Dissociation of slow waves and fast oscillations above 200 Hz during GABA application in rat somatosensory cortex

We present the first direct comparison of the major candidates proposed to underlie the slow phase of the force increase seen following myocardial stretch: (i) the Na⁺–H⁺ exchanger (NHE) (ii) nitric oxide (NO) and the ryanodine receptor (RyR) and (iii) the stretch-activated channel (SAC) in both single myocytes and multicellular muscle preparations from the rat heart. Ventricular myocytes were stretched by approximately 7% using carbon fibres. Papillary muscles were stretched from 88 to 98% of the length at which maximum tension is generated ( L _max). Inhibition of NHE with HOE 642 (5 μ m ) significantly reduced ( P < 0.05) the magnitude of the slow force response in both muscle and myocytes. Neither inhibition of phosphatidylinositol-3-OH kinase (PtdIns-3-OH kinase) with LY294002 (10 μ m ) nor NO synthase with l -NAME (1 m m ) reduced the slow force response in muscle or myocytes ( P > 0.05), and the slow response was still present in the single myocyte when the sarcoplasmic reticulum was rigorously inhibited with 1 μ m ryanodine and 1 μ m thapsigargin. We saw a significant reduction ( P < 0.05) in the slow force response in the presence of the SAC blocker streptomycin in both muscle (80 μ m ) and myocytes (40 μ m ). In fura 2-loaded myocytes, HOE 642 and streptomycin, but not l -NAME, ablated the stretch-induced increase in [Ca²⁺]_i transient amplitude. Our data suggest that in the rat, under our experimental conditions, there are two mechanisms that underlie the slow inotropic response to stretch: activation of NHE; and of activation of SACs. Both these mechanisms are intrinsic to the myocyte.     

Sensory modulation of synchronous thalamocortical interactions in the somatosensory system of the cat

Neuronal responses to hairy skin stimulation were simultaneously recorded in the ventral posterolateral nucleus (VPL) of the thalamus and primary somatosensory cortex (SI) of halothane-anesthetized cats. Among 233 thalamocortical neuron pairs, cross-correlation analysis revealed significant interactions in 120 pairs. Excitatory interactions were most prevalent and included influences occurring exclusively in the thalamocortical (41 pairs) or corticothalamic (23 pairs) directions as well as multiphasic interactions (40 pairs) in both directions. Only 16 pairs exhibited inhibitory interactions and 7 of these involved multiphasic combinations of excitation and inhibition. In 14 of these neuron pairs, inhibition was exerted in the corticothalamic direction. Receptive field (RF) overlap between thalamic and cortical neurons varied considerably, and neuronal interactions were more likely for neuron pairs sharing large portions of their combined RFs. Computer-controlled stimulation was delivered to multiple RF sites but only 46% of the neuron pairs displayed interactions at more than one stimulation site and only four neuron pairs showed interactions at all stimulus positions. When interactions occurred at multiple stimulus sites, 40% of these interactions were characterized by timing shifts where the time interval between VPL and SI discharges varied as much as 20 ms because of stimulus relocation. In nine neuron pairs, systematic shifts in stimulus position produced reversals in the temporal sequence of thalamic and cortical neuronal discharges. Functional interactions between thalamic and cortical neurons were detected during both spontaneous and stimulus-induced activity. Matched-sample comparisons of connection strength and half-widths of thalamocortical peaks during spontaneous and stimulus-induced activity indicated that functional interactions produced by cutaneous stimulation were significantly stronger and had less temporal variability than those occurring spontaneously.     

Intracellular correlates of fast (>200 Hz) electrical oscillations in rat somatosensory cortex

Oscillatory activity in excess of several hundred hertz has been observed in somatosensory evoked potentials (SEP) recorded in both humans and animals and is attracting increasing interest regarding its role in brain function. Currently, however, little is known about the cellular events underlying these oscillations. The present study employed simultaneous in-vivo intracellular and epipial field-potential recording to investigate the cellular correlates of fast oscillations in rat somatosensory cortex evoked by vibrissa stimulation. Two distinct types of fast oscillations were observed, here termed "fast oscillations" (FO) (200-400 Hz) and "very fast oscillations" (VFO) (400-600 Hz). FO coincided with the earliest slow-wave components of the SEP whereas VFO typically were later and of smaller amplitude. Regular spiking (RS) cells exhibited vibrissa-evoked responses associated with one or both types of fast oscillations and consisted of combinations of spike and/or subthreshold events that, when superimposed across trials, clustered at latencies separated by successive cycles of FO or VFO activity, or a combination of both. Fast spiking (FS) cells responded to vibrissae stimulation with bursts of action potentials that closely approximated the periodicity of the surface VFO. No cells were encountered that produced action potential bursts related to FO activity in an analogous fashion. We propose that fast oscillations define preferred latencies for action potential generation in cortical RS cells, with VFO generated by inhibitory interneurons and FO reflecting both sequential and recurrent activity of stations in the cortical lamina.     

Effects of bicuculline methiodide on fast (>200 Hz) electrical oscillations in rat somatosensory cortex

Fast oscillatory activity (more than approximately 200 Hz) has been attracting increasing attention regarding its possible role in both normal brain function and epileptogenesis. Yet, its underlying cellular mechanism remains poorly understood. Our prior investigation of the phenomenon in rat somatosensory cortex indicated that fast oscillations result from repetitive synaptic activation of cortical pyramidal cells originating from GABAergic interneurons (). To test this hypothesis, the effects of topical application of the gamma-aminobutyric acid-A (GABA(A)) antagonist bicuculline methiodide (BMI) on fast oscillations were examined. At subconvulsive concentrations (approximately 10 microM), BMI application resulted in a pronounced enhancement of fast activity, in some trials doubling the number of oscillatory cycles evoked by whisker stimulation. The amplitude and frequency of fast activity were not affected by BMI in a statistically significant fashion. At higher concentrations, BMI application resulted in the emergence of recurring spontaneous slow-wave discharges resembling interictal spikes (IIS) and the eventual onset of seizure. High-pass filtering of the IIS revealed that a burst of fast oscillations accompanied the spontaneous discharge. This activity was present in both the pre- and the postictal regimes, in which its morphology and spatial distribution were largely indistinguishable. These data indicate that fast cortical oscillations do not reflect GABAergic postsynaptic currents. An alternate account consistent with results observed to date is that this activity may instead arise from population spiking in pyramidal cells, possibly mediated by electrotonic coupling in a manner analogous to that underlying 200-Hz ripple in the hippocampus. Additionally, fast oscillations occur within spontaneous epileptiform discharges. However, at least under the present experimental conditions, they do not appear to be a reliable predictor of seizure onset nor an indicator of the seizure focus.     

Effects of ventrobasal lesion and cortical cooling on fast oscillations (>200 Hz) in rat somatosensory cortex

High-frequency oscillatory activity (>200 Hz) termed "fast oscillations" (FO) have been recorded in the rodent somatosensory cortex and may reflect very rapid integration of vibrissal information in sensory cortex. Yet, while electrophysiological correlates suggest that FO is generated within intracortical networks, contributions of subcortical structures along the trigeminal pathway remain uncertain. Using surface and laminar electrode arrays, in vivo recordings of vibrissal and electrically evoked FO were made within somatosensory cortex of anesthetized rodents before and after ablation of the ventrobasal thalamus (VB) or during reversible cortical cooling. In VB-lesioned animals, vibrissal stimulation failed to evoke FO, while epicortical stimulation in lesioned animals remained effective in generating FO. In nonlesioned animals, cortical cooling eliminated vibrissal-evoked FO despite the persistence of thalamocortical input. Vibrissal-evoked FO returned with the return to physiological temperatures. Results from this study indicate that somatosensory cortex alone is able to initiate and sustain FO. Moreover, these data suggest that cortical network interactions are solely responsible for the generation of FO, while synchronized thalamocortical input serves as the afferent trigger.     

Development of thalamocortical response transformations in the rat whisker-barrel system

Extracellular single-unit recordings were used to characterize responses of thalamic barreloid and cortical barrel neurons to controlled whisker deflections in 2, 3-, and 4-wk-old and adult rats in vivo under fentanyl analgesia. Results indicate that response properties of thalamic and cortical neurons diverge during development. Responses to deflection onsets and offsets among thalamic neurons mature in parallel, whereas among cortical neurons responses to deflection offsets become disproportionately smaller with age. Thalamic neuron receptive fields become more multiwhisker, whereas those of cortical neurons become more single-whisker. Thalamic neurons develop a higher degree of angular selectivity, whereas that of cortical neurons remains constant. In the temporal domain, response latencies decrease both in thalamic and cortical neurons, but the maturation time-course differs between the two populations. Response latencies of thalamic cells decrease primarily between 2 and 3 wk of life, whereas response latencies of cortical neurons decrease in two distinct steps--the first between 2 and 3 wk of life and the second between the fourth postnatal week and adulthood. Although the first step likely reflects similar subcortical changes, the second phase likely corresponds to developmental myelination of thalamocortical fibers. Divergent development of thalamic and cortical response properties indicates that thalamocortical circuits in the whisker-to-barrel pathway undergo protracted maturation after 2 wk of life and provides a potential substrate for experience-dependent plasticity during this time.     

Topographic organization of the auditory thalamocortical system in the albino rat

Summary The organization of the auditory thalamocortical connections was studied in rats. Retrograde transport of horseradish peroxidase conjugated to wheat germ agglutinin following injections into parietal, occipital and temporal cortex was used. The medial geniculate body, the suprageniculate, the lateral part of the nucleus posterior thalami, the posterior part of the nucleus lateralis thalami, and the nucleus ventroposterior project to the investigated part of the neocortex. Corresponding to different patterns of labeling, five areas of auditory neocortex were distinguished: 1. The rostral area is innervated by neurons of the nucleus ventroposterior, the lateral part of the nucleus posterior thalami, and the medial division of the medial geniculate body. 2. The dorsal area is innervated by neurons of the suprageniculate, the posterior part of the nucleus lateralis thalami and the rostral region of the dorsal division of the medial geniculate body. 3. The caudal area is innervated by neurons of the posterior part of the nucleus lateralis thalami, the suprageniculate, the medial division, the caudal region of the dorsal division and the ventrolateral nucleus of the medial geniculate body. 4. The ventral area is innervated by neurons of the suprageniculate, the medial division, the caudal region of the dorsal division, and the ventrolateral nucleus of the medial geniculate body. 5. The core area of the temporal cortex is exclusively connected to the caudal region of the medial division and the ventral division of the medial geniculate body.The findings of the present study indicate topographic organizations of the ventral division of the medial geniculate body and of the corea area. Four segments (a-d) of the ventral division each show a different set of topographic axes. They correspond to sets of topographic axes in the core area of the auditory cortex. These topographies characterize the segments which are each exclusively connected to one of the four fields of the core area.Abbreviations AC Auditory Cortex - c Caudal - d Dorsal - FR Fissura rhinalis, Rhinal Fissure - l Lateral - LTP Nucleus lateralis thalami, pars posterior - m Medial - MGB Medial geniculate body - MGBd Medial geniculate body, dorsal division - MGBm Medial geniculate body, medial division - MGBmc Medial geniculate body, caudal third of MGBm - MGBv Medial geniculate body, ventral division - MGBvl Medial geniculate body, ventrolateral nucleus - NPT Nucleus posterior thalami, pars lateralis - r Rostral - SG Suprageniculatum - VP Nucleus ventroposterior     

Quantitative analysis of high-frequency oscillations (80-500 Hz) recorded in human epileptic hippocampus and entorhinal cortex

High-frequency oscillations (100-200 Hz), termed ripples, have been identified in hippocampal (Hip) and entorhinal cortical (EC) areas of rodents and humans. In contrast, higher-frequency oscillations (250-500 Hz), termed fast ripples (FR), have been described in seizure-generating limbic areas of rodents made epileptic by intrahippocampal injection of kainic acid and observed in humans ipsilateral to areas of seizure initiation. However, quantitative studies supporting the existence of two spectrally distinct oscillatory events have not been carried out in humans nor has the preferential appearance of FR within seizure generating areas received statistical evaluation based on analysis of a large sample of oscillatory events. Interictal oscillations within the bandwidth of 80-500 Hz were detected in Hip and EC areas of patients with mesial temporal lobe epilepsy using wideband EEG recorded during non-rapid eye-movement sleep from chronically implanted depth electrodes. Power spectral analysis showed that oscillations detected from Hip and EC areas were composed of two spectrally distinct groups. The lower-frequency ripple group was defined by a frequency of 96 +/- 14 Hz (median +/- width), while the higher-frequency FR group had a frequency of 262 +/- 59 Hz. FR oscillations were significantly shorter in duration compared with ripple oscillations (P < 0.0001). In regard to the occurrence of FR and ripples in epileptic Hip and EC, the mean ratio of the number of FR to ripples generated in areas ipsilateral to seizure onset was significantly higher compared with the mean ratio of FR to ripple generation from contralateral areas (P = 0.008). Furthermore, sites ipsilateral to seizure onset with hippocampal atrophy had significantly higher ratios compared with sites contralateral to both seizure onset and hippocampal atrophy (P = 0.001). These data provide compelling quantitative and statistical evidence for the existence of two spectrally distinct groups of limbic oscillations that have frequency and duration characteristics similar to those previously described in epileptic rat and human Hip and EC. The strong association between FR and regions of seizure initiation supports the view that FR reflects pathological hypersynchronous events crucially associated with seizure genesis.     

Host–tumor interactions during the regression of a rat histiocytoma, AK-5

Summary: An efficient immune response comprises a highly intricate, integrated circuitry involving both the cellular and the humoral arms of the immune system of the host interacting with the rapidly proliferating microcosm of the tumor. The mechanism of tumor rejection involving multiple arms of the immune system was reviewed in a spontaneously regressing rat histiocytoma, AK-5, an autologous tumor–host system. Intraperitoneal tumor transplantation leads to death in all animals, whereas subcutaneously (s.c.) transplanted tumor undergoes regression in 70% of animals. Regression of the tumor occurs by both apoptosis and necrosis, and natural killer (NK) cells were identified as the chief effectors mediating tumor cell death in vivo . A type 1 helper T cell (Th1)-driven cytokine cascade played a crucial role in enhancing cellular functions at the tumor site and obtaining a sufficient immune response for tumor rejection. The s.c. tumor-bearing hosts were shown to produce a factor which induced apoptosis in tumor cells, mediating tumor rejection. This review emphasizes the daunting complexities and interesting liaisons between the host immune system and the tumor, highlighting the work from our laboratory, and stressing that it is the interaction of several factors in concert or antagonizing each other that is responsible for the spontaneous regression of a tumor.     

Nucleus- and species-specific properties of the slow (<1 Hz) sleep oscillation in thalamocortical neurons

The slow (<1 Hz) rhythm is an electroencephalogram hallmark of resting sleep. In thalamocortical neurons this rhythm correlates with a slow (<1 Hz) oscillation comprising recurring UP and DOWN membrane potential states. Recently, we showed that metabotropic glutamate receptor activation brings about an intrinsic slow oscillation in thalamocortical neurons of the cat dorsal lateral geniculate nucleus in vitro which is identical to that observed in vivo. The aim of this study was to further assess the properties of this oscillation and compare them with those observed in thalamocortical neurons of three other thalamic nuclei in the cat (ventrobasal complex, medial geniculate body; ventral lateral nucleus) and two thalamic nuclei in rats and mice (lateral geniculate nucleus and ventrobasal complex). Slow oscillations were evident in all of these additional structures and shared several basic properties including, i) the stereotypical, rhythmic alternation between distinct UP and DOWN states with the UP state always commencing with a low-threshold Ca2+ potential, and ii) an inverse relationship between frequency and injected current so that slow oscillations always increase in frequency with hyperpolarization, often culminating in delta (delta) activity at approximately 1-4 Hz. However, beyond these common properties there were important differences in expression between different nuclei. Most notably, 44% of slow oscillations in the cat lateral geniculate nucleus possessed UP states that comprised sustained tonic firing and/or high-threshold bursting. In contrast, slow oscillations in cat ventrobasal complex, medial geniculate body and ventral lateral nucleus thalamocortical neurons exhibited such UP states in only 16%, 11% and 10% of cases, respectively, whereas slow oscillations in the lateral geniculate nucleus and ventrobasal complex of rats and mice did so in <12% of cases. Thus, the slow oscillation is a common feature of thalamocortical neurons that displays clear species- and nuclei-related differences. The potential functional significance of these results is discussed.     

Change in somatosensory evoked potential in the rat recorded at the hemisphere with iron-induced epileptic focus

In rats, microinjection of FeCl3 solution into the left sensorimotor cortex was performed to induce a chronic epileptic focus. One month or more after the microinjection, electrocutaneous stimuli were applied to part of the wrist joint and 50 consecutive somatosensory evoked potentials (SEPs) were averaged. SEP from the left cortex showed only an initial negative monophasic deflection while SEP from the contralateral cortex showed a normal configuration with initial positive-negative biphasic deflection in the majority of experimental animals.     

Reappraisal of the corticothalamic and thalamocortical interactions that contribute to the augmenting response in the rat.

In urethane-anesthetized rats, low frequency electrical stimulation of the thalamic radiation (TR) evoked an augmenting response in the somatosensory cortex (SCx) which was followed by rhythmic slow waves. The augmenting response mainly consists of the incremental secondary response (II-response). Simultaneously, augmentation also occurs in the ventrobasal nucleus of thalamus (VB) on the late component responses, C- and D-waves, to TR stimulation. The latencies of these augmented responses were shorter for the C-wave and the accompanying unit discharges in the VB relay neurons than for the D-wave and the II-response. We hypothesized that the thalamo-cortico-thalamic reverberating circuit was crucial in generating the augmenting response in the SCx. To test this hypothesis, an attempt was made to block temporarily the corticothalamic glutamatergic transmission by means of microinjections of kynurenate (KYN), an antagonist of glutamate, into the VB with a dose of more than 2 mM. This local procedure blocked all of the augmenting phenomena completely with a full recovery after the duration that depended on the dose of KYN. Besides, in the stage of complete blocking of the II-response to the test TR stimuli, the augmentation was able to be restored by adding a short train of high frequency TR stimuli that mimicked a burst discharge of VB relay neurons. These results in support of the hypothesis would reappraise the functional significance of the reverberating circuit in augmentation that has recently been controversial.     

Low-frequency (<1 Hz) oscillations in the human sleep electroencephalogram

Low-frequency (<1 Hz) oscillations in intracellular recordings from cortical neurons were first reported in the anaesthetized cat and then also during natural sleep. The slow sequences of hyperpolarization and depolarization were reflected by slow oscillations in the electroencephalogram. The aim of the present study was to examine whether comparable low-frequency components are present in the human sleep electroencephalogram. All-night sleep recordings from eight healthy young men were subjected to spectral analysis in which the low-frequency attenuation of the amplifier was compensated. During sleep stages with a predominance of slow waves and in the first two episodes of non-rapid-eye-movement sleep, the mean power spectrum showed a peak at 0.7–0.8 Hz (range 0.55–0.95 Hz). The typical decline in delta activity from the first to the second non-rapid-eye-movement sleep episode was not present at frequencies below 2 Hz. To detect very low frequency components in the pattern of slow waves and sleep spindles, a new time series was computed from the mean voltage of successive 0.5 s epochs of the low-pass (<4.5 Hz) or band-pass (12–15 Hz) filtered electroencephalogram. Spectral analysis revealed a periodicity of 20–30 s in the prevalence of slow waves and a periodicity of 4 s in the occurrence of activity in the spindle frequency range.The results demonstrate that distinct components below 1 Hz are also present in the human sleep electroencephalogram spectrum. The differences in the dynamics between the component with a mean peak value at 0.7–0.8 Hz and delta waves above 2 Hz is in accordance with results from animal experiments.     

40‐Hz oscillations underlying perceptual binding in young and older adults

Auditory object perception requires binding of elementary features of complex stimuli. Synchronization of high‐frequency oscillation in neural networks has been proposed as an effective alternative to binding via hard‐wired connections because binding in an oscillatory network can be dynamically adjusted to the ever‐changing sensory environment. Previously, we demonstrated in young adults that gamma oscillations are critical for sensory integration and found that they were affected by concurrent noise. Here, we aimed to support the hypothesis that stimulus evoked auditory 40‐Hz responses are a component of thalamocortical gamma oscillations and examined whether this oscillatory system may become less effective in aging. In young and older adults, we recorded neuromagnetic 40‐Hz oscillations, elicited by monaural amplitude‐modulated sound. Comparing responses in quiet and under contralateral masking with multitalker babble noise revealed two functionally distinct components of auditory 40‐Hz responses. The first component followed changes in the auditory input with high fidelity and was of similar amplitude in young and older adults. The second, significantly smaller in older adults, showed a 200‐ms interval of amplitude and phase rebound and was strongly attenuated by contralateral noise. The amplitude of the second component was correlated with behavioral speech‐in‐noise performance. Concurrent noise also reduced the P2 wave of auditory evoked responses at 200‐ms latency, but not the earlier N1 wave. P2 modulation was reduced in older adults. The results support the model of sensory binding through thalamocortical gamma oscillations. Limitation of neural resources for this process in older adults may contribute to their speech‐in‐noise understanding deficits.