Single neuron burst firing in the human hippocampus during sleep

Although there are numerous non-primate studies of the single neuron correlates of sleep-related hippocampal EEG patterns, very limited hippocampal neuronal data are available for correlation with human sleep. We recorded human hippocampal single neuron activity in subjects implanted with depth electrodes required for medical diagnosis and quantitatively evaluated discharge activity from each neuron during episodes of wakefulness (Aw), combined stage 3 and 4 slow-wave sleep (SWS), and rapid eye movement (REM) sleep. The mean firing rate of the population of single neurons was significantly higher during SWS and Aw compared with REM sleep (p = 0.002; p < 0.0001). In addition, burst firing was significantly greater during SWS compared with Aw (p = 0.001) and REM sleep (p < 0.0001). The synchronized state of SWS and associated high-frequency burst discharge found in human hippocampus may subserve functions similar to those reported in non-primate hippocampus that require burst firing to induce synaptic modifications in hippocampal circuitry and in hippocampal projections to neocortical targets that participate in memory consolidation.     

Single neuron binding properties and the magical number 7

When we observe a scene, we can almost instantly recognize a familiar object or can quickly distinguish among objects differing by apparently minor details. Individual neurons in the medial temporal lobe of humans have been shown to be crucial for the recognition process, and they are selectively activated by different views of known individuals or objects. However, how single neurons could implement such a sparse and explicit code is unknown and almost impossible to investigate experimentally. Hippocampal CA1 pyramidal neurons could be instrumental in this process. Here, in an extensive series of simulations with realistic morphologies and active properties, we demonstrate how n radial (oblique) dendrites of these neurons may be used to bind n inputs to generate an output signal. The results suggest a possible neural code as the most effective n-ple of dendrites that can be used for short-term memory recollection of persons, objects, or places. Our analysis predicts a straightforward physiological explanation for the observed puzzling limit of about 7 short-term memory items that can be stored by humans.     

Dynamical properties of firing patterns in ELL pyramidal neuron under external electric field stimulus

Pyramidal neurons in the electrosensory lateral line lobe (ELL) of weakly electric fish activate in an environment of time-varying electric fields, which are generated by the fish itself, while how these pyramidal neurons would behave or what kinds of firing patterns these neurons would produce under different electric fields is still unclear. In this research, the firing behaviors of ELL pyramidal neuron under DC and AC electric field stimulus are investigated in a two-compartment neuron model. By means of numerical simulations we show that firing patterns of the model ELL pyramidal neuron are much diverse under different values of DC electric field, and neuronal spike frequency exhibits a monotone decreasing trend with the linearly increased DC fields, moreover, the transition mode between these firing patterns with the variation of DC electric fields demonstrates an explicit periodic route. While for AC electric fields, neuronal firing frequency periodically transforms with the increase of AC frequency, particularly, a special transition pattern (from multi-period bursting to spiking) repeatedly appears with the change of AC frequency. Our simulation results indicate that ELL pyramidal neurons fire dynamically under the time-varying electric fields, the diversity of firing patterns and their periodic transition modes may imply the potential roles of these dynamical firings in the coding strategy of sensory information processing.     

Experience-dependent phase-reversal of hippocampal neuron firing during REM sleep

The idea that sleep could serve a cognitive function has remained popular since Freud stated that dreams were "not nonsense" but a time to sort out experiences [S. Freud, Letter to Wilhelm Fliess, May 1897, in The Origins of Psychoanalysis - Personal Letters of Sigmund Freud, M. Bonaparte, A. Freud, E. Kris (Eds.), Translated by E. Mosbacher, J. Strachey, Basic Books and Imago Publishing, 1954]. Rapid eye movement (REM) sleep, which is associated with dream reports, is now known to be is important for acquisition of some tasks [A. Karni, D. Tanne, B.S. Rubenstein, J.J.M. Askenasy, D. Sagi, Dependence on REM sleep of overnight improvement of a perceptual skill, Science 265 (1994) 679-682; C. Smith, Sleep states and learning: a review of the animal literature, Biobehav. Rev. 9 (1985) 157-168]; although why this is so remains obscure. It has been proposed that memories may be consolidated during REM sleep or that forgetting of unnecessary material occurs in this state [F. Crick, G. Mitchison, The function of dream sleep, Nature 304 (1983) 111-114; D. Marr, Simple memory: a theory for archicortex, Philos. Trans. R. Soc. B. 262 (1971) 23-81]. We studied the firing of multiple single neurons in the hippocampus, a structure that is important for episodic memory, during familiar and novel experiences and in subsequent REM sleep. Cells active in familiar places during waking exhibited a reversal of firing phase relative to local theta oscillations in REM sleep. Because firing-phase can influence whether synapses are strengthened or weakened [C. Holscher, R. Anwyl, M.J. Rowan, Stimulation on the positive phase of hippocampal theta rhythm induces long-term potentiation that can be depotentiated by stimulation on the negative phase in area CA1 in vivo, J. Neurosci. 15 (1977) 6470-6477; P.T. Huerta, J.E. Lisman, Bidirectional synaptic plasticity induced by a single burst during cholinergic theta oscillation in CA1 in vitro, Neuron 15 (1995) 1053-1063; C. Pavlides, Y.J. Greenstein, M. Grudman, J. Winson, Long-term potentiation in the dentate gyrus is induced preferentially on the positive phase of theta-rhythm, Brain Res. 439 (1988) 383-387] this experience-dependent phase shift, which developed progressively over multiple sessions in the environment, is consistent with the hypothesis that circuits may be restructured during REM sleep by selectively strengthening recently acquired memories and weakening older ones.     

Space-rate coding in an adaptive silicon neuron.

Neurophysiology is largely the study of spike rates of single neurons, under controlled conditions, with the hope that these results reflect how populations of neurons compute. However, the population response differs radically from the single-neuron response if the membrane voltage's rate of change drops dramatically when it is close to the spike-firing threshold. By delaying spiking, this slew-rate adaptation has been shown to regulate spike rate and prolong synaptic integration at the single-neuron level. We show here that it sharpens sensitivity and shortens latency at the population level. Thus, slew-rate adaptation enables neurons to process information faster than their interspike interval by using space-rate coding, instead of time-rate coding. This study also suggests how neural populations can modulate their gain and synchrony by regulating active conductances. Our results are extrapolated from experiments and analysis performed on a single silicon neuron, with Ca- and voltage-dependent potassium-channel analogs.     

Modification of vestibular-induced pause neuron firing during anesthesia and light sleep

Anatomic and electrophysiologic evidence suggests there is a vestibular input to eye movement-related pause neurons in the midline of the pontine reticular formation of the cat. The present investigation sought to explore the functional significance of this vestibular drive by examining pause neuron response to horizontal rotational stimulation as cats were anesthetized with halothane or went into natural light sleep. Anesthesia unmasks the vestibular input to pause neurons in that during anesthesia, pause neurons continue to fire but their firing rate is modulated by vestibular stimulation. The particular response patterns of pause neurons to anesthesia are not uniform. We suggest that the results observed could be explained if pause neurons received input from both vestibular nuclei, either directly or possibly via the prepositus hypoglossi.     

Single neuron studies of inferior temporal cortex

This paper reviews our experiments on the response properties of single neurons in inferior temporal (IT) cortex in the monkey that were carried out starting in 1965. It describes situational factors that led us to find neurons sensitive to images of faces and hands and summarizes the basic sensory properties of IT neurons. Subsequent developments on the cognitive properties of IT neurons and on imaging the responses of human temporal cortex to facial images are outlined. Finally, this paper summarizes recent results on fMRI imaging of the responses of temporal cortex to facial images.     

Functional evidence for visuospatial coding in the Mauthner neuron

When startled by sound, goldfish make large turns away from a rostral stimulus and small responses away from caudal stimuli, suggesting that rostral startling stimuli recruit larger pools of reticulospinal neurons in the Brainstem Escape Network (BEN) than do caudal stimuli. Consistent with this idea, the zebrafish Mauthner (M-) cell fires when the fish is startled by tail-directed stimuli, but the M-cell homologues (MiD2cm and MiD3cm) are also recruited when the fish is startled by displacing the head. Because vision is known to modulate M-cell activity, a nonstartling, modulatory sensory 'signal' conveyed to the reticular formation may be stronger if the visual sensory image is from a rostral vs. caudal spatial location and could account for a differential neuron pool recruitment and response magnitude. In this study, electrophysiological recordings from cichlid Mauthner neurons showed that visual stimulation of the caudal retina (by a rostral cue) generates a depolarization that is about 1.5 times the amplitude of that generated by stimulation of the rostral retina (by a caudal cue). In behavioral testing, where fish were stimulated visually for 30 ms and then startled by sound, fish startled in the presence of a rostral visual stimulus performed larger amplitude and faster turns than when startled in the presence of a caudal visual stimulus. Thus, M-cell potentials might reflect the strength of visual input to the BEN in general. For a particular visual spatial location, the relative strength of descending visual input appears to contribute to a recruitment of a reticulospinal neuron population that generates a turn magnitude appropriate to the visual cue, and suggests that a retinotopic representation is preserved in the BEN.     

Anatomic basis of sequence-dependent predictability exhibited by nigral dopamine neuron firing patterns

Interspike intervals (ISIs) of dopamine (DA) neurons recorded in the substantia nigra are predicted partially by their immediate prior history. This study was designed to assess neuroanatomic origins of these sequential relationships. ISI data recorded from three groups of nigral DA neurons were studied: 1) 16 neurons recorded in unlesioned animals, 2) 14 neurons recorded after forebrain hemisection, 3) 12 neurons recorded after partial forebrain hemisection that reproduced nonspecific effects of the surgical lesion while leaving forebrain connections intact. As predicted, DA neurons recorded after full forebrain hemisection yielded statistically significant reductions in sequential predictability relative to control neurons and neurons recorded following partial hemisection. These data support the hypothesis that the sequence-dependent behavior of DA neurons arise in part from interactions with forebrain structures. ISI sequences recorded from unlesioned rats demonstrated maximum predictability when an average of 3.7 prior events were incorporated into the forecasting algorithm, thereby suggesting a physiological process whose "depth" of history-dependence is approximately 600-800 msec. Additional studies examining the functional significance of sequence-dependent ISI structure exhibited by nigral DA neurons are indicated.     

Role of neuron soma firing in the restoration of neurotensin store in sympathetic preganglionic neuron terminals after stimulus-evoked depletion

We have previously shown that prolonged preganglionic stimulation (e.g., 40 Hz 20 min) depletes the neurotensin (NT) store of preganglionic axon terminals in the stellate ganglion (SG) of the cat and that replenishment of the store requires several days. The present study investigates the mechanisms which control turnover of the NT store in sympathetic preganglionic axon terminals. NT content of the SG and of the preganglionic axons which innervate it was determined by radioimmunoassay in the anesthetized cat. This study shows that, during the 24 h after 40-Hz 20-min stimulation of the preganglionic input to the SG, the rate of NT accumulation proximal to a ligature on the stimulated input is three times that observed in the control. The poststimulus increase in NT accumulation rate is prevented by treatment with protein-synthesis inhibitors. When the centripetal propagation of action potentials from the stimulus site on the preganglionic axons is prevented by a tetrodotoxin bloxk applied locally during the stimulation period, the poststimulus increase in NT accumulation rate and the replenishment of the store are both prevented. These data suggest that the level of activity of the neuron regulates NT supply to the axon terminals, presumably by regulating NT synthesis. Thus, in the sympathetic preganglionic neuron, the action potential provides a mechanism for matching peptide synthesis to release.     

Clozapine modulates midbrain dopamine neuron firing via interaction with the NMDA receptor complex

The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still relatively unknown. A recent study shows that a pharmacologically increased concentration of brain kynurenic acid, an endogenous antagonist at the glycine-site of the NMDA receptor as well as at the alpha7* nicotinic receptor, reverses the excitatory effects of clozapine on ventral tegmental area (VTA) dopamine (DA) neurons into an inhibitory action. In the present in vivo electrophysiological study, we further investigated the mechanisms of action of clozapine on VTA DA neurons. In control rats intravenously administered clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, administration of the N-methyl-D-aspartate (NMDA)-receptor antagonist MK 801 blocked the excitatory action of clozapine. Moreover, in rats pretreated with the antagonist of the glycine-site of the NMDA receptor, L-701,324, the effects of clozapine on VTA DA neurons were converted to purely inhibitory responses, including a decrease in firing rate and burst firing activity. Pretreatment with the alpha7* nicotinic receptor antagonist MLA did not affect the excitatory action of clozapine on VTA DA neurons. The results of the present study suggest that clozapine interacts with the NMDA receptor complex. In this regard, clozapine could affect the glycine site of the NMDA receptor or tentatively inhibit the glycine transporter. The inhibitory action of clozapine on VTA DA neurons may account for its beneficial effects in ameliorating symptoms of schizophrenia and may suggest further studies to investigate a role of the glycine site of the NMDA receptor as a target for novel antipsychotics.     

Differential effects of cocaine on dopamine neuron firing in awake and anesthetized rats

Cocaine (benzoylmethylecgonine), a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are not clear. We investigated the effects of cocaine on the firing of midbrain dopaminergic (DA) neurons, both in anesthetized and awake rats, using pre-implanted multielectrode arrays and a recently developed telemetric recording system. In anesthetized animals, cocaine (10 mg/kg, intraperitoneally) produced a general decrease of the firing rate and bursting of DA neurons, sometimes preceded by a transient increase in both parameters, as previously reported by others. In awake rats, however, injection of cocaine led to a very different pattern of changes in firing. A decrease in firing rate and bursting was observed in only 14% of DA neurons. Most of the other DA neurons underwent increases in firing rate and bursting: these changes were correlated with locomotor activity in 52% of the neurons, but were uncorrelated in 29% of them. Drug concentration measurements indicated that the observed differences between the two conditions did not have a pharmacokinetic origin. Taken together, our results demonstrate that cocaine injection differentially affects the electrical activity of DA neurons in awake and anesthetized states. The observed increases in neuronal activity may in part reflect the cocaine-induced synaptic potentiation found ex vivo in these neurons. Our observations also show that electrophysiological recordings in awake animals can uncover drug effects, which are masked by general anesthesia.     

Stimulus intensity determines experience‐dependent modifications in neocortical neuron firing rates

Although subthreshold inputs of neocortical sensory neurons are broadly tuned, the spiking output is more restricted. These subthreshold inputs provide a substrate for stimulus intensity‐dependent changes their spiking output, as well as for experience‐dependent plasticity to alter firing properties. Here we investigated how different stimulus intensities modified the firing output of individual neurons in layer 2/3 of the mouse barrel cortex. Decreasing stimulus intensity over a 30‐fold range lowered the firing rates evoked by principal whisker stimulation and reduced the overall size of the responding ensemble in whisker‐undeprived animals. We then examined how these responses were changed after single‐whisker experience (SWE). After 7 days of SWE, the mean magnitude of response to spared whisker stimulation at the highest stimulus intensity was not altered. However, lower‐intensity whisker stimulation revealed a more than 10‐fold increase in mean firing output compared with control animals. Also, under control conditions, only ~15% of neurons showed any firing at low stimulus intensity, compared with more than 70% of neurons after SWE. However, response changes measured in the immediately surrounding representations were detected only for the highest stimulus intensity. Overall, these data showed that the measurement of experience‐dependent changes in the spike output of neocortical neurons was highly dependent upon stimulus intensity.     

Spatial firing properties of lateral septal neurons

The present study describes the spatial firing properties of neurons in the lateral septum (LS). LS neuronal activity was recorded in rats as they performed a spatial navigation task in an open field. In this task, the rat acquired an intracranial self-stimulation reward when it entered a certain place, a location that varied randomly from trial to trial. Of 193 neurons recorded in the LS, 81 showed place-related activity. The majority of the tested neurons changed place-related activity when spatial relations between environmental cues were altered by rotating intrafield (proximal) cues. The comparison of place activities between LS place-related neurons recorded in the present study and hippocampal place cells recorded in our previous study, using identical behavioral and recording procedures, revealed that spatial parameters (spatial information content, coherence, and cluster size) were smaller in the LS than in the hippocampus. Of the 193 LS neurons, 86 were influenced by intracranial self-stimulation rewards; 31 of these 86 were also place-related. These results, together with previous anatomical and behavioral observations, suggest that the spatial information sent from the hippocampus to the LS is modulated by and interacts with signals related to reward in the LS.     

Spatial firing properties of hippocampal theta cells

Previous studies have shown that complex-spike cells, the most common cell type recorded in the hippocampus of freely moving rats, have the property of spatial firing--that is, a cell will fire rapidly only when the animal is in a particular part of its environment (O'Keefe and Dostrovsky, 1971). In the current study, we analyze the spatial firing of theta cells, the second major class of cells in the hippocampus, which are thought to correspond to nonpyramidal neurons (Fox and Ranck, 1975, 1981). Our purposes were to extend findings from earlier spatial analyses (McNaughton et al., 1983; Christian and Deadwyler, 1986), and to determine whether the spatial firing is cell specific and independent of behavior. Theta cells were recorded from rats in a cylindrical enclosure using techniques previously used for the analysis of spatial firing in complex-spike cells (Muller et al., 1987). The spatial firing patterns of individual neurons appeared as a complex surface with several regions of high and low firing. The ratio of firing from high- to low-rate regions averaged 2.5. These spatial firing patterns were smooth and reproducible, but less so than for complex-spike cells. When a cue card on the wall was moved, theta cell firing patterns remained in register with the cue. Two analyses were performed to determine whether spatial firing patterns were secondary to spatial distributions of behavior. When only locomotor data segments were selected, spatial variations were more clear-cut. In an attempt to test whether theta cells had cell-specific patterns of firing, pairs of theta cells were recorded simultaneously. On all occasions, the firing distribution for each of the cells in a pair was clearly distinctive. These findings support the conclusions that theta cell activity contains a spatial signal that is cell specific and not secondary to other firing correlates.     

Single motor unit H-reflex in motor neuron disorders.

The latency fluctuation of single motor unit potentials (MUPH) in the H-reflex is greater than the latency fluctuation of MUPs in the direct (MUPM) and recurrent (MUPF) responses. This has been attributed to the variability in the impulse generation at the site of nerve stimulation, and to the variation in the synaptic delay at the anterior horn cell. We studied the latency fluctuation of single motor unit H-reflex in patients with motor neuron disorders (MND) in comparison with normal subjects. The mean jitter of the H-reflex was 264.3 +/- 17.8 microseconds (mean +/- SEM) in 30 MUPH recorded from 10 patients with ALS, 302.7 +/- 25.2 microseconds in 16 MUPH from 6 patients with chronic motor neuron diseases, as compared with 137.4 +/- 7.3 microseconds in 34 MUPH recorded from 10 normal subjects. This difference, which persisted even after the correction for the latency variation of MUPM, cannot be explained on the basis of an enhanced reciprocal inhibition. Thus, the increased latency fluctuation of the single motor unit H-reflex in patients with MND may reflect changes in the motoneuron pool excitability that may be secondary to altered intrinsic electrophysiological properties of motoneurons, or to an abnormal temporal and spatial summation of synaptic inputs on motoneurons.     

The sequential-interval state space: a means of displaying temporal information in neuron firing

Variability in neuronal firing exhibits sufficient uncertainty so that a simple average firing frequency code is probably inadequate for most nervous system signalling. Temporal patterns certainly play an important role in neuronal coding. We have used interval histogram and 3-dimensional sequential interval state space plots to investigate various common patterns of firing in neurons of the land snail, Helix aspersa. Typical firing patterns included random, highly regular, doublet, and burst firing. Individual neurons could be made to change their temporal firing pattern in response to changes in transmembrane currents, or temperature, or the application of convulsant drugs. In every instance, the sequential interval state space plot provided a more distinctive display of temporal pattern than did the more common interval histogram. State space plots were also investigated for evidence of a predicted chaotic attractor. In no instance was this type of state space plot observed.     

Burst firing transitions in two-compartment pyramidal neuron induced by the perturbation of membrane capacitance

Neuronal membrane capacitance C (m) is one of the prominent factors in action potential initiation and propagation and then influences the firing patterns of neurons. Exploring the roles that C (m) plays in different firing patterns can facilitate the understanding of how different factors might influence neuronal firing behaviors. However, the impacts of variations in C (m) on neuronal firing patterns have been only partly explored until now. In this study, the influence of C (m) on burst firing behaviors of a two-compartment pyramidal neuron (including somatic compartment and dendritic compartment) was investigated by means of computer simulation, the value of C (m) in each compartment was denoted as C (m,s) and C (m,d), respectively. Two cases were considered, in the first case, we let C (m,s) =C (m,d), and then changed them simultaneously. While in the second case, we assumed C (m,s) ≠C (m,d), and then changed them, respectively. From the simulation results obtained from these two cases, it was found that the variation of C (m) in the somatic compartment and the dendritic compartment show much difference, simulated results obtained from the variation of C (m,d) have much more similarities than that of C (m,s) when comparing with the results obtained in the first case under which C (m,s) =C (m,d). These different effects of C (m,s) and C (m,d) on neuronal firing behaviors may result from the different topology and functional roles of soma and dendrites. Numerical results demonstrated in this paper may give us some inspiration in understanding the possible roles of C (m) in burst firing patterns, especially their transitions in compartmental neurons.