Irregular Interspike Intervals Research Articles

Kcns3 deficiency disrupts Parvalbumin neuron physiology in mouse prefrontal cortex: Implications for the pathophysiology of schizophrenia

The unique fast spiking (FS) phenotype of cortical parvalbumin-positive (PV) neurons depends on the expression of multiple subtypes of voltage-gated potassium channels (Kv). PV neurons selectively express Kcns3, the gene encoding Kv9.3 subunits, suggesting that Kcns3 expression is critical for the FS phenotype. KCNS3 expression is lower in PV neurons in the neocortex of subjects with schizophrenia, but the effects of this alteration are unclear, because Kv9.3 subunit function is poorly understood. Therefore, to assess the role of Kv9.3 subunits in PV neuron function, we combined gene expression analyses, computational modeling, and electrophysiology in acute slices from the cortex of Kcns3-deficient mice.Kcns3 mRNA levels were ~ 50% lower in cortical PV neurons from Kcns3-deficient relative to wildtype mice. While silent per se, Kv9.3 subunits are believed to amplify the Kv2.1 current in Kv2.1-Kv9.3 channel complexes. Hence, to assess the consequences of reducing Kv9.3 levels, we simulated the effects of decreasing the Kv2.1-mediated current in a computational model. The FS cell model with reduced Kv2.1 produced spike trains with irregular inter-spike intervals, or stuttering, and greater Na+ channel inactivation. As in the computational model, PV basket cells (PVBCs) from Kcns3-deficient mice displayed spike trains with strong stuttering, which depressed PVBC firing. Moreover, Kcns3 deficiency impaired the recruitment of PVBC firing at gamma frequency by stimuli mimicking synaptic input observed during cortical UP states. Our data indicate that Kv9.3 subunits are critical for PVBC physiology and suggest that KCNS3 deficiency in schizophrenia could impair PV neuron firing, possibly contributing to deficits in cortical gamma oscillations in the illness.

A biophysical model examining the role of low-voltage-activated potassium currents in shaping the responses of vestibular ganglion neurons.

The vestibular nerve is characterized by two broad groups of neurons that differ in the timing of their interspike intervals; some fire at highly regular intervals, whereas others fire at highly irregular intervals. Heterogeneity in ion channel properties has been proposed as shaping these firing patterns (Highstein SM, Politoff AL. Brain Res 150: 182-187, 1978; Smith CE, Goldberg JM. Biol Cybern 54: 41-51, 1986). Kalluri et al. (J Neurophysiol 104: 2034-2051, 2010) proposed that regularity is controlled by the density of low-voltage-activated potassium currents (IKL). To examine the impact of IKL on spike timing regularity, we implemented a single-compartment model with three conductances known to be present in the vestibular ganglion: transient sodium (gNa), low-voltage-activated potassium (gKL), and high-voltage-activated potassium (gKH). Consistent with in vitro observations, removing gKL depolarized resting potential, increased input resistance and membrane time constant, and converted current step-evoked firing patterns from transient (1 spike at current onset) to sustained (many spikes). Modeled neurons were driven with a time-varying synaptic conductance that captured the random arrival times and amplitudes of glutamate-driven synaptic events. In the presence of gKL, spiking occurred only in response to large events with fast onsets. Models without gKL exhibited greater integration by responding to the superposition of rapidly arriving events. Three synaptic conductance were modeled, each with different kinetics to represent a variety of different synaptic processes. In response to all three types of synaptic conductance, models containing gKL produced spike trains with irregular interspike intervals. Only models lacking gKL when driven by rapidly arriving small excitatory postsynaptic currents were capable of generating regular spiking.

Force sensor in simulated skin and neural model mimic tactile SAI afferent spiking response to ramp and hold stimuli

BackgroundThe next generation of prosthetic limbs will restore sensory feedback to the nervous system by mimicking how skin mechanoreceptors, innervated by afferents, produce trains of action potentials in response to compressive stimuli. Prior work has addressed building sensors within skin substitutes for robotics, modeling skin mechanics and neural dynamics of mechanotransduction, and predicting response timing of action potentials for vibration. The effort here is unique because it accounts for skin elasticity by measuring force within simulated skin, utilizes few free model parameters for parsimony, and separates parameter fitting and model validation. Additionally, the ramp-and-hold, sustained stimuli used in this work capture the essential features of the everyday task of contacting and holding an object.MethodsThis systems integration effort computationally replicates the neural firing behavior for a slowly adapting type I (SAI) afferent in its temporally varying response to both intensity and rate of indentation force by combining a physical force sensor, housed in a skin-like substrate, with a mathematical model of neuronal spiking, the leaky integrate-and-fire. Comparison experiments were then conducted using ramp-and-hold stimuli on both the spiking-sensor model and mouse SAI afferents. The model parameters were iteratively fit against recorded SAI interspike intervals (ISI) before validating the model to assess its performance.ResultsModel-predicted spike firing compares favorably with that observed for single SAI afferents. As indentation magnitude increases (1.2, 1.3, to 1.4 mm), mean ISI decreases from 98.81 ± 24.73, 54.52 ± 6.94, to 41.11 ± 6.11 ms. Moreover, as rate of ramp-up increases, ISI during ramp-up decreases from 21.85 ± 5.33, 19.98 ± 3.10, to 15.42 ± 2.41 ms. Considering first spikes, the predicted latencies exhibited a decreasing trend as stimulus rate increased, as is observed in afferent recordings. Finally, the SAI afferent’s characteristic response of producing irregular ISIs is shown to be controllable via manipulating the output filtering from the sensor or adding stochastic noise.ConclusionsThis integrated engineering approach extends prior works focused upon neural dynamics and vibration. Future efforts will perfect measures of performance, such as first spike latency and irregular ISIs, and link the generation of characteristic features within trains of action potentials with current pulse waveforms that stimulate single action potentials at the peripheral afferent.

Ion Channels Set Spike Timing Regularity of Mammalian Vestibular Afferent Neurons

In the mammalian vestibular nerve, some afferents have highly irregular interspike intervals and others have highly regular intervals. To investigate whether spike timing is determined by the afferents' ion channels, we studied spiking activity in their cell bodies, isolated from the vestibular ganglia of young rats. Whole cell recordings were made with the perforated-patch method. As previously reported, depolarizing current steps revealed distinct firing patterns. Transient neurons fired one or two onset spikes, independent of current level. Sustained neurons were more heterogeneous, firing either trains of spikes or a spike followed by large voltage oscillations. We show that the firing pattern categories are robust, occurring at different temperatures and ages, both in mice and in rats. A difference in average resting potential did not cause the difference in firing patterns, but contributed to differences in afterhyperpolarizations. A low-voltage-activated potassium current (I(LV)) was previously implicated in the transient firing pattern. We show that I(LV) grew from the first to second postnatal week and by the second week comprised Kv1 and Kv7 (KCNQ) components. Blocking I(LV) converted step-evoked firing patterns from transient to sustained. Separated from their normal synaptic inputs, the neurons did not spike spontaneously. To test whether the firing-pattern categories might correspond to afferent populations of different regularity, we injected simulated excitatory postsynaptic currents at pseudorandom intervals. Sustained neurons responded to a given pattern of input with more regular firing than did transient neurons. Pharmacological block of I(LV) made firing more regular. Thus ion channel differences that produce transient and sustained firing patterns in response to depolarizing current steps can also produce irregular and regular spike timing.

Relating firing rate and spike time irregularity in motor cortical neurons

Introduction Cortical neurons exhibit highly irregular inter-spike intervals (ISIs) [1]. Differences in irregularity could be in part due to imbalances of excitatory and inhibitory inputs to the neurons, which determines the statistics of the net input [2]. There is experimental evidence that the intrinsic irregularity of neurons in the awake monkey is constant [3]. However, changes in irregularity have also been reported [4,5] in different cortical areas and different behavioral tasks. The classical measure of spike time irregularity is the coefficient of variation (CV), a global measure defined as the dispersion of the ISIs. However, the CV largely overestimates the irregularity in the case of pronounced changes in firing rate. This led several researchers to propose alternative measures of irregularity that are local in time and therefore relatively independent of rate changes. To our knowledge, these measures have never been compared to each other. Here we compare four such measures: the local coefficient of variation CV2 [6], the local variation LV [3], the measure IR [4] and the measure SI [7]. The first question we address is which of these measures is the most efficient for analyzing experimental data in a time-resolved manner where the number of ISIs is limited. Second, we study the variation of the spike time irregularity of neurons recorded in the motor cortex of a monkey while performing a delayed center-out task.

Input of anterior and posterior semicircular canal interneurons encoding head-velocity to the dorsal Y group of the vestibular nuclei.

Neurons in the Y group of the vestibular nuclei are activated disynaptically from the ipsilateral VIIIth nerve and polysynaptically from the contralateral nerve. The ipsilateral anterior and posterior semicircular canals project to the Y group via interneurons in the vestibular nuclei. Candidate interneurons located in the rostrolateral corner of the superior (SVN) and in the caudal medial (MVN) vestibular nuclei were retrogradely labeled by the iontophoretic injection of biocytin into the Y group. The physiology of these interneurons named Y-group projecting neurons (YPNs) was studied in the SVN. SVN-YPNs were activated antidromically by electric pulse stimulation in the Y group. The properties of SVN-YPNs are distinct from those of SVN flocculus projecting neurons (FPNs). Namely, YPNs have a lower resting rate than FPNs, have more irregular interspike intervals, show a different phase and gain during the vestibuloocular reflex, and are located differentially within the SVN. After the injection of biocytin into the Y group, the locations of Purkinje cells that project to the Y group were confined to the vertical zones of the flocculus and ventral paraflocculus. However, mossy fibers originating in the Y group terminate in both the vertical and horizontal zones of the flocculus and ventral paraflocculus as well as in the ipsilateral nodulus.

The origins of aperiodicities in sensory neuron entrainment

Aperiodic entrainment to rhythmic sensory input was obtained with either a single neuron or an excitatory network model, without addition of a stochastic or “noisy” element. The entrainment properties of primary sensory neurons were well captured by the dynamics of the Hodgkin–Huxley ordinary differential equations with a quiescent resting state or threshold for spike output. The frequency–amplitude parameter space was compressed and aperiodic regimes were small in comparison to those of periodically activated pacemaker-like neurons. Transitions between phase-locked and aperiodic entrainment patterns were predictable and determined by the equation dynamics, supporting the contention that some aperiodicities observed in situ arise from the inherent membrane properties of neurons. When the rhythmically activated neuron was embedded in an excitatory network of Hodgkin–Huxley neurons with heterogeneous synaptic delays, aperiodic entrainment patterns were more frequently encountered and these were associated with asynchronous output from the network. Embedding the rhythmically activated neuron in a network with synaptic delays greatly reduced the range of entrained spike frequencies and increased the variability in the neuronal firing. The temporal coding of sensory stimuli may be dependent on these findings. Sensory stimuli are signaled in the periphery by a mixture of periodic and irregular interspike intervals. Most models of such temporal codes assume intrinsic rhythmicity arising from the ionic currents, with variations attributed to membrane or synaptic noise. In contrast, we demonstrate irregular neural codes that arise completely in the absence of noise. In the proposed model, the sources of these irregular sensory patterns are the extensive cross-connections and resultant interactions between neurons. The balance between the regular and irregular entrainment of a neuron in situ could uniquely identify a stimulus. Other biological mechanisms of modifying the entrainment properties and promoting aperiodic entrainment are discussed.

Noise, neural codes and cortical organization

Cortical circuitry must facilitate information transfer in accordance with a neural code. In this article we examine two candidate neural codes: information is represented in the spike rate of neurons, or information is represented in the precise timing of individual spikes. These codes can be distinguished by examining the physiological basis of the highly irregular interspike intervals typically observed in cerebral cortex. Recent advances in our understanding of cortical microcircuitry suggest that the timing of neuronal spikes conveys little, if any, information. The cortex is likely to propagate a noisy rate code through redundant, patchy interconnections.

Antidromic responses of single units from the spiral ganglion

1. Antidromic responses of single units in the guinea pig spiral ganglion were recorded in response to shocks to the auditory nerve root. The orthodromic responses of these units were also recorded in response to sound. The aim of this study was 1) to classify units according to their response patterns to shocks and to sound and 2) to propose anatomic types that might correlate with these responses. The four classes of units were as follows: type I, olivocochlear (OC), long-latency: locked, and long-latency: jittering. 2. Type I units responded antidromically to shocks with little jitter and short latency. Their responses to sound were also of short latency and had irregular interspike intervals. Some of these units had complex spike waveforms. These units likely correspond to type I primary afferent neurons, the majority population of spiral ganglion cells. 3. One-third of the OC units responded to shocks, with little jitter and intermediate latency (2 ms). OC unit responses to sound were of long latency and had regular interspike intervals. These units likely correspond to efferent neurons that originate in the superior olivary complex of the brain and end on outer hair cells in the cochlea. 4. Long-latency: locked units responded to shocks with little jitter and long latency (4-11 ms). Many of these units had complex spike waveforms and most did not respond to high-level noise bursts. Long-latency: locked units may correspond to type II spiral ganglion neurons. 5. Long-latency: jittering units responded to shocks with a jitter of several milliseconds and long latency. Some of these units responded to sound in a pattern reminiscent of OC units. These units may constitute a subgroup of OC units that respond to shocks via activation of the reflex pathway from the cochlea to the superior olive and back out to the cochlea. 6. Further data were collected on the type I response to shocks. Antidromic spikes lacked the inflections seen on the waveforms that are typically seen on orthodromic spikes. Type I shock responses depended on shock level and duration and were reduced when a click preceded the shock by approximately 2 ms. Several type I characteristics depended on the rate of spontaneous discharge: for units of low and medium spontaneous rates (when compared with units of high rates), the shock thresholds were lower, shock latencies were longer, and the probability of firing repetitive spikes to a single shock was higher.(ABSTRACT TRUNCATED AT 400 WORDS)

Electrical properties and synaptic connections to neurons in parasympathetic colonic ganglia of the cat.

Intracellular recording techniques were used in vitro to analyze the electrophysiological properties and synaptic connections to cat parasympathetic neurons in ganglia located on the serosal surface of the distal colon. Neurons were classified into two types. The first type exhibited spontaneous action potentials at regular and irregular interspike intervals. Spontaneous action potentials were 1) not abolished by superfusion of the ganglia with a modified Krebs solution containing low Ca2+, high Mg2+, or nicotinic ganglionic blocking agents, 2) reduced or abolished by intracellular injection of hyperpolarizing current, and 3) increased by intracellular injection of depolarizing current. We suggest that the generation of spontaneous action potentials may be due to an endogenous depolarizing mechanism and not to cholinergic synaptic input from other neurons located in the ganglia. The second type of neuron termed "quiescent" exhibited a stable transmembrane potential and elicited action potentials in response to electrical stimulation of nerve trunks. Both quiescent and spontaneously discharging neurons receive synaptic input from preganglionic fibers in the pelvic nerve and project their postganglionic axons to colonic nerve fibers that innervate effector structures in the colon.