (nimodipine and nifedipine) abolished NT-induced increases in action potential firing rate and sIPSC frequency and reduction in AHP amplitude, suggesting that the effects of NT are mediated by interaction with L-type Ca²⁺ channels. NT-induced increase in sIPSC frequency was blocked by application of the specific NTS1 antagonist SR48692, the phospholipase C (PLC) inhibitor U73122, the IP₃ receptor antagonist 2-APB, and the protein kinase C inhibitor GF109203X, suggesting that NT increases -aminobutyric acid release via a PLC pathway. Our results provide a cellular mechanism by which NT controls GABAergic neuronal activity in hippocampus.

Responses to Binary Taste Mixtures in the Nucleus of the Solitary Tract: Neural Coding With Firing Rate

Chen, J.-Y., Di Lorenzo, P. M. — 2008-05-13

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

Role of Interneuron Diversity in the Cortical Microcircuit for Attention

Buia, C. I., Tiesinga, P. H. — 2008-05-13

Receptive fields of neurons in cortical area V4 are large enough to fit multiple stimuli, making V4 the ideal place to study the effects of selective attention at the single-neuron level. Experiments have revealed evidence for stimulus competition and have characterized the effect thereon of spatial and feature-based attention. We developed a biophysical model with spiking neurons and conductance-based synapses. To account for the comprehensive set of experimental results, it was necessary to include in the model, in addition to regular spiking excitatory (E) cells, two types of interneurons: feedforward interneurons (FFI) and top-down interneurons (TDI). Feature-based attention was mediated by a projection of the TDI to the FFI, stimulus competition was mediated by a cross-columnar excitatory connection to the FFI, whereas spatial attention was mediated by an increase in activity of the feedforward inputs from cortical area V2. The model predicts that spatial attention increases the FFI firing rate, whereas feature-based attention decreases the FFI firing rate and increases the TDI firing rate. During strong stimulus competition, the E cells were synchronous in the beta frequency range (15–35 Hz), but with feature-based attention, they became synchronous in the gamma frequency range (35–50 Hz). We propose that the FFI correspond to fast-spiking, parvalbumin-positive basket cells and that the TDI correspond to cells with a double-bouquet morphology that are immunoreactive to calbindin or calretinin. Taken together, the model results provide an experimentally testable hypothesis for the behavior of two interneuron types under attentional modulation.

Calcium- and Calmodulin-Dependent Inactivation of Calcium Channels in Inner Hair Cells of the Rat Cochlea

Grant, L., Fuchs, P. — 2008-05-13

Modulation of voltage-gated calcium channels was studied in inner hair cells (IHCs) in an ex vivo preparation of the apical turn of the rat organ of Corti. Whole cell voltage clamp in the presence of potassium channel blockers showed inward calcium currents with millisecond activation and deactivation kinetics. When temperature was raised from 22 to 37°C, the calcium currents of immature IHCs [<12 days postnatal (P12)] increased threefold in amplitude, and developed more pronounced inactivation. This was determined to be calcium-dependent inactivation (CDI) on the basis of its reliance on external calcium (substitution with barium), sensitivity to internal calcium-buffering, and voltage dependence (reflecting the calcium driving force). After the onset of hearing at P12, IHC calcium current amplitude and the extent of inactivation were greatly reduced. Although smaller than in prehearing IHCs, CDI remained significant in the mature IHC near the resting membrane potential. CDI in mature IHCs was enhanced by application of the endoplasmic calcium pump blocker, benzo-hydroquinone. Conversely, CDI in immature IHCs was reduced by calmodulin inhibitors. Thus voltage-gated calcium channels in mammalian IHCs are subject to a calmodulin-mediated process of CDI. The extent of CDI depends on the balance of calcium buffering mechanisms and may be regulated by calmodulin-specific processes. CDI provides a means for the rate of spontaneous transmitter release to be adjusted to variations in hair cell resting potential and steady state calcium influx.

Hand Position Affects Saccadic Reaction Times in Monkeys and Humans

Thura, D., Boussaoud, D., Meunier, M. — 2008-05-13

In daily life, activities requiring the hand and eye to work separately are as frequent as activities requiring tight eye–hand coordination, and we effortlessly switch from one type of activity to the other. Such flexibility is unlikely to be achieved without each effector "knowing" where the other one is at all times, even when it is static. Here, we provide behavioral evidence that the mere position of the static hand affects one eye movement parameter: saccadic reaction time. Two monkeys were trained and 11 humans instructed to perform nondelayed or delayed visually guided saccades to either a right or a left target while holding their hand at a location either near or far from the eye target. From trial to trial, target locations and hand positions varied pseudorandomly. Subjects were tested both when they could and when they could not see their hand. The main findings are 1) the presence of the static hand in the workspace did affect saccade initiation; 2) this interaction persisted when the hand was invisible; 3) it was strongly influenced by the delay duration: hand–target proximity retarded immediate saccades, whereas it could hasten delayed saccades; and 4) this held true both for humans and for each of the two monkeys. We propose that both visual and nonvisual hand position signals are used by the primates' oculomotor system for the planning and execution of saccades, and that this may result in a hand–eye competition for spatial attentional resources that explains the delay-dependent reversal observed.

Enhanced Ih Depresses Rat Entopeduncular Nucleus Neuronal Activity From High-Frequency Stimulation or Raised Ke+

Shin, D. S., Carlen, P. L. — 2008-05-13

High-frequency stimulation (HFS) is used to treat a variety of neurological diseases, yet its underlying therapeutic action is not fully elucidated. Previously, we reported that HFS-induced elevation in [K⁺]_e or bath perfusion of raised K_e⁺ depressed rat entopeduncular nucleus (EP) neuronal activity via an enhancement of an ionic conductance leading to marked depolarization. Herein, we show that the hyperpolarization-activated (I_h) channel mediates the HFS- or K⁺-induced depression of EP neuronal activity. The perfusion of an I_h channel inhibitor, 50 µM ZD7288 or 2 mM CsCl, increased input resistance by 23.5 ± 7% (ZD7288) or 35 ± 10% (CsCl), hyperpolarized cells by 3.4 ± 1.7 mV (ZD7288) or 2.3 ± 0.9 mV (CsCl), and decreased spontaneous action potential (AP) frequency by 51.5 ± 12.5% (ZD7288) or 80 ± 13.5% (CsCl). The I_h sag was absent with either treatment, suggesting a block of I_h channel activity. Inhibition of the I_h channel prior to HFS or 6 mM K⁺ perfusion not only prevented the previously observed decrease in AP frequency, but increased neuronal activity. Under voltage-clamp conditions, I_h currents were enhanced in the presence of 6 mM K⁺. Calcium is also involved in the depression of EP neuronal activity, since its removal during raised K_e⁺ application prevented this attenuation and blocked the I_h sag. We conclude that the enhancement of I_h channel activity initiates the HFS- and K⁺-induced depression of EP neuronal activity. This mechanism could underlie the inhibitory effects of HFS used in deep brain stimulation in output basal ganglia nuclei.

How Do Brain Areas Communicate During the Processing of Noxious Stimuli? An Analysis of Laser-Evoked Event-Related Potentials Using the Granger Causality Index

2008-05-13

Several imaging techniques have identified different brain areas involved in the processing of noxious stimulation and thus in the constitution of pain. However, only little is known how these brain areas communicate with one another after activation by stimulus processing and which areas directionally affect or modulate the activity of succeeding areas. One measure for the analysis of such interactions is represented by the Granger Causality Index (GCI). In applying time-varying bivariate and partial variants of this concept (tvGCI), the aim of the present study was to investigate the interaction of neural activities between a set of scalp electrodes that best represent the brain electrical neural activity of major cortical areas involved in the processing of noxious laser-heat stimuli and their variation in time. Bivariate and partial tvGCIs were calculated within four different intervals of laser-evoked event-related potentials (LEPs) including a baseline period prior to stimulus application and three intervals immediately following stimulus application, i.e., between 170 and 200 ms (at the N2 component), between 260 and 320 ms (P2 component), and between 320 and 400 ms (P3 component of LEPs). Results show some similarities, but also some striking differences between bivariate and partial tvGCIs. These differences might be explained by the nature of bivariate and partial tvGCIs. However, both tvGCI approaches revealed a directed interaction between medial and lateral electrodes of the centroparietal region. This result was interpreted as a directed interaction between the anterior cingulate cortex and the secondary somatosensory cortex and the insula, structures that are significantly involved in the constitution of pain.

Discharge Variability of Motor Units in an Intrinsic Muscle of Transplanted Hand

Farina, D., Pozzo, M., Lanzetta, M., Enoka, R. M. — 2008-05-13

The study analyzed the discharge characteristics of the motor units in an intrinsic muscle of a transplanted hand. Multichannel electromyographic (EMG) recordings were obtained in 11 experimental sessions over 16 mo starting from day 205 after a hand was transplanted in a 35-yr-old man who had lost his right hand 22 yr earlier. The action potentials discharged by single motor units were identified from the surface EMG signals of the abductor digiti minimi muscle in the transplanted hand as the individual performed 60-s maximal and linearly increasing (ramp) contractions. Discharge rate decreased from 27.1 ± 8.4 pulses per second (pps) at the start of the maximal contractions to 17.2 ± 2.9 pps at the end (P < 0.001) and increased from 17.4 ± 4.3 to 22.1 ± 5.0 pps during the ramp contractions (P < 0.05). The SD of the interspike interval (ISI) nearly related to the mean ISI with a similar regression slope for the maximal (0.49 ± 0.09) and ramp contractions (0.43 ± 0.10). The coefficient of variation for ISI was higher than values in able-bodied persons and did not change during either the maximal (36.8 ± 10.8%) or the ramp contractions (35.9 ± 7.4%). High-frequency bursts of activity with <20 ms between two and six action potentials occurred during both maximal and ramp contractions. In conclusion, motor neurons that reinnervated a muscle in a transplanted hand discharged action potentials with a high degree of variability that suggested greater synaptic noise during the voluntary contractions.

Biophysical Properties of Human Nav1.7 Splice Variants and Their Regulation by Protein Kinase A

Chatelier, A., Dahllund, L., Eriksson, A., Krupp, J., Chahine, M. — 2008-05-13

The sodium channel Na_v1.7 is preferentially expressed in nociceptive neurons and is believed to play a crucial role in pain sensation. Four alternative splice variants are expressed in human dorsal root ganglion neurons, two of which differ in exon 5 by two amino acids in the S3 segment of domain I (exons 5A and 5N). Two others differ in exon 11 by the presence (11L) or absence (11S) of an 11 amino acid sequence in the loop between domains I and II, an important region for PKA regulation. In the present study, we used the whole cell configuration of the patch-clamp technique to investigate the biophysical properties and 8-bromo-cyclic adenosine monophosphate (8Br-cAMP) modulation of these splice variants expressed in tsA201 cells in the presence of the β₁-subunit. The alternative splicing of Na_v1.7 had no effect on most of the biophysical properties of this channel, including activation, inactivation, and recovery from inactivation. However, development of inactivation experiments revealed that the isoform containing exon 5A had slower kinetics of inactivation for negative potentials than that of the variant containing exon 5N. This difference was associated with higher ramp current amplitudes for isoforms containing exon 5A. Moreover, 8Br-cAMP–mediated phosphorylation induced a negative shift of the activation curve of variants containing exon 11S, whereas inactivation properties were unchanged. Isoforms with exon 11L were not modulated by 8Br-cAMP–induced phosphorylation. We conclude that alternative splicing of human Na_v1.7 can specifically modulate the biophysical properties and cAMP-mediated regulation of this channel. Changing the proportions of these variants may thus influence neuronal excitability and pain sensation.

Modulation of Trigeminal Spinal Subnucleus Caudalis Neuronal Activity Following Regeneration of Transected Inferior Alveolar Nerve in Rats

2008-05-13

Modulation of trigeminal spinal subnucleus caudalis neuronal activity following regeneration of transected inferior alveolar nerve in rats. To clarify the neuronal mechanisms of abnormal pain in the face innervated by the regenerated inferior alveolar nerve (IAN), nocifensive behavior, trigeminal ganglion neuronal labeling following Fluorogold (FG) injection into the mental skin, and trigeminal spinal subnucleus caudalis (Vc) neuronal properties were examined in rats with IAN transection. The mechanical escape threshold was significantly higher at 3 days and lower at 14 days after IAN transection, whereas head withdrawal latency to heat was significantly longer at 3, 14, and 60 days after IAN transection. The number of FG-labeled ganglion neurons was significantly reduced at 3 days after IAN transection but increased at 14 and 60 days. The number of wide dynamic range (WDR) neurons with background (BG) activity was significantly higher at 14 and 60 days after IAN transection compared with naïve rats, and the number of WDR and low-threshold mechanoreceptive (LTM) neurons with irregularly bursting BG activity was increased at these two time points. Mechanically evoked responses were significantly larger in WDR and LTM neurons 14 days after IAN transection compared with naïve rats. Heat- and cold-evoked responses in WDR neurons were significantly lower at 14 days after transection compared with naïve rats. Mechanoreceptive fields were also significantly larger in WDR and LTM neurons at 14 and 60 days after IAN transection. These findings suggest that these alterations may be involved in the development of mechanical allodynia in the cutaneous region innervated by the regenerated IAN.

Body-Tilt and Visual Verticality Perception During Multiple Cycles of Roll Rotation

Vingerhoets, R.A.A., Medendorp, W. P., Van Gisbergen, J.A.M. — 2008-05-13

To assess the effects of degrading canal cues for dynamic spatial orientation in human observers, we tested how judgments about visual-line orientation in space (subjective visual vertical task, SVV) and estimates of instantaneous body tilt (subjective body-tilt task, SBT) develop in the course of three cycles of constant-velocity roll rotation. These abilities were tested across the entire tilt range in separate experiments. For comparison, we also obtained SVV data during static roll tilt. We found that as tilt increased, dynamic SVV responses became strongly biased toward the head pole of the body axis (A-effect), as if body tilt was underestimated. However, on entering the range of near-inverse tilts, SVV responses adopted a bimodal pattern, alternating between A-effects (biased toward head-pole) and E-effects (biased toward feet-pole). Apart from an onset effect, this tilt-dependent pattern of systematic SVV errors repeated itself in subsequent rotation cycles with little sign of worsening performance. Static SVV responses were qualitatively similar and consistent with previous reports but showed smaller A-effects. By contrast, dynamic SBT errors were small and unimodal, indicating that errors in visual-verticality estimates were not caused by errors in body-tilt estimation. We discuss these results in terms of predictions from a canal-otolith interaction model extended with a leaky integrator and an egocentric bias mechanism. We conclude that the egocentric-bias mechanism becomes more manifest during constant velocity roll-rotation and that perceptual errors due to incorrect disambiguation of the otolith signal are small despite the decay of canal signals.

Updating Target Distance Across Eye Movements in Depth

Van Pelt, S., Medendorp, W. P. — 2008-05-13

We tested between two coding mechanisms that the brain may use to retain distance information about a target for a reaching movement across vergence eye movements. If the brain was to encode a retinal disparity representation (retinal model), i.e., target depth relative to the plane of fixation, each vergence eye movement would require an active update of this representation to preserve depth constancy. Alternatively, if the brain was to store an egocentric distance representation of the target by integrating retinal disparity and vergence signals at the moment of target presentation, this representation should remain stable across subsequent vergence shifts (nonretinal model). We tested between these schemes by measuring errors of human reaching movements (n = 14 subjects) to remembered targets, briefly presented before a vergence eye movement. For comparison, we also tested their directional accuracy across version eye movements. With intervening vergence shifts, the memory-guided reaches showed an error pattern that was based on the new eye position and on the depth of the remembered target relative to that position. This suggests that target depth is recomputed after the gaze shift, supporting the retinal model. Our results also confirm earlier literature showing retinal updating of target direction. Furthermore, regression analyses revealed updating gains close to one for both target depth and direction, suggesting that the errors arise after the updating stage during the subsequent reference frame transformations that are involved in reaching.

Proprioceptive and Cutaneous Representations in the Rat Ventral Posterolateral Thalamus

Francis, J. T., Xu, S., Chapin, J. K. — 2008-05-13

Determining how and where proprioceptive information is represented in the rat ventral posterolateral (VPL) is important in allowing us to further investigate how this sense is utilized during motor control and learning. Here we demonstrate using electrophysiological techniques that the rostral portion of the rat VPL nucleus (rVPL, –2 to –2.5 mm bregma) carries a large amount of proprioceptive information. Caudal to this region is a zone where the cutaneous receptive fields are focal (mVPL for middle VPL, –2.5 to –3.2 mm bregma) with a fine topographic map of the fore- and hindlimbs. The forepaw is represented with digit 1 medial and each subsequent digit increasingly lateral, all of which are dorsal to the pads. The caudal VPL (cVPL, –3.2 to –4.0 mm bregma) has broad receptive fields and is the target of lamina 1 and lamina 2, as well as the dorsal column nuclei, and may represent the flow of nociceptive information through the VPL. Thus we propose that the VPL may be thought of as three subnuclei—the rostral, middle, and caudal VPL—each carrying preferentially a different modality of information. This pattern of information flow through the rat VPL is similar, although apparently rotated, to that of many primates, indicating that these regions in the rat (rVPL, mVPL, and cVPL) have become further differentiated in primates where they are seen as separate nuclei (VPS, VPL, and VPI/VMpo).

Representations of Cat Meows and Human Vowels in the Primary Auditory Cortex of Awake Cats

Qin, L., Wang, J. Y., Sato, Y. — 2008-05-13

Previous investigation of neural responses to cat meows in the primary auditory cortex (A1) of the anesthetized cat revealed a preponderance of phasic responses aligned to stimulus onset, offset, or envelope peaks. Sustained responses during stationary components of the stimulus were rarely seen. This observation motivates further investigation into how stationary components of naturalistic auditory stimuli are encoded by A1 neurons. We therefore explored neuronal response patterns in A1 of the awake cat using natural meows, time-reversed meows, and human vowels as stimuli. We found heterogeneous response types: ~2/3 of units classified as "phasic cells" responding only to amplitude envelope variations and the remaining 1/3 were "phasic-tonic cells" with continuous responses during the stationary components. The classification was upheld across all stimuli tested for a given cell. The differences of phasic responses were correlated with amplitude-envelope differences in the early stimulus portion (<100 ms), whereas the differences between tonic responses were correlated with ongoing spectral differences in the later stimulus portion. Phasic-tonic cells usually had a characteristic frequency (CF) <5 kHz, which corresponded to the dominant spectral range of vocalizations, suggesting that the cells encode spectral information. Phasic cells had CFs across the tested frequency range (<16 kHz). Instantaneous firing rates for natural and time-reversed meows were different, but mean rates for different categories of stimuli were similar. Evidence for cat's A1 preferring conspecific meows was not found. These functionally heterogeneous responses may serve to encode ongoing changes in sound spectra or amplitude envelope occurring throughout the entirety of the sound stimulus.

A Cost-Benefit Analysis of Neuronal Morphology

Wen, Q., Chklovskii, D. B. — 2008-05-13

Over hundreds of millions of years, evolution has optimized brain design to maximize its functionality while minimizing costs associated with building and maintenance. This observation suggests that one can use optimization theory to rationalize various features of brain design. Here, we attempt to explain the dimensions and branching structure of dendritic arbors by minimizing dendritic cost for given potential synaptic connectivity. Assuming only that dendritic cost increases with total dendritic length and path length from synapses to soma, we find that branching, planar, and compact dendritic arbors, such as those belonging to Purkinje cells in the cerebellum, are optimal. The theory predicts that adjacent Purkinje dendritic arbors should spatially segregate. In addition, we propose two explicit cost function expressions, falsifiable by measuring dendritic caliber near bifurcations.

Eye Movements in Response to Dichoptic Motion: Evidence for a Parallel-Hierarchical Structure of Visual Motion Processing in Primates

Hayashi, R., Miura, K., Tabata, H., Kawano, K. — 2008-05-13

Brief movements of a large-field visual stimulus elicit short-latency tracking eye movements termed "ocular following responses" (OFRs). To address the question of whether OFRs can be elicited by purely binocular motion signals in the absence of monocular motion cues, we measured OFRs from monkeys using dichoptic motion stimuli, the monocular inputs of which were flickering gratings in spatiotemporal quadrature, and compared them with OFRs to standard motion stimuli including monocular motion cues. Dichoptic motion did elicit OFRs, although with longer latencies and smaller amplitudes. In contrast to these findings, we observed that other types of motion stimuli categorized as non-first-order motion, which is undetectable by detectors for standard luminance-defined (first-order) motion, did not elicit OFRs, although they did evoke the sensation of motion. These results indicate that OFRs can be driven solely by cortical visual motion processing after binocular integration, which is distinct from the process incorporating non-first-order motion for elaborated motion perception. To explore the nature of dichoptic motion processing in terms of interaction with monocular motion processing, we further recorded OFRs from both humans and monkeys using our novel motion stimuli, the monocular and dichoptic motion signals of which move in opposite directions with a variable motion intensity ratio. We found that monocular and dichoptic motion signals are processed in parallel to elicit OFRs, rather than suppressing each other in a winner-take-all fashion, and the results were consistent across the species.

Descending Projections From Auditory Cortex Modulate Sensitivity in the Midbrain to Cues for Spatial Position

Nakamoto, K. T., Jones, S. J., Palmer, A. R. — 2008-05-13

The function of the profuse descending innervation from the auditory cortex is largely unknown; however, recent studies have demonstrated that focal stimulation of auditory cortex effects frequency tuning curves, duration tuning, and other auditory parameters in the inferior colliculus. Here we demonstrate that, in an anesthetized guinea pig, nonfocal deactivation of the auditory cortex alters the sensitivity of populations of neurons in the inferior colliculus (IC) to one of the major cues for the localization of sound in space, interaural level differences (ILDs). Primary and secondary auditory cortical areas were inactivated by cooling. The ILD functions of 46% of IC cells changed when the cortex was inactivated. In extreme cases, the ILD functions changed from monotonic to nonmonotonic during cooling and vice versa. Eight percent of the cells became unresponsive after deactivation of the auditory cortex. Deactivation of the cortex has previously been shown to alter the maximum spike count of cells in the IC; the change in normalized ILD functions is shown to be separate from this effect. In some cases, the ILD function changed shape when there was no change in the maximum spike count and in other cases there was no change in the shape of the ILD function even though there was a large change in the maximum spike count. Overall, the sensitivity of the IC neural population to ILD is radically altered by the corticofugal pathway.

Spatial Heterogeneity of Cortical Receptive Fields and Its Impact on Multisensory Interactions

Carriere, B. N., Royal, D. W., Wallace, M. T. — 2008-05-13

Investigations of multisensory processing at the level of the single neuron have illustrated the importance of the spatial and temporal relationship of the paired stimuli and their relative effectiveness in determining the product of the resultant interaction. Although these principles provide a good first-order description of the interactive process, they were derived by treating space, time, and effectiveness as independent factors. In the anterior ectosylvian sulcus (AES) of the cat, previous work hinted that the spatial receptive field (SRF) architecture of multisensory neurons might play an important role in multisensory processing due to differences in the vigor of responses to identical stimuli placed at different locations within the SRF. In this study the impact of SRF architecture on cortical multisensory processing was investigated using semichronic single-unit electrophysiological experiments targeting a multisensory domain of the cat AES. The visual and auditory SRFs of AES multisensory neurons exhibited striking response heterogeneity, with SRF architecture appearing to play a major role in the multisensory interactions. The deterministic role of SRF architecture was tightly coupled to the manner in which stimulus location modulated the responsiveness of the neuron. Thus multisensory stimulus combinations at weakly effective locations within the SRF resulted in large (often superadditive) response enhancements, whereas combinations at more effective spatial locations resulted in smaller (additive/subadditive) interactions. These results provide important insights into the spatial organization and processing capabilities of cortical multisensory neurons, features that may provide important clues as to the functional roles played by this area in spatially directed perceptual processes.

Head Movements Produced During Whole Body Rotations and Their Sensitivity to Changes in Head Inertia in Squirrel Monkeys

Reynolds, J. S., Gdowski, G. T. — 2008-05-13

The head's inertia produces forces on the neck when the body moves. One collective function of the vestibulocollic and cervicocollic reflexes (VCR and CCR) is thought to be to stabilize the head with respect to the trunk during whole body movements. Little is known as to whether their head-movement kinematics produced by squirrel monkeys during whole body rotations are similar to those of cats and humans. Prior experiments with cats and human subjects have shown that yaw head-movement kinematics are unaffected by changes in the head's inertia when the whole body is rotated. These observations have led to the hypothesis that the combined actions of the VCR and CCR accommodate for changes in the head's inertia. To test this hypothesis in squirrel monkeys, it was imperative to first characterize the behavior of head movements produced during whole body rotation and then investigate their sensitivity to changes in the head's inertia. Our behavioral studies show that squirrel monkeys produce only small head movements with respect to the trunk during whole body rotations over a wide range of stimulus frequencies and velocities (0.5–4.0 Hz; 0–100°/s). Similar head movements were produced when only small additional changes in the head's inertia occurred. Electromyographic recordings from the splenius muscle revealed that an active process was utilized such that increases in muscle activation occurred when the inertia of the head was increased. These results are consistent with prior cat and human studies, suggesting that squirrel monkeys have a similar horizontal VCR and CCR.

Frequency Modulation During Song in a Suboscine Does Not Require Vocal Muscles

Amador, A., Goller, F., Mindlin, G. B. — 2008-05-13

The physiology of sound production in suboscines is poorly investigated. Suboscines are thought to develop song innately unlike the closely related oscines. Comparing phonatory mechanisms might therefore provide interesting insight into the evolution of vocal learning. Here we investigate sound production and control of sound frequency in the Great Kiskadee (Pitangus sulfuratus) by recording air sac pressure and vocalizations during spontaneously generated song. In all the songs and calls recorded, the modulations of the fundamental frequency are highly correlated to air sac pressure. To test whether this relationship reflects frequency control by changing respiratory activity or indicates synchronized vocal control, we denervated the syringeal muscles by bilateral resection of the tracheosyringeal nerve. After denervation, the strong correlation between fundamental frequency and air sac pressure patterns remained unchanged. A single linear regression relates sound frequency to air sac pressure in the intact and denervated birds. This surprising lack of control by syringeal muscles of frequency in Kiskadees, in strong contrast to songbirds, poses the question of how air sac pressure regulates sound frequency. To explore this question theoretically, we assume a nonlinear restitution force for the oscillating membrane folds in a two mass model of sound production. This nonlinear restitution force is essential to reproduce the frequency modulations of the observed vocalizations.

Sensitivity of Inferior Colliculus Neurons to Interaural Time Differences in the Envelope Versus the Fine Structure With Bilateral Cochlear Implants

Smith, Z. M., Delgutte, B. — 2008-05-13

Bilateral cochlear implantation seeks to improve hearing by taking advantage of the binaural processing of the central auditory system. Cochlear implants typically encode sound in each spectral channel by amplitude modulating (AM) a fixed-rate pulse train, thus interaural time differences (ITD) are only delivered in the envelope. We investigated the ITD sensitivity of inferior colliculus (IC) neurons with sinusoidally AM pulse trains. ITD was introduced independently to the AM and/or carrier pulses to measure the relative efficacy of envelope and fine structure for delivering ITD information. We found that many IC cells are sensitive to ITD in both the envelope (ITD_env) and fine structure (ITD_fs) for appropriate modulation frequencies and carrier rates. ITD_env sensitivity was generally similar to that seen in normal-hearing animals with AM tones. ITD_env tuning generally improved with increasing modulation frequency up to the maximum modulation frequency that elicited a sustained response in a neuron (tested ≤160 Hz). ITD_fs sensitivity was present in about half the neurons for 1,000 pulse/s (pps) carriers and was nonexistent at 5,000 pps. The neurons that were sensitive to ITD_fs at 1,000 pps were those that showed the best ITD sensitivity to low-rate pulse trains. Overall, the best ITD sensitivity was found for ITD contained in the fine structure of a moderate rate AM pulse train (1,000 pps). These results suggest that the interaural timing of current pulses should be accurately controlled in a bilateral cochlear implant processing strategy that provides salient ITD cues.

Rostral Versus Caudal Differences in Mechanical Entrainment of the Lamprey Central Pattern Generator for Locomotion

Tytell, E. D., Cohen, A. H. — 2008-05-13

In fishes, undulatory swimming is produced by sets of spinal interneurons constituting a central pattern generator (CPG). The CPG generates waves of muscle activity that travel from head to tail, which then bend the body into wave shapes that also travel from head to tail. In many fishes, the wavelengths of the neural and mechanical waves are different, resulting in a rostral-to-caudal gradient in phase lag between muscle activity and bending. The neural basis of this phase gradient was investigated in the lamprey spinal cord using an isolated in vitro preparation. Fictive swimming was induced using d-glutamate and the output of the CPG was measured using suction electrodes placed on the ventral roots. The spinal cord was bent sinusoidally at various points along its length. First, the ranges of entrainment were estimated. Middle segments were able to entrain to frequencies approximately twice as high as those at end segments. Next, phase lags between centers of ventral root bursts and the stimulus were determined. Two halves of the cycle were identified: stretching and shortening of the edge of spinal cord on the same side as the electrode. Stimuli at rostral segments tended to entrain segmental bursting at the beginning of the stretch phase, almost 50% out of phase with previously measured in vivo electromyography data. Stimuli at caudal segments, in contrast, entrained segments at the end of stretch and the beginning of shortening, approximately the same phase as in vivo data.

Hyperthermic Preconditioning of Presynaptic Calcium Regulation in Drosophila

Klose, M. K., Atwood, H. L., Robertson, R. M. — 2008-05-13

We examined the thermosensitivity of calcium regulation in Drosophila larval neuromuscular junctions, testing effects of prior heat shock and Hsp70 expression. Motor neurons were loaded with either the ratiometric indicator Fura-dextran or the nonratiometric indicator Oregon Green bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid to monitor parameters of calcium regulation as temperature increased. Nerve terminals treated to a prior heat shock, and those of transgenic flies expressing higher than normal levels of Hsp70, were better able to maintain near-normal resting calcium concentrations, calcium influx, and calcium clearance at higher temperatures. Synaptic transmission was also protected by prior heat shock and by higher than normal Hsp70 expression. Thus the thermal limit of synaptic transmission may be directly linked to the stability of calcium regulation.

Changes in Granule Cell Firing Rates Precede Locally Recorded Spontaneous Seizures by Minutes in an Animal Model of Temporal Lobe Epilepsy

Bower, M. R., Buckmaster, P. S. — 2008-05-13

Although much is known about persistent molecular, cellular, and circuit changes associated with temporal lobe epilepsy, mechanisms of seizure onset remain unclear. The dentate gyrus displays many persistent epilepsy-related abnormalities and is in the mesial temporal lobe where seizures initiate in patients. However, little is known about seizure-related activity of individual neurons in the dentate gyrus. We used tetrodes to record action potentials of multiple, single granule cells before and during spontaneous seizures in epileptic pilocarpine-treated rats. Subsets of granule cells displayed four distinct activity patterns: increased firing before seizure onset, decreased firing before seizure onset, increased firing only after seizure onset, and unchanged firing rates despite electrographic seizure activity in the immediate vicinity. No cells decreased firing rate immediately after seizure onset. During baseline periods between seizures, action potential waveforms and firing rates were similar among the four subsets of granule cells in epileptic rats and in granule cells of control rats. The mean normalized firing rate of granule cells whose firing rates increased before seizure onset deviated from baseline earliest, beginning 4 min before dentate gyrus electrographic seizure onset, and increased progressively, more than doubling by seizure onset. It is generally assumed that neuronal firing rates increase abruptly and synchronously only when electrographic seizures begin. However, these findings show heterogeneous and gradually building changes in activity of individual granule cells minutes before spontaneous seizures.

Regulation of Cholinergic Phenotype in Developing Neurons

2008-05-13

Specification of neurotransmitter phenotype is critical for neural circuit development and is influenced by intrinsic and extrinsic factors. Recent findings in rat hypothalamus in vitro suggest the role of neurotransmitter glutamate in the regulation of cholinergic phenotype. Here we extended our previous studies on the mechanisms of glutamate-dependent regulation of cholinergic phenotypic properties in hypothalamic neurons. Using immunocytochemistry, electrophysiology, and calcium imaging, we demonstrate that hypothalamic expression of choline acetyltransferase (the cholinergic marker) and responsiveness of neurons to acetylcholine (ACh) receptor agonists increase during chronic administration of an N-methyl-d-aspartate receptor (NMDAR) blocker, MK-801, in developing rats in vivo and genetic and pharmacological inactivation of NMDARs in mouse and rat developing neuronal cultures. In hypothalamic cultures, an inactivation of NMDA receptors also induces ACh-dependent synaptic activity, as do inactivations of PKA, ERK/MAPK, CREB, and NF-B, which are known to be regulated by NMDA receptors. Interestingly, the increase in cholinergic properties in developing neurons that is induced by NMDAR blockade is prevented by the blockade of ACh receptors, suggesting that function of ACh receptor is required for the cholinergic up-regulation. Using dual recording of monosynaptic excitatory postsynaptic currents, we further demonstrate that chronic inactivation of ionotropic glutamate receptors induces the cholinergic phenotype in a subset of glutamatergic neurons. The phenotypic switch is partial as ACh and glutamate are coreleased. The results suggest that developing neurons may not only coexpress multiple transmitter phenotypes, but can also change the phenotypes following changes in signaling in neuronal circuits.

Neural Coding of Global Form in the Human Visual Cortex

Ostwald, D., Lam, J. M., Li, S., Kourtzi, Z. — 2008-05-13

Extensive psychophysical and computational work proposes that the perception of coherent and meaningful structures in natural images relies on neural processes that convert information about local edges in primary visual cortex to complex object features represented in the temporal cortex. However, the neural basis of these mid-level vision mechanisms in the human brain remains largely unknown. Here, we examine functional MRI (fMRI) selectivity for global forms in the human visual pathways using sensitive multivariate analysis methods that take advantage of information across brain activation patterns. We use Glass patterns, parametrically varying the perceived global form (concentric, radial, translational) while ensuring that the local statistics remain similar. Our findings show a continuum of integration processes that convert selectivity for local signals (orientation, position) in early visual areas to selectivity for global form structure in higher occipitotemporal areas. Interestingly, higher occipitotemporal areas discern differences in global form structure rather than low-level stimulus properties with higher accuracy than early visual areas while relying on information from smaller but more selective neural populations (smaller voxel pattern size), consistent with global pooling mechanisms of local orientation signals. These findings suggest that the human visual system uses a code of increasing efficiency across stages of analysis that is critical for the successful detection and recognition of objects in complex environments.

Expansion of Visual Space During Optokinetic Afternystagmus (OKAN)

Kaminiarz, A., Krekelberg, B., Bremmer, F. — 2008-05-13

The mechanisms underlying visual perceptual stability are usually investigated using voluntary eye movements. In such studies, errors in perceptual stability during saccades and pursuit are commonly interpreted as mismatches between actual eye position and eye-position signals in the brain. The generality of this interpretation could in principle be tested by investigating spatial localization during reflexive eye movements whose kinematics are very similar to those of voluntary eye movements. Accordingly, in this study, we determined mislocalization of flashed visual targets during optokinetic afternystagmus (OKAN). These eye movements are quite unique in that they occur in complete darkness and are generated by subcortical control mechanisms. We found that during horizontal OKAN slow phases, subjects mislocalize targets away from the fovea in the horizontal direction. This corresponds to a perceived expansion of visual space and is unlike mislocalization found for any other voluntary or reflexive eye movement. Around the OKAN fast phases, we found a bias in the direction of the fast phase prior to its onset and opposite to the fast-phase direction thereafter. Such a biphasic modulation has also been reported in the temporal vicinity of saccades and during optokinetic nystagmus (OKN). A direct comparison, however, showed that the modulation during OKAN was much larger and occurred earlier relative to fast-phase onset than during OKN. A simple mismatch between the current eye position and the eye-position signal in the brain is unlikely to explain such disparate results across similar eye movements. Instead, these data support the view that mislocalization arises from errors in eye-centered position information.

Effect of Reversible Inactivation of Superior Colliculus on Head Movements

Walton, M. M. G., Bechara, B., Gandhi, N. J. — 2008-05-13

Because of limitations in the oculomotor range, many gaze shifts must be accomplished using coordinated movements of the eyes and head. Stimulation and recording data have implicated the primate superior colliculus (SC) in the control of these gaze shifts. The precise role of this structure in head movement control, however, is not known. The present study uses reversible inactivation to gain insight into the role of this structure in the control of head movements, including those that accompany gaze shifts and those that occur in the absence of a change in gaze. Forty-five lidocaine injections were made in two monkeys that had been trained on a series of behavioral tasks that dissociate movements of the eyes and head. Reversible inactivation resulted in clear impairments in the animals’ ability to perform gaze shifts, manifested by increased reaction times, lower peak velocities, and increased durations. In contrast, comparable effects were not found for head movements (with or without gaze shifts) with the exception of a very small increase in reaction times of head movements associated with gaze shifts. Eye-head coordination was clearly affected by the injections with gaze onset occurring relatively later with respect to head onset. Following the injections, the head contributed slightly more to the gaze shift. These results suggest that head movements (with and without gaze shifts) can be controlled by pathways that do not involve SC.

On the Importance of Static Nonlinearity in Estimating Spatiotemporal Neural Filters With Natural Stimuli

Sharpee, T. O., Miller, K. D., Stryker, M. P. — 2008-05-13

Understanding neural responses with natural stimuli has increasingly become an essential part of characterizing neural coding. Neural responses are commonly characterized by a linear–nonlinear (LN) model, in which the output of a linear filter applied to the stimulus is transformed by a static nonlinearity to determine neural response. To estimate the linear filter in the LN model, studies of responses to natural stimuli commonly use methods that are unbiased only for a linear model (in which there is no static nonlinearity): spike-triggered averages with correction for stimulus power spectrum, with or without regularization. Although these methods work well for artificial stimuli, such as Gaussian white noise, we show here that they estimate neural filters of LN models from responses to natural stimuli much more poorly. We studied simple cells in cat primary visual cortex. We demonstrate that the filters computed by directly taking the nonlinearity into account have better predictive power and depend less on the stimulus than those computed under the linear model. With noise stimuli, filters computed using the linear and LN models were similar, as predicted theoretically. With natural stimuli, filters of the two models can differ profoundly. Noise and natural stimulus filters differed significantly in spatial properties, but these differences were exaggerated when filters were computed using the linear rather than the LN model. Although regularization of filters computed under the linear model improved their predictive power, it also led to systematic distortions of their spatial frequency profiles, especially at low spatial and temporal frequencies.

Relative Roles of Different Mechanisms of Depression at the Mouse Endbulb of Held

Yang, H., Xu-Friedman, M. A. — 2008-05-13

Several mechanisms can underlie short-term synaptic depression, including vesicle depletion, receptor desensitization, and changes in presynaptic release probability. To determine which mechanisms affect depression under physiological conditions, we studied the synapse formed by auditory nerve fibers onto bushy cells in the anteroventral cochlear nucleus (the "endbulb of Held") using voltage-clamp recordings of brain slices from P15–P21 mice near physiological temperatures. Depression of both -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) excitatory postsynaptic currents (EPSCs) showed two phases of recovery. The fast component of depression for the AMPA EPSC was eliminated by cyclothiazide and aniracetam, suggesting it results from desensitization. The fast component of depression for the NMDA EPSC was reduced by the low-affinity antagonist l-AP5, suggesting it results from saturation. The remaining depression in AMPA and NMDA components is identical and therefore presynaptic in origin. It is likely to result from presynaptic vesicle depletion. Recovery from depression after trains of activity was slowed by the application of EGTA-AM, suggesting that the endbulb has a residual-calcium-dependent form of recovery. We developed a model that incorporates depletion, desensitization, and calcium-dependent recovery. This model replicated experimental findings over a range of experimental conditions. The model further indicated that desensitization plays only a minor role during prolonged activity, in large part because presynaptic release is so depleted. Thus depletion appears to be the dominant mechanism of depression at the endbulb during normal activity. Furthermore, calcium-dependent recovery at the endbulb is critical to prevent complete rundown during high activity and to preserve the reliability of information transmission.

Melanopsin Ganglion Cells Use a Membrane-Associated Rhabdomeric Phototransduction Cascade

2008-05-13

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are photoreceptors of the mammalian eye that drive pupillary responses, synchronization of circadian rhythms, and other reflexive responses to daylight. Melanopsin is the ipRGC photopigment, but the signaling cascade through which this invertebrate-like opsin triggers the photocurrent in these cells is unknown. Here, using patch-clamp recordings from dissociated ipRGCs in culture, we show that a membrane-associated phosphoinositide cascade lies at the heart of the ipRGC phototransduction mechanism, similar to the cascade in rhabdomeric photoreceptors of invertebrate eyes. When ipRGCs were illuminated, melanopsin activated a G protein of the G_q/11 class, stimulating the effector enzyme phospholipase C. The presence of these signaling components in ipRGCs was confirmed by single-cell RT-PCR and immunofluorescence. The photoresponse was fully functional in excised inside-out patches of ipRGC membrane, indicating that all core signaling components are within or tightly coupled to the plasma membrane. The striking similarity of phototransduction in ipRGCs and invertebrate rhabdomeric photoreceptors reinforces the emerging view that these cells have a common evolutionary origin.

Activity of Ventroposterior Thalamus Neurons During Rotation and Translation in the Horizontal Plane in the Alert Squirrel Monkey

Marlinski, V., McCrea, R. A. — 2008-05-13

The firing behavior of 107 vestibular-sensitive neurons in the ventroposterior thalamus was studied in two alert squirrel monkeys during whole body rotation and translation in the horizontal plane. Vestibular-sensitive neurons were distributed primarily along the anterior and posterior borders of ventroposterior nuclei; three clusters of these neurons could be distinguished based on their location and inputs. Eighty-four neurons responded to rotation; 66 (78%) of them responded to rotation only and 18 (22%) to both rotation and translation. Forty-one neurons were sensitive to linear translation; 23 (56%) of them responded to translation only. The population rotational response to 0.5-Hz sinusoids with a peak velocity of 40°/s showed a gain of 0.23 ± 0.15 spike·s^–1·deg^–1·s^–1 and phase lagging behind the angular velocity by –9.3 ± 34.1°. Although rotational response amplitude increased with the stimulus velocity across the range 4–100°/s, the rotational sensitivity decreased with and was inversely proportional to the stimulus velocity. The rotational response amplitude and sensitivity increased with the stimulus frequency across the range 0.2–4.0 Hz. The population response to sinusoidal translation at 0.5 Hz and 0.1 g amplitude had a gain of 111.3 ± 53.7 spikes·s^–1·g^–1 and lagged behind stimulus acceleration by –71.9 ± 42.6°. Translational sensitivity decreased as acceleration increased and this was inversely proportional to the square root of the acceleration. Results of this study imply that changes in the discharge rate of vestibular-sensitive thalamic neurons can be approximated using power functions of the angular and linear velocity of spatial motion.

Contributions of Online Visual Feedback to the Learning and Generalization of Novel Finger Coordination Patterns

Liu, X., Scheidt, R. A. — 2008-05-13

We explored how people learn new ways to move objects through space using neuromuscular control signals having more degrees of freedom than needed to unambiguously specify object location. Subjects wore an instrumented glove that recorded finger motions. A linear transformation matrix projected joint angle signals (a high-dimensional control vector) onto a two-dimensional cursor position on a video monitor. We assessed how visual information influences learning and generalization of novel finger coordination patterns as subjects practiced using hand gestures to manipulate cursor location. Three groups of test subjects practiced moving a visible cursor between different sets of screen targets. The hand-to-screen transformation was designed such that the different sets of targets (which we called implicit spatial cues) varied in how informative they were about the gestures to be learned. A separate control group practiced gesturing with explicit cues (pictures of desired gestures) without ongoing cursor feedback. Another control group received implicit spatial cueing and feedback only of final cursor position. We found that test subjects and subjects provided with explicit cues could learn to produce desired gestures, although training efficacy decreased as the amount of task-relevant feedback decreased. Although both control groups learned to associate screen targets with specific gestures, only subjects provided with online feedback of cursor motion learned to generalize in a manner consistent with the internal representation of an inverse hand-to-screen mapping. These findings suggest that spatial learning and generalization require dynamic feedback of object motion in response to control signal changes; static information regarding geometric relationships between controller and endpoint configurations does not suffice.

Human Updating of Visual Motion Direction During Head Rotations

Ruiz-Ruiz, M., Martinez-Trujillo, J. C. — 2008-05-13

Previous studies have demonstrated that human subjects update the location of visual targets for saccades after head and body movements and in the absence of visual feedback. This phenomenon is known as spatial updating. Here we investigated whether a similar mechanism exists for the perception of motion direction. We recorded eye positions in three dimensions and behavioral responses in seven subjects during a motion task in two different conditions: when the subject's head remained stationary and when subjects rotated their heads around an anteroposterior axis (head tilt). We demonstrated that after head-tilt subjects updated the direction of saccades made in the perceived stimulus direction (direction of motion updating), the amount of updating varied across subjects and stimulus directions, the amount of motion direction updating was highly correlated with the amount of spatial updating during a memory-guided saccade task, subjects updated the stimulus direction during a two-alternative forced-choice direction discrimination task in the absence of saccadic eye movements (perceptual updating), perceptual updating was more accurate than motion direction updating involving saccades, and subjects updated motion direction similarly during active and passive head rotation. These results demonstrate the existence of an updating mechanism for the perception of motion direction in the human brain that operates during active and passive head rotations and that resembles the one of spatial updating. Such a mechanism operates during different tasks involving different motor and perceptual skills (saccade and motion direction discrimination) with different degrees of accuracy.

Spontaneous Recovery of Motor Memory During Saccade Adaptation

Ethier, V., Zee, D. S., Shadmehr, R. — 2008-05-13

It is possible that motor adaptation in timescales of minutes is supported by two distinct processes: one process that learns slowly from error but has strong retention, and another that learns rapidly from error but has poor retention. This two-state model makes the prediction that if a period of adaptation is followed by a period of reverse-adaptation, then in the subsequent period in which errors are clamped to zero (error-clamp trials) there will be a spontaneous recovery, i.e., a rebound of behavior toward the initial level of adaptation. Here we tested and confirmed this prediction during double-step, on-axis, saccade adaptation. When people adapted their saccadic gain to a magnitude other than one (adaptation) and then the gain was rapidly reversed back to one (reverse-adaptation), in the subsequent error-clamp trials (visual target placed on the fovea after the saccade) the gain reverted toward the initially adapted value and then gradually reverted toward normal. We estimated that the fast system was about 20-fold more sensitive to error than the slow system, but had a time constant of 28 s, whereas the slow system had a time constant of nearly 8 min. Therefore short-term adaptive mechanisms that maintain accuracy of saccades rely on a memory system that has characteristics of a multistate process with a logarithmic distribution of timescales.

Spatiotemporally Graded NMDA Spike/Plateau Potentials in Basal Dendrites of Neocortical Pyramidal Neurons

Major, G., Polsky, A., Denk, W., Schiller, J., Tank, D. W. — 2008-05-13

Glutamatergic inputs clustered over ~20–40 µm can elicit local N-methyl-d-aspartate (NMDA) spike/plateau potentials in terminal dendrites of cortical pyramidal neurons, inspiring the notion that a single terminal dendrite can function as a decision-making computational subunit. A typical terminal basal dendrite is ~100–200 µm long: could it function as multiple decision-making subunits? We test this by sequential focal stimulation of multiple sites along terminal basal dendrites of layer 5 pyramidal neurons in rat somatosensory cortical brain slices, using iontophoresis or uncaging of brief glutamate pulses. There was an approximately sevenfold spatial gradient in average spike/plateau amplitude measured at the soma, from ~3 mV for distal inputs to ~23 mV for proximal inputs. Spike/plateaus were NMDA receptor (NMDAR) conductance-dominated at all locations. Large Ca²⁺ transients accompanied spike/plateaus over a ~10- to 40-µm zone around the input site; smaller Ca²⁺ transients extended approximately uniformly to the dendritic tip. Spike/plateau duration grew with increasing glutamate and depolarization; high Ca²⁺ zone size grew with spike/plateau duration. The minimum high Ca²⁺ zone half-width (just above NMDA spike threshold) increased from distal (~10 µm) to proximal locations (~25 µm), as did the NMDA spike glutamate threshold. Depolarization reduced glutamate thresholds. Simulations exploring multi-site interactions based on this demonstrate that if appropriately timed and localized inputs occur in vivo, a single basal dendrite could correspond to a cascade of multiple co-operating dynamic decision-making subunits able to retain information for hundreds of milliseconds, with increasing influence on neural output from distal to proximal. Dendritic NMDA spike/plateaus are thus well-suited to support graded persistent firing.

The Brain Stem Saccadic Burst Generator Encodes Gaze in Three-Dimensional Space

Van Horn, M. R., Sylvestre, P. A., Cullen, K. E. — 2008-05-13

When we look between objects located at different depths the horizontal movement of each eye is different from that of the other, yet temporally synchronized. Traditionally, a vergence-specific neuronal subsystem, independent from other oculomotor subsystems, has been thought to generate all eye movements in depth. However, recent studies have challenged this view by unmasking interactions between vergence and saccadic eye movements during disconjugate saccades. Here, we combined experimental and modeling approaches to address whether the premotor command to generate disconjugate saccades originates exclusively in "vergence centers." We found that the brain stem burst generator, which is commonly assumed to drive only the conjugate component of eye movements, carries substantial vergence-related information during disconjugate saccades. Notably, facilitated vergence velocities during disconjugate saccades were synchronized with the burst onset of excitatory and inhibitory brain stem saccadic burst neurons (SBNs). Furthermore, the time-varying discharge properties of the majority of SBNs (>70%) preferentially encoded the dynamics of an individual eye during disconjugate saccades. When these experimental results were implemented into a computer-based simulation, to further evaluate the contribution of the saccadic burst generator in generating disconjugate saccades, we found that it carries all the vergence drive that is necessary to shape the activity of the abducens motoneurons to which it projects. Taken together, our results provide evidence that the premotor commands from the brain stem saccadic circuitry, to the target motoneurons, are sufficient to ensure the accurate control shifts of gaze in three dimensions.

Olfactory Behavior of Swimming C. elegans Analyzed by Measuring Motile Responses to Temporal Variations of Odorants

Luo, L., Gabel, C. V., Ha, H.-I., Zhang, Y., Samuel, A. D. T. — 2008-05-13

Caenorhabditis elegans responds to chemical cues using a small number of chemosensory neurons that detect a large variety of molecules in its environment. During chemotaxis, C. elegans biases its migration in spatial chemical gradients by lengthening (/shortening) periods of forward movement when it happens to be moving toward (/away) from preferred locations. In classical assays of chemotactic behavior, a group of crawling worms is placed on an agar plate containing a point source of chemical, the group is allowed to navigate for a period of time, and aggregation of worms near the source is quantified. Here we show that swimming worms exhibit acute motile responses to temporal variations of odor in their surrounding environment, allowing our development of an automated assay of chemotactic behavior with single-animal resolution. By placing individual worms in small microdroplets and quantifying their movements as they respond to the addition and removal of odorized airstreams, we show that the sensorimotor phenotypes of swimming worms (wild-type behavior, the effects of certain mutations, and the effects of laser ablation of specific olfactory neurons) are consistent with aggregation phenotypes previously obtained in crawling assays. The microdroplet swimming assay has certain advantages over crawling assays, including flexibility and precision in defining the stimulus waveform and automated quantification of motor response during stimulus presentation. In this study, we use the microdroplet assay to quantify the temporal dynamics of the olfactory response, the sensitivity to odorant concentration, combinations, and gradients, and the contribution of specific olfactory neurons to overall behavior.

Intercostal and Abdominal Respiratory Motoneurons in the Neonatal Rat Spinal Cord: Spatiotemporal Organization and Responses to Limb Afferent Stimulation

Giraudin, A., Cabirol-Pol, M.-J., Simmers, J., Morin, D. — 2008-05-13

Respiration requires the coordinated rhythmic contractions of diverse muscles to produce ventilatory movements adapted to organismal requirements. During fast locomotion, locomotory and respiratory movements are coordinated to reduce mechanical conflict between these functions. Using semi-isolated and isolated in vitro brain stem-spinal cord preparations from neonatal rats, we have characterized for the first time the respiratory patterns of all spinal intercostal and abdominal motoneurons and explored their functional relationship with limb sensory inputs. Neuroanatomical and electrophysiological procedures were initially used to locate intercostal and abdominal motoneurons in the cord. Intercostal motoneuron somata are distributed rostrocaudally from C₇–T₁₃ segments. Abdominal motoneuron somata lie between T₈ and L₂. In accordance with their soma distributions, inspiratory intercostal motoneurons are recruited in a rostrocaudal sequence during each respiratory cycle. Abdominal motoneurons express expiratory-related discharge that alternates with inspiration. Lesioning experiments confirmed the pontine origin of this expiratory activity, which was abolished by a brain stem transection at the rostral boundary of the VII nucleus, a critical area for respiratory rhythmogenesis. Entrainment of fictive respiratory rhythmicity in intercostal and abdominal motoneurons was elicited by periodic low-threshold dorsal root stimulation at lumbar (L₂) or cervical (C₇) levels. These effects are mediated by direct ascending fibers to the respiratory centers and a combination of long-projection and polysynaptic descending pathways. Therefore the isolated brain stem-spinal cord in vitro generates a complex pattern of respiratory activity in which alternating inspiratory and expiratory discharge occurs in functionally identified spinal motoneuron pools that are in turn targeted by both forelimb and hindlimb somatic afferents to promote locomotor-respiratory coupling.