Slow adaptation in fast-spiking neurons of visual cortex

Fast-spiking (FS) neurons are a class of inhibitory interneurons classically characterized as having short-duration action potentials (<0.5 ms at half height) and displaying little to no spike-frequency adaptation during short (<500 ms) depolarizing current pulses. As a consequence, the resulting injected current intensity versus firing frequency relationship is typically steep, and they can achieve firing frequencies of < or =1 kHz. Here we have investigated the properties of FS neurons discharges on a longer time scale. Twenty second discharges were induced in electrophysiologically identified FS neurons by means of current injection either with sinusoidal current or with square pulses. We found that virtually all FS neurons recorded in cortical slices do show spike-frequency adaptation but with a slow time course (tau = 2-19 s). This slow time course has precluded the observation of this property in previous studies that used shorter pulses. Contrary to the classical view of FS neurons functional properties, long-duration discharges were followed by a slow afterhyperpolarization lasting < or =23 s. During this postadaptation period, the excitability of the neurons was decreased on average for 16.7 +/- 6.8 s, therefore rendering the cell less responsive to subsequent afferent inputs. Slow adaptation is also reported here for FS neurons recorded in vivo. This longer time scale of adaptation in FS neurons may be critical for balancing excitation and inhibition as well as for the understanding of cortical network computations.     

Encoder adaptation modulates the visual responses of crayfish interneurons

The responses of sustaining and dimming fibers were characterized by the time varying firing rates elicited by extrinsic current and flashes of light. These data were simulated by an adaptive integrate-and-fire model. A postimpulse shunt conductance simulated spike-frequency adaptation. The correlation between observed and model current-elicited impulse rates was 0.94-0.98. However, except for a difference in input resistance (both measured and simulated), the voltage to impulse encoders of the two cell groups was similar and exhibited comparable degrees of spike-frequency adaptation (40 to 45%). The encoder model derived from current-elicited responses (with fixed parameters) was used to simulate visual responses elicited by light flashes. These simulations included a synaptic current derived from the time course of the postsynaptic potential (PSP). The sustaining fiber visual response consisted of a large excitatory PSP and high-frequency transient burst that adapted (by approximately 80%) to a low-frequency plateau discharge. The simulations indicated that spike-frequency adaptation had no effect on the transient discharge but reduced the plateau firing rate by approximately 60%. Encoder adaptation enhances the sustaining fiber response to the time derivative of the stimulus. In dimming fibers, the light flash elicits an inhibitory PSP that interrupts the "dark discharge" and an off response following the end of the flash. The simulations indicated that spike-frequency adaptation reduces the firing rate of both the dark discharge and the off response. Thus the model suggests that different effects of encoder adaptation on the two cell types arise from the same encoder mechanisms, but different actions are determined by differences in impulse rate and the time course of the discharge.     

Adaptation and temporal decorrelation by single neurons in the primary visual cortex

Limiting redundancy in the real-world sensory inputs is of obvious benefit for efficient neural coding, but little is known about how this may be accomplished by biophysical neural mechanisms. One possible cellular mechanism is through adaptation to relatively constant inputs. Recent investigations in primary visual (V1) cortical neurons have demonstrated that adaptation to prolonged changes in stimulus contrast is mediated in part through intrinsic ionic currents, a Ca2+-activated K+ current (IKCa) and especially a Na+-activated K+ current (IKNa). The present study was designed to test the hypothesis that the activation of adaptation ionic currents may provide a cellular mechanism for temporal decorrelation in V1. A conductance-based neuron model was simulated, which included an IKCa and an IKNa. We show that the model neuron reproduces the adaptive behavior of V1 neurons in response to high contrast inputs. When the stimulus is stochastic with 1/f 2 or 1/f-type temporal correlations, these autocorrelations are greatly reduced in the output spike train of the model neuron. The IKCa is effective at reducing positive temporal correlations at approximately 100-ms time scale, while a slower adaptation mediated by IKNa is effective in reducing temporal correlations over the range of 1-20 s. Intracellular injection of stochastic currents into layer 2/3 and 4 (pyramidal and stellate) neurons in ferret primary visual cortical slices revealed neuronal responses that exhibited temporal decorrelation in similarity with the model. Enhancing the slow afterhyperpolarization resulted in a strengthening of the decorrelation effect. These results demonstrate the intrinsic membrane properties of neocortical neurons provide a mechanism for decorrelation of sensory inputs.     

Riluzole-induced oscillations in spinal networks

We previously showed in dissociated cultures of fetal rat spinal cord that disinhibition-induced bursting is based on intrinsic spiking, network recruitment, and a network refractory period after the bursts. A persistent sodium current (I(NaP)) underlies intrinsic spiking, which, by recurrent excitation, generates the bursting activity. Although full blockade of I(NaP) with riluzole disrupts such bursting, the present study shows that partial blockade of I(NaP) with low doses of riluzole maintains bursting activity with unchanged burst rate and burst duration. More important, low doses of riluzole turned bursts composed of persistent activity into bursts composed of oscillatory activity at around 5 Hz. In a search for the mechanisms underlying the generation of such intraburst oscillations, we found that activity-dependent synaptic depression was not changed with low doses of riluzole. On the other hand, low doses of riluzole strongly increased spike-frequency adaptation and led to early depolarization block when bursts were simulated by injecting long current pulses into single neurons in the absence of fast synaptic transmission. Phenytoin is another I(NaP) blocker. When applied in doses that reduced intrinsic activity by 80-90%, as did low doses of riluzole, it had no effect either on spike-frequency adaptation or on depolarization block. Nor did phenytoin induce intraburst oscillations after disinhibition. A theoretical model incorporating a depolarization block mechanism could reproduce the generation of intraburst oscillations at the network level. From these findings we conclude that riluzole-induced intraburst oscillations are a network-driven phenomenon whose major accommodation mechanism is depolarization block arising from strong sodium channel inactivation.     

Influence of electrotonic structure and synaptic mapping on the receptive field properties of a collision-detecting neuron

The lobula giant movement detector (LGMD) is a visual interneuron of Orthopteran insects involved in collision avoidance and escape behavior. The LGMD possesses a large dendritic field thought to receive excitatory, retinotopic projections from the entire compound eye. We investigated whether the LGMD's receptive field for local motion stimuli can be explained by its electrotonic structure and the eye's anisotropic sampling of visual space. Five locust (Schistocerca americana) LGMD neurons were stained and reconstructed. We show that the excitatory dendritic field and eye can be fitted by ellipsoids having similar geometries. A passive compartmental model fit to electrophysiological data was used to demonstrate that the LGMD is not electrotonically compact. We derived a spike rate to membrane potential transform using intracellular recordings under visual stimulation, allowing direct comparison between experimental and simulated receptive field properties. By assuming a retinotopic mapping giving equal weight to each ommatidium and equally spaced synapses, the model reproduced the experimental data along the eye equator, though it failed to reproduce the receptive field along the ventral-dorsal axis. Our results illustrate how interactions between the distribution of synaptic inputs and the electrotonic properties of neurons contribute to shaping their receptive fields.     

A distinct form of calcium release down-regulates membrane excitability in neocortical pyramidal cells

We reported a novel type of calcium release from inositol-1,4,5-trisphosphate (IP(3))-sensitive calcium stores synergistically induced by muscarinic acetylcholine receptor (mAchR)-mediated increase in IP(3) and action potential-induced calcium influx (IP(3)-assisted calcium-induced calcium release, IP(3)-assisted CICR). To clarify its functional significance, the effects of IP(3)-assisted CICR on spike-frequency adaptation were examined in layer II/III neurons from rat visual cortex slices. IP(3)-assisted CICR was enabled with a high concentration of the mAchR agonist carbachol (10 microM). The magnitude of this CICR was the more augmented at higher firing frequencies. With 10 microM carbachol, spike-frequency adaptation was reduced for spike trains at 'low' firing frequencies (6-10 Hz), but was rather enhanced at 'high' firing rates (16-22 Hz): excitability was down-regulated at 'high' frequencies. With 1 microM carbachol, by contrast, IP(3)-assisted CICR failed to occur, and spike-frequency adaptation was always reduced at any spike frequencies. Intracellular injection of the IP(3) receptor blocker heparin prevented both the mAchR-mediated occurrence of IP(3)-assisted CICR and enhancement of spike-frequency adaptation with 10 microM carbachol. Both of these mAchR-mediated effects were reproduced by intracellular IP(3) injection, and were shown to be associated with each other by simultaneous recordings of membrane potential and intracellular calcium increase. We propose that IP(3)-assisted CICR offers a novel way to protect these cortical neurons from hyperexcitability and presumably from excitotoxic cell death.     

Analysis and simulation of gain control and precision in crayfish visual interneurons

Impulse trains in sustaining and dimming fibers of crayfish optic lobe (in situ) were elicited with sinusoidal extrinsic current and sine-wave illumination. Extrinsic currents and currents derived from postsynaptic potentials (PSPs) were used to compute the time course of the spike train with an adaptive integrate-and-fire model. The neurons exhibit variations in gain and spike timing precision related to the frequency of stimulation. These phenomena are influenced by spike-frequency adaptation and nonlinearities in the PSP. Dimming fibers exhibit relatively strong spike-frequency adaptation and an associated increase in gain with the frequency of sinusoidal extrinsic current and sine-wave illumination. The dimming fiber IPSP promotes spike train rectification, and rectification contributes to spike timing precision. Sustaining fibers exhibit weaker spike-frequency adaptation and the gain of the current-elicited response is less sensitive to stimulus frequency. The sustaining fiber excitatory PSP, however, exhibits a strong frequency-dependent nonlinearity that influences the frequency response. Spike timing precision is a function of stimulus frequency in all cells and it is enhanced by rectification of the discharge and/or resonance. In rectified responses the jitter in spike times is closely related to the variance in the times the membrane potential reaches spike threshold. These gain and spike timing results are well approximated by the simulated responses. Because the nonlinearity of the sustaining fiber PSP entails a high rate of depolarization, the PSP can increase the precision of spike timing by 10- to 100-fold compared with the response to pure sine-wave stimuli. This enhanced precision has implications for crayfish oculomotor reflexes that are driven by sustaining fibers and highly sensitive to impulse timing during transient excitation.     

Contribution of persistent sodium currents to spike-frequency adaptation in rat hypoglossal motoneurons

In response to constant current inputs, the firing rates of motoneurons typically show a continuous decline over time. The biophysical mechanisms underlying this process, called spike-frequency adaptation, are not well understood. Spike-frequency adaptation normally exhibits a rapid initial phase, followed by a slow, later phase that continues throughout the duration of firing. One possible mechanism mediating the later phase might be a reduction in the persistent sodium current (I(NaP)) that has been shown to diminish the capacity of cortical pyramidal neurons and spinal motoneurons to sustain repetitive firing. In this study, we used the anticonvulsant phenytoin to reduce the I(NaP) of juvenile rat hypoglossal motoneurons recorded in brain stem slices, and we examined the consequences of a reduction in I(NaP) on the magnitude and time course of spike-frequency adaptation. Adding phenytoin to the bathing solution (> or =50 microM) generally produced a marked reduction in the persistent inward currents (PICs) recorded at the soma in response to slow, voltage-clamp triangular ramp commands (-70 to 0 mV and back). However, the same concentrations of phenytoin appeared to have no significant effect on spike-frequency adaptation even though the phenytoin often augmented the reduction in action potential amplitude that occurs during repetitive firing. The surprising finding that the reduction of a source of sustained inward current had no appreciable effect on the pattern of spike generation suggests that several types of membrane channels must act cooperatively to insure that these motoneurons can generate the sustained repetitive firing required for long-lasting motor behaviors.     

A firing-rate model of spike-frequency adaptation in sinusoidally-driven thalamocortical relay neurons

In a systematic study of thalamocortical relay neuron responses to sinusoidal current injection [J. Neurophysiol. 83 (1), 588], we found that the Fourier fundamental of tonic responses was regularly phase advanced during low temporal frequency stimulation (1/10 cycle at 0.1 Hz). We hypothesized that such phase advances of the Fourier fundamental response were due to a slow spike-frequency adaptation. Here we measure the time-dependence of the instantaneous firing rate during a current pulse protocol, confirm the presence of a slow spike-frequency adaptation, and quantify the adaptation time constant (0.6–2.0 s) and percentage adaptation of spike rate (40–60%). In light of these results, we augment a previously reported minimal integrate-and-fire-or-burst (IFB) neuron model with an adaptation current. When the parameters for this current are fit using a quantitative theory of spike-frequency adaptation [J. Neurophysiol. 79, 1549], the IFB model reproduces the experimentally observed phase advance of the Fourier fundamental response during sinusoidal current injection. Using fast-slow variable analysis, we develop a firing-rate reduction of the IFB model and perform parameter studies to investigate the dependence of the Fourier fundamental response (amplitude and phase) on the maximum conductance and recovery time constant for the adaptation current. Analytical calculations clarify the relationship between dc and ac measures of the suppression of response due to spike-frequency adaptation, show how the latter depends on stimulation frequency, and confirm the adaptation-induced phase advance of the Fourier fundamental observed in both experiment and simulation.     

Linear versus nonlinear signal transmission in neuron models with adaptation currents or dynamic thresholds

Spike-frequency adaptation is a prominent aspect of neuronal dynamics that shapes a neuron's signal processing properties on timescales ranging from about 10 ms to >1 s. For integrate-and-fire model neurons spike-frequency adaptation is incorporated either as an adaptation current or as a dynamic firing threshold. Whether a physiologically observed adaptation mechanism should be modeled as an adaptation current or a dynamic threshold, however, is not known. Here we show that a dynamic threshold has a divisive effect on the onset f-I curve (the initial maximal firing rate following a step increase in an input current) measured at increasing mean threshold levels, i.e., adaptation states. In contrast, an adaptation current subtractively shifts this f-I curve to higher inputs without affecting its slope. As a consequence, an adaptation current acts essentially linearly, resulting in a high-pass filter component of the neuron's transfer function for current stimuli. With a dynamic threshold, however, the transfer function strongly depends on the input range because of the multiplicative effect on the f-I curves. Simulations of conductance-based spiking models with adaptation currents, such as afterhyperpolarization (AHP)-type, M-type, and sodium-activated potassium currents, do not show the divisive effects of a dynamic threshold, but agree with the properties of integrate-and-fire neurons with adaptation current. Notably, the effects of slow inactivation of sodium currents cannot be reproduced by either model. Our results suggest that, when lateral shifts of the onset f-I curve are seen in response to adapting inputs, adaptation should be modeled with adaptation currents and not with a dynamic threshold. In contrast, when the slope of onset f-I curves depends on the adaptation state, then adaptation should be modeled with a dynamic threshold. Further, the observation of divisively altered onset f-I curves in adapted neurons with notable variability of their spike threshold could hint to yet known biophysical mechanisms directly affecting the threshold.     

A model of reverse spike frequency adaptation and repetitive firing of subthalamic nucleus neurons

Subthalamic nucleus neurons exhibit reverse spike-frequency adaptation. This occurs only at firing rates of 20-50 spikes/s and higher. Over this same frequency range, there is an increase in the steady-state frequency-intensity (F-I) curve's slope (the secondary range). Specific blockade of high-voltage activated calcium currents reduced the F-I curve slope and reverse adaptation. Blockade of calcium-dependent potassium current enhanced secondary range firing. A simple model that exhibited these properties used spike-triggered conductances similar to those in subthalamic neurons. It showed: 1) Nonaccumulating spike afterhyperpolarizations produce positively accelerating F-I curves and spike-frequency adaptation that is complete after the second spike. 2) Combinations of accumulating aftercurrents result in a linear F-I curve, whose slope depends on the relative contributions of inward and outward currents. Spike-frequency adaptation can be gradual. 3) With both accumulating and nonaccumulating aftercurrents, primary and secondary ranges will be present in the F-I curve. The slope of the primary range is determined by the nonaccumulating conductance; the accumulating conductances govern the secondary range. The transition is determined by the relative strengths of accumulating and nonaccumulating currents. 4) Spike-threshold accommodation contributes to the secondary range, reducing its slope at high firing rates. Threshold accommodation can stabilize firing when inward aftercurrents exceed outward ones. 5) Steady-state reverse adaptation results when accumulated inward aftercurrents exceed outward ones. This requires spike-threshold accommodation. Transient speedup arises when inward currents are smaller than outward ones at steady state, but accumulate more rapidly. 6) The same mechanisms alter firing in response to irregular patterns of synaptic conductances, as cell excitability fluctuates with changes in firing rate.     

Physiological properties of neurons in the ventral nucleus of the lateral lemniscus of the rat: intrinsic membrane properties and synaptic responses.

The physiological properties including current-voltage relationships, firing patterns, and synaptic responses of the neurons in the ventral nucleus of the lateral lemniscus (VNLL) were studied in brain slices taken through the young rat's (17-37 days old) auditory brain stem. Intracellular recordings were made from VNLL neurons, and synaptic potentials were elicited by electrical stimulation of the lateral lemniscus ventral to the VNLL. Current-voltage relations and firing patterns were tested by recording the electrical potentials produced by intracellular injection of positive and negative currents. There were two types of VNLL neurons (type I and II) that exhibited different current-voltage relationships. In response to negative current, both type I and II neurons produced a graded hyperpolarization. Type I neurons responded to positive current with a graded depolarization and multiple action potentials the number of which was related to the strength of the current injected. The current-voltage relations of type I neurons were nearly linear. Type II neurons responded to positive current with a limited depolarization and only one or a few action potentials. The current-voltage relations of type II neurons were nonlinear near the resting potential. The membrane properties of the type II VNLL neurons may play an important role for processing information about time of onset of a sound. Type I neurons showed three different firing patterns, i.e., regular, onset-pause and adaptation, in response to small positive current. The onset-pause and adaptation patterns could become sustained when a large current was injected. The regular, onset-pause, and adaptation patterns in type I neurons and the onset pattern in type II neurons resemble "chopper," "pauser, " "primary-like," and "on" responses, respectively, as defined in in vivo VNLL studies. The results suggest that different responses to acoustic stimulation could be attributed to intrinsic membrane properties of VNLL neurons. Many VNLL neurons responded to stimulation of the lateral lemniscus with excitatory or inhibitory responses or both. Excitatory and inhibitory responses showed interaction, and the output of the synaptic integration depended on the relative strength of excitatory and inhibitory responses. Neurons with an onset-pause firing pattern were more likely to receive mixed excitatory and inhibitory inputs from the lower auditory brain stem.     

Firing properties of chopper and delay neurons in the lateral superior olive of the rat

 Neurons in the lateral superior olivary nucleus (LSO) respond to acoustic stimuli with the ”chopper response”, a regular repetitive firing pattern with a short and precise latency. In the past, this pattern has been attributed to dendritic integration of synaptic inputs. We investigated a possible contribution of intrinsic membrane properties using intracellular recording techniques in a tissue slice preparation. We found two electrophysiological classes of neurons in the LSO. Chopper neurons responded to depolarizing current pulses with a single onset spike at short, precise latency close to threshold and with repetitive, regular, but accommodating discharges at greater current intensities. An emphasis of response onset and subsequent rate accommodation resulted from the activation of a voltage- and time-dependent sustained outward rectification in a range depolarized from rest. Responses to hyperpolarizing pulses were characterized by an inward rectification, which caused a depolarizing voltage sag in a range negative to –65 mV. Peristimulus time histograms were multimodal, and discharge regularity was evident in narrow unimodal interspike interval time histograms and low coefficients of variation. The accommodation time course was usually fit best by two exponentials with time constants of τ₁=3–8 ms and τ₂=32–97 ms. Delay neurons responded with a regular repetitive firing to depolarization by current pulses. However, repetitive spike discharge occurred with a prolonged, variable delay of 25–180 ms. High current intensities evoked an additional onset spike with short, precise latency. Activation of a transient outward conductance in the depolarized voltage range caused an early repolarization, which terminated as a depolarizing ramp, reaching spike threshold after the delay. Flat peristimulus time histograms characterized the repetitive discharge in spite of narrow unimodal interspike interval time histograms and low coefficients of variation. Intracellular neurobiotin injections revealed morphological differences between these classes. Chopper neurons were large and fusiform, with a bipolar dendritic distribution oriented perpendicular to the curvature of the LSO. Delay neurons were small and spherical, with highly branched tortuous dendritic arbours of bipolar origin and variable orientation. Chopper and delay neurons are probably LSO principal cells and lateral olivocochlear efferent neurons, respectively. Our findings suggest that the pattern of firing activity of LSO neurons to sound, in vivo, is determined to a large extent by intrinsic membrane properties. Somato-dendritic integration of synaptic inputs are fundamental to the encoding of interaural sound differences, but membrane non-linearities play an important role in determining postsynaptic response patterns. Received: 3 December 1997 / Accepted: 28 July 1998     

Electrophysiological characterization of neurons in the dorsolateral pontine rapid-eye-movement sleep induction zone of the rat: Intrinsic membrane properties and responses to carbachol and orexins

Pharmacological, lesion and single-unit recording techniques in several animal species have identified a region of the pontine reticular formation (subcoeruleus, SubC) just ventral to the locus coeruleus as critically involved in the generation of rapid-eye-movement (REM) sleep. However, the intrinsic membrane properties and responses of SubC neurons to neurotransmitters important in REM sleep control, such as acetylcholine and orexins/hypocretins, have not previously been examined in any animal species and thus were targeted in this study. We obtained whole-cell patch-clamp recordings from visually identified SubC neurons in rat brain slices in vitro. Two groups of large neurons (mean diameter 30 and 27 mum) were tentatively identified as cholinergic (rostral SubC) and noradrenergic (caudal SubC) neurons. SubC reticular neurons (non-cholinergic, non-noradrenergic) showed a medium-sized depolarizing sag during hyperpolarizing current pulses and often had a rebound depolarization (low-threshold spike, LTS). During depolarizing current pulses they exhibited little adaptation and fired maximally at 30-90 Hz. Those SubC reticular neurons excited by carbachol (n=27) fired spontaneously at 6 Hz, often exhibited a moderately sized LTS, and varied widely in size (17-42 mum). Carbachol-inhibited SubC reticular neurons were medium-sized (15-25 mum) and constituted two groups. The larger group (n=22) was silent at rest and possessed a prominent LTS and associated one to four action potentials. The second, smaller group (n=8) had a delayed return to baseline at the offset of hyperpolarizing pulses. Orexins excited both carbachol excited and carbachol inhibited SubC reticular neurons. SubC reticular neurons had intrinsic membrane properties and responses to carbachol similar to those described for other reticular neurons but a larger number of carbachol inhibited neurons were found (>50%), the majority of which demonstrated a prominent LTS and may correspond to pontine-geniculate-occipital burst neurons. Some or all carbachol-excited neurons are presumably REM-on neurons.     

Effects of persistent inward currents, accommodation, and adaptation on motor unit behavior: a simulation study

Motor neurons are often assumed to generate spikes in proportion to the excitatory synaptic input received. There are, however, many intrinsic properties of motor neurons that might affect this relationship, such as persistent inward currents (PICs), spike-threshold accommodation, or spike-frequency adaptation. These nonlinear properties have been investigated in reduced animal preparation but have not been well studied during natural motor behaviors because of the difficulty in characterizing synaptic input in intact animals. Therefore, we studied the influence of each of these intrinsic properties on spiking responses and muscle force using a population model of motor units that simulates voluntary contractions in human subjects. In particular, we focused on the difference in firing rate of low-threshold motor units when higher threshold motor units were recruited and subsequently derecruited, referred to as ΔF. Others have used ΔF to evaluate the extent of PIC activation during voluntary behavior. Our results showed that positive ΔF values could arise when any one of these nonlinear properties was included in the simulations. Therefore, a positive ΔF should not be considered as exclusive evidence for PIC activation. Furthermore, by systematically varying contraction duration and speed in our simulations, we identified a means that might be used experimentally to distinguish among PICs, accommodation, and adaptation as contributors to ΔF.     

Bistability of cerebellar Purkinje cells modulated by sensory stimulation

A persistent change in neuronal activity after brief stimuli is a common feature of many neuronal microcircuits. This persistent activity can be sustained by ongoing reverberant network activity or by the intrinsic biophysical properties of individual cells. Here we demonstrate that rat and guinea pig cerebellar Purkinje cells in vivo show bistability of membrane potential and spike output on the time scale of seconds. The transition between membrane potential states can be bidirectionally triggered by the same brief current pulses. We also show that sensory activation of the climbing fiber input can switch Purkinje cells between the two states. The intrinsic nature of Purkinje cell bistability and its control by sensory input can be explained by a simple biophysical model. Purkinje cell bistability may have a key role in the short-term processing and storage of sensory information in the cerebellar cortex.     

Emergence of a functional coupling between inositol-1,4,5-trisphosphate receptors and calcium channels in developing neocortical neurons

Cortical pyramidal neurons are considered to be less excitable in the immature cortex than in adults. Our previous report revealed that a negative feedback regulation of membrane excitability is highly correlated with a novel form of calcium release from inositol-1,4,5-trisphosphate (IP(3))-sensitive calcium stores (IP(3)-assisted calcium-induced calcium release) in neocortical pyramidal neurons under muscarinic cholinergic activation. As a step to understand the ground for the low membrane excitability in immature tissue, we examined development of IP(3)-assisted calcium-induced calcium release. In visual cortex neurons from 'juvenile' rats (2-3 weeks of age), an enhancement of spike-frequency adaptation occurred at high spike-frequencies (16-22 Hz), whereas the reduction was observed at low frequencies (6-10 Hz). IP(3)-assisted calcium-induced calcium release occurred at the higher frequencies only. In 'early' postnatal tissue (1 week of age), by contrast, at neither high nor low frequencies did this form of calcium release occur, and muscarinic cholinergic activation always induced a reduction of spike-frequency adaptation at any spike-frequencies. The mechanism for the failure of induction of IP(3)-assisted calcium-induced calcium release in 'early' postnatal tissue was investigated. Both an ample supply of calcium influx, elicited by higher frequency spike trains, and a supplementary injection of IP(3) through whole-cell pipets, combined together or applied alone, failed to enable IP(3)-assisted calcium-induced calcium release in 'early' postnatal tissue. Muscarinic cholinergic activation alone induced a conventional IP(3)-induced calcium release similar to that observed in neurons from 'juvenile' tissue. Together, it is most likely that functional IP(3)Rs and calcium channels are already present and functional, but are not yet adequately assembled to allow IP(3)-assisted calcium-induced calcium release in cortical pyramidal neurons from rats of 1 week old.     

Neocortical pyramidal cells respond as integrate-and-fire neurons to in vivo-like input currents

In the intact brain neurons are constantly exposed to intense synaptic activity. This heavy barrage of excitatory and inhibitory inputs was recreated in vitro by injecting a noisy current, generated as an Ornstein-Uhlenbeck process, into the soma of rat neocortical pyramidal cells. The response to such in vivo-like currents was studied systematically by analyzing the time development of the instantaneous spike frequency, and when possible, the stationary mean spike frequency as a function of both the mean and the variance of the input current. All cells responded with an in vivo-like action potential activity with stationary statistics that could be sustained throughout long stimulation intervals (tens of seconds), provided the frequencies were not too high. The temporal evolution of the response revealed the presence of mechanisms of fast and slow spike frequency adaptation, and a medium duration mechanism of facilitation. For strong input currents, the slow adaptation mechanism made the spike frequency response nonstationary. The minimal frequencies that caused strong slow adaptation (a decrease in the spike rate by more than 1 Hz/s), were in the range 30-80 Hz and depended on the pipette solution used. The stationary response function has been fitted by two simple models of integrate-and-fire neurons endowed with a frequency-dependent modification of the input current. This accounts for all the fast and slow mechanisms of adaptation and facilitation that determine the stationary response, and proved necessary to fit the model to the experimental data. The coefficient of variability of the interspike interval was also in part captured by the model neurons, by tuning the parameters of the model to match the mean spike frequencies only. We conclude that the integrate-and-fire model with spike-frequency-dependent adaptation/facilitation is an adequate model reduction of cortical cells when the mean spike-frequency response to in vivo-like currents with stationary statistics is considered.     

Physiological and anatomical properties of mouse medial vestibular nucleus neurons projecting to the oculomotor nucleus

Neurons in the medial vestibular nucleus (MVN) vary in their projection patterns, responses to head movement, and intrinsic firing properties. To establish whether neurons that participate in the vestibulo-ocular reflex (VOR) have distinct intrinsic physiological properties, oculomotor nucleus (OMN)-projecting neurons were identified in mouse brainstem slices by fluorescent retrograde labeling from the oculomotor complex and targeted for patch-clamp recordings. Such neurons were located in the magnocellular portion of the MVN contralateral to tracer injection, were mostly multipolar, and had soma diameters of around 20 mum. They fired spontaneous action potentials at rates higher than those of other MVN neurons and their spikes were of unusually short duration. OMN-projecting neurons responded to 1-s intracellular current injection with exceptionally high firing rates of >500 spikes/s. Their current-firing relationship was highly linear, with weak firing response adaptation during steady depolarization and little postinhibitory rebound firing after membrane hyperpolarization. Their firing responses were approximately in phase with sinusoidal current injection. The response dynamics of OMN-projecting neurons could be simulated with a simple integrate-and-fire model modified with the addition of small adaptation and rebound conductances. These findings indicate that the membrane properties of OMN-projecting neurons allow them to respond to head movements reliably and with high sensitivity but without substantially altering input dynamics.