Single Spike Responses Research Articles

Biologically Realistic Behaviors From a Superconducting Neuron Model

In previous work, we introduced the “Josephson junction neuron,” a superconducting circuit that can reproduce some important properties of biological neurons like action potentials and refractory periods. Circuits of Josephson junction neurons have very fast dynamics and operate fully in parallel, and large simulations would be possible with them that are not feasible using traditional computers. Here, we show that this model reproduces 15 common dynamical behaviors of individual cortical spiking neurons for various choices of the intrinsic circuit parameters, while 4 more behaviors can be produced by also including a sinusoidal bias current, giving a total of 19. Behaviors such as single spike response, tonic (periodic) spiking only when stimulated, bursting, tonic bursting, frequency adaptation, and subthreshold oscillations are some of the common behaviors seen. Even bistability of periodic firing and quiescent modes are possible. This suggests that Josephson junction neurons could be fabricated and used to simulate biologically realistic neural circuits, networks, and perhaps even larger regions of the brain.

Kv2.1 Potassium Channels Regulate Repetitive Burst Firing in Extratelencephalic Neocortical Pyramidal Neurons

Abstract Coincidence detection and cortical rhythmicity are both greatly influenced by neurons’ propensity to fire bursts of action potentials. In the neocortex, repetitive burst firing can also initiate abnormal neocortical rhythmicity (including epilepsy). Bursts are generated by inward currents that underlie a fast afterdepolarization (fADP) but less is known about outward currents that regulate bursting. We tested whether Kv2 channels regulate the fADP and burst firing in labeled layer 5 PNs from motor cortex of the Thy1-h mouse. Kv2 block with guangxitoxin-1E (GTx) converted single spike responses evoked by dendritic stimulation into multispike bursts riding on an enhanced fADP. Immunohistochemistry revealed that Thy1-h PNs expressed Kv2.1 (not Kv2.2) channels perisomatically (not in the dendrites). In somatic macropatches, GTx-sensitive current was the largest component of outward current with biophysical properties well-suited for regulating bursting. GTx drove ~40% of Thy1 PNs stimulated with noisy somatic current steps to repetitive burst firing and shifted the maximal frequency-dependent gain. A network model showed that reduction of Kv2-like conductance in a small subset of neurons resulted in repetitive bursting and entrainment of the circuit to seizure-like rhythmic activity. Kv2 channels play a dominant role in regulating onset bursts and preventing repetitive bursting in Thy1 PNs.

Occurrence of Calcium Oscillations in Human Spermatozoa Is Based on Spatial Signaling Enzymes Distribution.

In human spermatozoa, calcium dynamics control most of fertilization events. Progesterone, present in the female reproductive system, can trigger several types of calcium responses, such as low-frequency oscillations. Here we aimed to identify the mechanisms of progesterone-induced calcium signaling in human spermatozoa. Progesterone-induced activation of fluorophore-loaded spermatozoa was studied by fluorescent microscopy. Two computational models were developed to describe the spermatozoa calcium responses: a homogeneous one based on a system of ordinary differential equations and a three-dimensional one with added space dimensions and diffusion for the cytosolic species. In response to progesterone, three types of calcium responses were observed in human spermatozoa: a single transient rise of calcium concentration in cytosol, a steady elevation, or low-frequency oscillations. The homogenous model provided qualitative description of the oscillatory and the single spike responses, while the three-dimensional model captured the calcium peak shape and the frequency of calcium oscillations. The model analysis demonstrated that an increase in the calcium diffusion coefficient resulted in the disappearance of the calcium oscillations. Additionally, in silico analysis suggested that the spatial distribution of calcium signaling enzymes governs the appearance of calcium oscillations in progesterone-activated human spermatozoa.

Novel Type of Synaptic Transistors Based on a Ferroelectric Semiconductor Channel.

Three-terminal synaptic transistors are basic units of neuromorphic computing chips, which may overcome the bottleneck of conventional von Neumann computing. So far, most of the three-terminal synaptic transistors use the dielectric layer to change the state of the channel and mimic the synaptic behavior. For this purpose, special dielectric layers are needed, such as ionic liquids, solid electrolytes, or ferroelectric insulators, which are difficult for miniaturization and integration. Here, we report a novel type of synaptic transistors using a two-dimensional ferroelectric semiconductor, i.e., α-In2Se3, as the channel material to mimic the synaptic behavior for the first time. The essential synaptic behaviors, such as single-spike response, paired-spike response, and multispike response have been experimentally demonstrated. Most importantly, the conventional gate dielectric material of our transistors may facilitate the miniaturization and batch manufacture of synaptic transistors. The results indicate that the three-terminal synaptic transistors based on two-dimensional ferroelectric semiconductors are very promising for neuromorphic systems.

Repetitive Perforant-Path Stimulation Induces Epileptiform Bursts in Minislices of Dentate Gyrus From Rats With Kainate-Induced Epilepsy

The epileptic hippocampus has an enhanced propensity for seizure generation, but how spontaneous seizures start is poorly understood. Using whole cell and field-potential recordings, this study explored whether repetitive perforant-path stimulation at physiological frequencies could induce epileptiform bursts in dentate gyrus minislices from rats with kainate-induced epilepsy. Control slices from saline-treated rats responded to single perforant-path stimulation with an excitatory postsynaptic potential (EPSP) and a single population spike in normal medium, and repetitive stimulation at different frequencies (0.1, 1, 2, 5, 10 Hz) did not cause significant increases in the responses. Most minislices (82%) from rats with kainate-induced epilepsy also responded to single perforant-path stimulation with an EPSP and a single population spike/action potential, but some slices (18%) had a more robust response with a prolonged duration and negative DC shift or responses with two to three population spikes. Repetitive perforant-path stimulation at 5-10 Hz, however, transformed the single-spike responses into epileptiform bursts with multiple spikes in half (52%) of the slices, while lower frequency (e.g., ≤ 1 Hz) stimulation failed to produce these changes. The emergence of epileptiform bursts was consistently associated with a negative field-potential DC shift and membrane depolarization. The results suggest that compared with the controls, the "gate" function of the dentate gyrus is compromised in rats with kainate-induced epilepsy, and epileptiform bursts (but not full-length seizure events) can be induced in minislices by repetitive synaptic stimulation at physiological frequencies in the range of hippocampal theta rhythm (i.e., 5-10 Hz).

Links between complex spikes and multiple synaptic plasticity mechanisms in the cerebellar cortex

Introduction In the classic cerebellar learning theory the climbing fiber (CF) is activated when the movement is inaccurate and this activation leads changes in the synaptic strength and in the Purkinje cell (PC) output [1,2]. Stimulation of a single CF activates hundreds of synaptic contacts across PC dendrites and triggers a high frequency burst of spikes called complex spike (CS) [3]. However, it is still unclear how changes in the complex spike probability and the time interval between the parallel fiber (PF) and CF inputs will affect the PC single spike response and learning, considering multiple plasticity mechanisms present at PF and CF synapses [4]. In this work, we used a computational model for synaptic transmission to simulate both longterm and short-term plasticity [5,6] and a single compartmental model of the PC [7] to investigate the links between CS probability, multiple plasticity mechanisms and changes in the PC output. The computational model includes the post-synaptic expression of long-term depression between CF and PC [8], long-term potentiation and depression between PF and PC [5] and short-term facilitation between PF and PC [6]. The models were based in previous models for synaptic transmission and were validated according to the available experimental data (Figure 1).

Fast oscillations trigger bursts of action potentials in neocortical neurons in vitro: A quasi-white-noise analysis study

Purpose: Recent evidence supports the importance of action potential bursts in physiological neural coding, as well as in pathological epileptogenesis. To better understand the temporal dynamics of neuronal input currents that trigger burst firing, we characterized spectral patterns of stimulation current that generate bursts of action potentials from regularly spiking neocortical neurons in vitro. Methods: Sharp microelectrodes were used for intracellular recording and stimulation of cortical neurons in rat brain slices. Quasi-white-noise (0–2 kHz) and “chirp” sine wave currents of decreasing wavelength were applied to represent a broad spectrum of stimulation frequencies. Action potential-related averaging of the stimulation current variations preceding bursting was used to characterize stimulation current patterns more likely to result in a burst rather than a single-spike response. Results: Bursts of action potentials were most reliably generated by a preceding series of ≥ 2 positive current transients at 164 ± 37 Hz of the quasi-white-noise, and to sine wave currents with frequencies greater than 90 Hz. The intraburst action potential rate was linearly related to the frequency of the input sine wave current. Conclusions: This study demonstrates that regularly spiking cortical neurons in vitro burst in response to fast oscillations of input currents. In the presence of positive cortical feedback loops, encoding input frequency in the intraburst action potential rate may be safer than producing a high-frequency regular output spike train. This leads to the experimentally testable and therapeutically important hypothesis that burst firing could be an antiepileptogenic and/or anti-ictogenic mechanism.

Impaired thalamic T-type calcium channel function: a possible mechanism for visceral hyperalgesia and functional abdominal pain

Impaired thalamic T-type calcium channel function: a possible mechanism for visceral hyperalgesia and functional abdominal pain

Thalamic Control of Visceral Nociception Mediated by T-Type Ca 2+ Channels

Sensations from viscera, like fullness, easily become painful if the stimulus persists. Mice lacking alpha1G T-type Ca2+ channels show hyperalgesia to visceral pain. Thalamic infusion of a T-type blocker induced similar hyperalgesia in wild-type mice. In response to visceral pain, the ventroposterolateral thalamic neurons evokeda surge of single spikes, which then slowly decayed as T type-dependent burst spikes gradually increased. In alpha1G-deficient neurons, the single-spike response persisted without burst spikes. These results indicate that T-type Ca2+ channels underlie an antinociceptive mechanism operating in the thalamus andsupport the idea that burst firing plays a critical role in sensory gating in the thalamus.

Differential distribution of burst and single-spike responses in auditory thalamus.

The medial geniculate body (MGB) of the auditory thalamus comprises lemniscal and nonlemniscal neurons that project to the primary auditory cortex and limbic structures, respectively. Here we show that in anesthetized guinea pigs, MGB responses to a noise-burst stimulus exhibit distinct and synaptic pathway-specific firing patterns. The majority of nonlemniscal MGB cells exhibited bursting responses, whereas lemniscal neurons discharged mainly single or spike doublets. The burst firing is delayed in nonlemniscal neurons and exhibited several features that are characteristics of those mediated by low-threshold Ca(2+) spikes. Such a synaptic pathway-specific allocation of bursting and single-spike firing patterns is consistent with the notion of parallel processing of auditory information in thalamocortical system.

The effects of afferent stimulation on neurons in slices of the medial septal area and their modulation by biologically active substances in hibernating and awake ground squirrels.

Evoked neuron activity in slices of the medial septal area and its modulation by neuropeptides and monoamines was studied in two groups of ground squirrels--hibernating and awake animals. Electrical stimulation of the medial forebrain bundle evoked predominantly inhibitory effects of different durations. In addition, responses were seen consisting of resetting of the phase of background volleys to the stimulus after initial inhibition: there were also small numbers of short-latency single-spike responses. All the neuropeptides tested. which had been identified from the brains of hibernating animals, induced differentiated reversible effects consisting of modulation of responses; changes in evoked activity were seen significantly more often than shifts in spontaneous activity. The effects depended on the state of the animal. Thus. peptide TSKYR increased the duration of inhibition in hibernating ground squirrels but shortened inhibition in awake animals. Peptide TSKY. which had little effect in hibernating animals, increased the duration of inhibition in awake animals. Dipeptide DY. which decreased the duration of inhibition and increased the amplitude of the activatory components of responses in hibernating ground squirrels. had little effect in awake animals. The effects of noradrenaline and serotonin correlated to a large extent with their effects on spontaneous activity. It is suggested that endogenous substances are involved in creating the conditions required for increasing the latent excitability and reactivity of septal neurons during hibernation. This allows the medial septal area to function as a "sentry post," allowing the receipt of signals and urgent arousal during hibernation.

The recruitment pattern of single vasoconstrictor neurons in human

The aim of this study is to determine the recruitment pattern among individual vasoconstrictor neurons under the baroreceptor-mediated influence in man. Spikes of single vasoconstrictor units were detected from microneurograms with a template-matching method. A total of 39 single vasoconstrictor units were detected. Single vasoconstrictor units were different from each other in their susceptibility to be activated in response to changes in the R–R interval or blood pressure. The units with higher firing probability had a shorter threshold R–R interval and a higher threshold diastolic blood pressure than units with lower firing probability. In sympathetic responses consisting of only one spike (single-spike responses), units with a lower threshold frequently appeared and units with a higher threshold joined mull-spike responses. The units with a short threshold R–R interval tended to have a long inhibitory latency from R wave, suggesting low conduction velocity. The correlation between firing probability and firing threshold and that between appearance in single-spike response and multi-spike response suggest a hierarchical manner of recruitment of vasoconstrictor units. For beat-to-beat responses, however, some deviation from the hierarchical recruitment was also observed.

Effects of area postrema stimulation on neurons of the nucleus of the solitary tract

Previous studies have suggested that neurons of the area postrema may modulate cardiovascular function through an interaction at the level of the nucleus of the solitary tract (NTS). Using an in vitro brain slice preparation of the rabbit medulla, the present study investigated the electrophysiological and pharmacological effects of area postrema stimulation on NTS neuronal activity. In the majority of neurons tested (85.7%), electrical stimulation of the area postrema consistently produced either single or multiple action potentials in NTS neurons. Latency values for neurons showing single spike responses to area postrema stimulation ranged from 3.0 to 17.0 ms with an average latency of 9.3 +/- 4.3 ms. The average threshold for area postrema activation of these nonspontaneously active NTS neurons was 99.8 +/- 12 microA with a stimulus threshold range between 15 and 200 microA (n = 53). Perfusion of the slice with phentolamine (1.0 microM) or yohimbine (200 nM) blocked the area postrema-evoked action potentials, whereas perfusion of the slice with prazosin (200 nM) had no effect. These findings suggest that area postrema neurons do modulate NTS neuronal activity and that this modulation results in an increase in NTS neuronal activation.

Electrophysiological characteristics of morphologically identified reticular thalamic neurons from rat slices

This study is aimed at the investigation of the morphological and electrophysiological characteristics of neurons from the nucleus reticularis thalami in rat thalamic slices incubated in vitro. Ten neurons were recorded in the ventrobasal complex, four of which were successfully injected following horseradish peroxidase injection. Two main types of reticular thalamic neurons were morphologically identified: (1) the small fusiform “f” cells characterized by a very elongated perikaryon, dendritic arborization prevalent in the rostrocaudal and dorsoventral planes and an axon without any collaterals branching within the nucleus reticularis thalami; and (2) the large fusiform ‘F’ neurons with dendrites arborizing mainly in the horizontal plane and with axonal branches within the nucleus reticularis thalami. The electrophysiological properties of the neurons were similar in F and f cells. The reticular neurons showed, in resting conditions, a single spike response followed by a postexcitatory hyperpolarizing potential. The hyperpolarization of these neurons transformed the single spike response into a burst discharge similar to that observed in thalamic relay neurons at resting membrane potential. The same phenomenon was observed when bicuculline was administered by perfusion to the slices and, in this case, a recovery to a single spike response was obtained by a depolarizing d.c. current injection. By contrast, the local administration of GABA induced a depolarization with a pronounced decrease in input resistance. The present data demonstrate the presence of at least two neuronal subtypes within the nucleus reticularis thalami, suggesting that only one is responsible for the phenomenon of auto-inhibition by means of intrinsic axon collaterals. Moreover, it is hypothesized that intranuclear GABAergic collaterals could control neuronal excitability of reticular thalamic cells by both shunting the membrane and shifting the burst firing to a single spike firing mode.

The functional states of the thalamus and the associated neuronal interplay.

The functional states of the thalamus and the associated neuronal interplay.

Modulation of the afferent input to the septal neurons by cholinergic drugs

The effects of cholinergic drugs upon the evoked activity of extracellularly recorded neurons of the medial septal nucleus-nucleus of the diagonal band (MS-DB complex) were tested in unanesthetized rabbits. Electrical stimulation of MFB resulted in entrainment of the background θ-cycles in the neurons with strong rhythmic discharge (types I and II). Phase-locking of the background θ-cycles to the stimulus occurred ‘by the burst’, or ‘by the pause’ within the θ-range of frequencies (3–12 Hz). Single-spike responses, following up to 30 Hz and more, were also evoked by MFB stimulation, especially in the cells with weak θ-modulation (type III) or without it (type IV). Injection of physostigmine increased background θ-modulation of neuronal activity and simultaneously blocked or diminished responses to repetitive MFB stimulation in 82% of the MS-DB units, independent of their type of response. Driving of θ-cycles both ‘by the burst’ and ‘by the pause’ was ineffective or drastically reduced. Single spike responses disappeared or became unstable, though their minimal latencies did not change. Initial inhibitory responses were blocked or became significantly shorter. Antimuscarinic drugs, scopolamine and atropine, which abolished θ-modulation in many MS-DB units, restored responses and sometimes enhanced them. Repetitive stimulation of the MFB in this condition was effective up to the high frequencies, well beyond the θ-range. Thus, the majority of the MS-DB units did not respond to the afferent stimuli during prominent θ-activity evoked by physostigmine. The role of the septal cholinergic system in gating of afferent input during the θ-state and its importance for learning and memory is suggested.

Frequency modulation of neuronal theta-bursts in rabbit's septum by low-frequency repetitive stimulation of the afferent pathways

Activity of the neurons with stable theta-bursts was recorded extracellularly in intact and hippocampectomized septum of unanesthetized chronic rabbits during low-frequency (3–17 Hz) stimulation of horizontal limb of diagonal band or lateral septal nucleus. The stimulation rarely evoked standard oligosynaptic single-spike responses in stable theta-bursting units. Instead, gradual entrainment and phase-locking of the spontaneous theta-cycles occurred. Two types of entrainment were observed: “entrainment by the pause”, where interburst interval was reset by the stimuli; and “entrainment by the burst”, where bursts were time-locked to the stimuli. Such reorganization of the spontaneous bursts occurred in the narrow frequency range of stimulation (from 4 Hz up to 9–12 Hz), with the best resonance following in the range of “basic” theta frequencies of the awake rabbit (5–6 Hz). With stimulation beyond the theta-range three phenomena occurred: shift of the burst frequencies to higher or lower harmonics of stimulation frequencies; complex interactions of basic background frequency with rhythm of stimulation (“beating”); return to background theta-burst frequency in spite of continuing stimulation (“escape”). The properties of the septal theta-bursting cells as presumable intrinsic bursting pacemakers are discussed.

Inferior colliculus single unit responses to peripheral electrical stimulation in normal and congenitally deaf mice

We have investigated the single unit response in the inferior colliculus of the mouse to electrical pulse stimulation at the auditory periphery. The experimental animals were deafness mutant mice (dn/dn), which have hereditary congenital peripheral pathology. The control animals were normal littermates ( +/dn). Monopolar electrical pulses were applied either to the modiolus or the round window and the evoked single unit activity was recorded in the contralateral inferior colliculus (IC). Two types of single unit response were observed: a single-spike response, and a multiple-spike response. There was a predominance of the former in the control animals and of the latter in the mutants. For both modes of stimulation the group mean threshold of response was lower in mutants compared to controls, whilst the maximum number of evoked spikes per 50 presentations was higher in mutants than control animals. The mutant response pattern was similar to that seen in animals with experimentally induced auditory deprivation. The suitability of the deafness mutant as a model for the investigation of coding strategies for cochlear implants is discussed.

Inhibitory influence of the mesocortical dopaminergic system on spontaneous activity or excitatory response induced from the thalamic mediodorsal nucleus in the rat medial prefrontal cortex

Since the medial prefrontal cortex receives converging projections from the mediodorsal nucleus of the thalamus (MD) and the dopaminergic neurons located in the ventromedial mesencephalic tegmentum (VMT) the responses of cortical neurons to ipsilateral VMT and MD stimulation (50–150 μA; 0.2–0.5 ms duration) were analyzed in ketamine anaesthetized rats. MD stimulation at 1 Hz blocked the firing of 90% of the spontaneously active cortical units tested (mean latency, 15 ms; mean duration, 182 ms). MD stimulation at 5–10Hz evoked single spike responses (mean latency, 16 ms) in 80% of the units tested. Ten to 15 days after kainic acid injection into the MD the number of cortical neurons inhibited (1 Hz) or excitated (5–10 Hz) was reduced to 57 and 18%, respectively. Following stimulation of the VMT (at a frequency of 1–5 Hz), 85% of cortical neurons showed an arrest of spontaneous firing occurring after a mean latency of 17 ms and lasting 109 ms on the average. Most of the cells displaying the VMT inhibitory effect were excitated by MD stimulation. Moreover VMT stimulation, applied 3–45 ms before that of MD, blocked the excitation induced by MD in 75% of the units tested. After injection of 6-hydroxydopamine into the medial forebrain bundle or intraperitoneal administration of α-methyl-paratyrosine (α-MpT), the number of units tested responding to VMT stimulation was of 19 and 35%, respectively. Moreover in these treated rats, the proportion of excitatory responses to MD blocked by VMT stimulation was reduced to 5 and 6%. On the other hand, the effects induced by VMT stimulation were not affected after specific destruction of the noradrenergic ascending system. These results suggest that the mesocortical dopaminergic neurons modulate the influence of the main thalamic afferent on the prefrontal cortical cells.

Physiological properties of afferents and synaptic reorganization in the rat cerebellum degranulated by postnatal x‐irradiation

Elimination of most granule, basket, and stellate interneurons in the rat cerebellum was achieved by repeated doses of low level x-irradiation applied during the first two weeks of postnatal life. Electrical stimulation of the brain stem and peripheral limbs was employed to investigate the properties of afferent cerebellar pathways and the nature of the reorganized neuronal synaptic circuitry in the degranulated cerebellum of the adult. Direct contacts of mossy fibers on Purkinje cells were indicated by short latency, single spike responses: 1.9 msec from the lateral reticular nucleus of brain stem and 5.4 msec from ipsilpateral forelimb. These were shorter than in normal rats by 0.9 and 2.1 msec, respectively. The topography of projections from peripheral stimulation was approximately normal. Mossy fiber responses followed stimulation at up to 20/sec, whereas climbing fiber pathways fatigued at 10/sec. The latency of climbing fiber input to peripheral limb stimulation in x-irradiated cerebellum was 23 +/- 8 (SD) msec. In x-irradiated rats, the climbing fiber pathways evoked highly variable extracellular burst responses and intracellular EPSPs of different, discrete sizes. These variable responses suggest that multiple climbing fibers contact single Purkinje cells. We conclude that each type of afferent retains identifying characteristics of transmission. However, rules for synaptic specification appear to break down so that: (1) abnormal classes of neurons develop synaptic connections, i.e., mossy fibers to Purkinje cells; (2) incorrect numbers of neurons share postsynaptic targets, i.e., more than one climbing fiber to a Purkinje cell; and (3) inhibitory synaptic actions may be carried out in the absence of the major inhibitory interneurons, i.e., Purkinje cell collaterals may be effective in lieu of basket and stellate cells.