The highly irregular firing of cortical cells is inconsistent with temporal integration of random EPSPs

How random is the discharge pattern of cortical neurons? We examined recordings from primary visual cortex (V1; Knierim and Van Essen, 1992) and extrastriate cortex (MT; Newsome et al., 1989a) of awake, behaving macaque monkey and compared them to analytical predictions. For nonbursting cells firing at sustained rates up to 300 Hz, we evaluated two indices of firing variability: the ratio of the variance to the mean for the number of action potentials evoked by a constant stimulus, and the rate-normalized coefficient of variation (Cv) of the interspike interval distribution. Firing in virtually all V1 and MT neurons was nearly consistent with a completely random process (e.g., Cv approximately 1). We tried to model this high variability by small, independent, and random EPSPs converging onto a leaky integrate-and-fire neuron (Knight, 1972). Both this and related models predicted very low firing variability (Cv < 1) for realistic EPSP depolarizations and membrane time constants. We also simulated a biophysically very detailed compartmental model of an anatomically reconstructed and physiologically characterized layer V cat pyramidal cell (Douglas et al., 1991) with passive dendrites and active soma. If independent, excitatory synaptic input fired the model cell at the high rates observed in monkey, the Cv and the variability in the number of spikes were both very low, in agreement with the integrate-and-fire models but in strong disagreement with the majority of our monkey data. The simulated cell only produced highly variable firing when Hodgkin-Huxley-like currents (INa and very strong IDR) were placed on distal dendrites. Now the simulated neuron acted more as a millisecond-resolution detector of dendritic spike coincidences than as a temporal integrator. We argue that neurons that act as temporal integrators over many synaptic inputs must fire very regularly. Only in the presence of either fast and strong dendritic nonlinearities or strong synchronization among individual synaptic events will the degree of predicted variability approach that of real cortical neurons.     

Electrophysical properties, synaptic transmission and neuromodulation in serotonergic caudal raphe neurons

1. We studied electrophysiological properties, synaptic transmission and modulation by 5-hydroxytryptamine (5-HT) of caudal raphe neurons using whole-cell recording in a neonatal rat brain slice preparation; recorded neurons were identified as serotonergic by post-hoc immunohistochemical detection of tryptophan hydroxylase, the 5-HT-synthesizing enzyme. 2. Serotonergic neurons fired spontaneously (approximately 1 Hz), with maximal steady state firing rates of < 4 Hz. 5-Hydroxytryptamine caused hyperpolarization and cessation of spike activity in these neurons by activating inwardly rectifying K+ conductance via somatodendritic 5-HT1A receptors. 3. Unitary glutamatergic excitatory post-synaptic potentials (EPSP) and currents (EPSC) were evoked in serotonergic neurons by local electrical stimulation. Evoked EPSC were potently inhibited by 5-HT, an effect mediated by presynaptic 5-HT1B receptors. 4. In conclusion, serotonergic caudal raphe neurons are spontaneously active in vitro; they receive prominent glutamatergic synaptic inputs. 5-Hydroxytryptamine regulates serotonergic neuronal activity of the caudal raphe by decreasing spontaneous activity via somatodendritic 5-HT1A receptors and by inhibiting excitatory synaptic transmission onto these neurons via presynaptic 5-HT1B receptors. These local modulatory mechanisms provide multiple levels of feedback autoregulation of serotonergic raphe neurons by 5-HT.     

Daily omeprazole surpasses intermittent dosing in preventing relapse of oesophagitis: a US multi-centre double-blind study

Simultaneous extracellular recordings were performed in stratum radiatum and stratum pyramidale of hippocampal slices 7 days following unilateral intracerebroventricular injections of kainic acid. In this ex vivo experimental model of human temporal lobe epilepsy, stimulation of the surviving commissural fibres in stratum radiatum produced graded epileptiform activity in the CA1 area. The oxidizing reagent 5,5'-dithiobis (2-nitrobenzoic acid) (DTNB) acting at NMDA receptors redox sites decreases NMDA receptor-mediated responses by half and suppresses evoked epileptiform discharges. We have examined the effect of DTNB on NMDA-dependent bidirectional synaptic plasticity and EPSP/spike coupling. DTNB treatment did not prevent either long-term potentiation induced by tetanic stimulation or long-term depression induced by low frequency stimulation of field EPSPs. Application of DTNB alone did not induce EPSP/spike dissociation. However, both high and low frequency stimulations induced EPSP/spike potentiation indicating that neurons had a high probability to discharge in synchrony. These results suggest that oxidizing reagents may provide novel antiepileptic treatments since they decrease NMDA-dependent evoked epileptiform activity but do not interfere with either NMDA-dependent synaptic plasticity or the probability of synchronous discharge.     

Synaptic reorganization in explanted cultures of rat hippocampus

Due to loss of afferent innervation, synaptic reorganization occurs in organotypic hippocampal slice cultures. With extra- and intracellular recordings, we confirm that the excitatory loop from the dentate gyrus (DG) to CA3 and further to CA1 is preserved. However, hilar stimulation evoked antidromic population spikes in the DG which were followed by a population postsynaptic potential (PPSP); intracellularly, an antidromic spike with a broad shoulder or EPSP/IPSP sequences were induced. Synaptic responses were blocked by glutamate receptor antagonists. Stimulation of CA1 induced a PPSP in DG. Dextranamine stained pyramidal cells of CA1 were shown to project to DG. After removal of area CA3, DG's and mossy fibers' (MF) stimulation still elicited PPSPs and EPSP/IPSP sequences in area CA1 which disappeared when a cut was made through the hippocampal fissure. During bicuculline perfusion, hilar stimulation caused EPSPs in granule cells and spontaneous and evoked repetitive firing appeared even after its isolation from areas CA3 and CA1. Collateral excitatory synaptic coupling between granule cells was confirmed by paired recordings. Besides the preservation of the trisynaptic pathway in this preparation, new functional synaptic contacts appear, presumably due to MF collateral sprouting and formation of pathways between areas CA1 and DG.     

The variable discharge of cortical neurons: implications for connectivity, computation, and information coding

Cortical neurons exhibit tremendous variability in the number and temporal distribution of spikes in their discharge patterns. Furthermore, this variability appears to be conserved over large regions of the cerebral cortex, suggesting that it is neither reduced nor expanded from stage to stage within a processing pathway. To investigate the principles underlying such statistical homogeneity, we have analyzed a model of synaptic integration incorporating a highly simplified integrate and fire mechanism with decay. We analyzed a "high-input regime" in which neurons receive hundreds of excitatory synaptic inputs during each interspike interval. To produce a graded response in this regime, the neuron must balance excitation with inhibition. We find that a simple integrate and fire mechanism with balanced excitation and inhibition produces a highly variable interspike interval, consistent with experimental data. Detailed information about the temporal pattern of synaptic inputs cannot be recovered from the pattern of output spikes, and we infer that cortical neurons are unlikely to transmit information in the temporal pattern of spike discharge. Rather, we suggest that quantities are represented as rate codes in ensembles of 50-100 neurons. These column-like ensembles tolerate large fractions of common synaptic input and yet covary only weakly in their spike discharge. We find that an ensemble of 100 neurons provides a reliable estimate of rate in just one interspike interval (10-50 msec). Finally, we derived an expression for the variance of the neural spike count that leads to a stable propagation of signal and noise in networks of neurons-that is, conditions that do not impose an accumulation or diminution of noise. The solution implies that single neurons perform simple algebra resembling averaging, and that more sophisticated computations arise by virtue of the anatomical convergence of novel combinations of inputs to the cortical column from external sources.     

Dendritic voltage and calcium-gated channels amplify the variability of postsynaptic responses in a Purkinje cell model

The dendrites of most neurons express several types of voltage and Ca2+-gated channels. These ionic channels can be activated by subthreshold synaptic input, but the functional role of such activations in vivo is unclear. The interaction between dendritic channels and synaptic background input as it occurs in vivo was studied in a realistic computer model of a cerebellar Purkinje cell. It previously was shown using this model that dendritic Ca2+ channels amplify the somatic response to synchronous excitatory inputs. In this study, it is shown that dendritic ion channels also increased the somatic membrane potential fluctuations generated by the background input. This amplification caused a highly variable somatic excitatory postsynaptic potential (EPSP) in response to a synchronous excitatory input. The variability scaled with the size of the response in the model with excitable dendrite, resulting in an almost constant coefficient of variation, whereas in a passive model the membrane potential fluctuations simply added onto the EPSP. Although the EPSP amplitude in the active dendrite model was quite variable for different patterns of background input, it was insensitive to changes in the timing of the synchronous input by a few milliseconds. This effect was explained by slow changes in dendritic excitability. This excitability was determined by how the background input affected the dendritic membrane potentials in the preceding 10-20 ms, causing changes in activation of voltage and Ca2+-gated channels. The most important model variables determining the excitability at the time of a synchronous input were the Ca2+-activation of K+ channels and the inhibitory synaptic conductance, although many other model variables could be influential for particular background patterns. Experimental evidence for the amplification of postsynaptic variability by active dendrites is discussed. The amplification of the variability of EPSPs has important functional consequences in general and for cerebellar Purkinje cells specifically. Subthreshold, background input has a much larger effect on the responses to coherent input of neurons with active dendrites compared with passive dendrites because it can change the effective threshold for firing. This gives neurons with dendritic calcium channels an increased information processing capacity and provides the Purkinje cell with a gating function.     

Differential effects of 4-aminopyridine, serotonin, and phorbol esters on facilitation of sensorimotor connections in Aplysia

Serotonergic modulation of sensory neurons in Aplysia and their synaptic connections with follower cells has been used extensively as a model system with which to study mechanisms underlying neuronal plasticity. Serotonin (5-HT)-induced facilitation of sensorimotor connections is due to at least two processes: a process related to the broadening of presynaptic action potentials and a spike-duration-independent (SDI) process that may involve mobilization of transmitter. We have examined the relationship between spike broadening and synaptic facilitation of relatively nondepressed sensorimotor connections in the intact pleural-pedal ganglia. Previously, 5-HT-induced spike broadening in the sensory neuron was shown to be primarily due to the modulation of a voltage-dependent K+ current (Ik.v). Low concentrations (20-30 microM) of 4-aminopyridine (4-AP) were used to rather selectively block Ik.v. 4-AP increased spike duration in the sensory neuron and the excitatory postsynaptic potential (EPSP) in the motor neuron. The temporal development of 4-AP-induced spike broadening closely parallel that of synaptic facilitation. Thus spike broadening via the reduction of Ik.v can directly contribute to synaptic facilitation. The relationship between spike broadening induced by 5-HT (10 microM) and enhancement of the EPSP was also analyzed. We found that components of 5-HT-induced synaptic facilitation preceded the development of 5-HT-induced spike broadening. The comparison between the results of 4-AP and 5-HT revealed that the SDI processes made an important contribution to the rapid development of 5-HT-induced synaptic facilitation and that spike broadening made an important contribution to its maintenance. The SDI process and a slowly developing component of 5-HT-induced spike broadening are mediated, at least in part, by the activation of protein kinase C (PKC). Application of phorbol 12,13-diacetate (PDAc), an activator of PKC, partially mimicked the effects of 5-HT on spike duration and the EPSP. PDAc-induced enhancement of the EPSP preceded the slower development of PDAc-induced spike broadening. Like 5-HT, PDAc enhanced the EPSP via both spike broadening and the SDI processes. In addition, a 15-min exposure to PDAc occluded 5-HT-induced enhancement of the EPSP, suggesting that PKC and 5-HT engage similar or overlapping mechanisms. On the basis of these results and others, we propose a time-dependent hypothesis for the 5-HT-induced synaptic facilitation of nondepressed synapses, in which multiple second-messenger/protein kinase systems mediate the actions of 5-HT via both spike-duration-dependent and SDI processes.     

Dynamics of membrane excitability determine interspike interval variability: a link between spike generation mechanisms and cortical spike train statistics

We propose a biophysical mechanism for the high interspike interval variability observed in cortical spike trains. The key lies in the nonlinear dynamics of cortical spike generation, which are consistent with type I membranes where saddle-node dynamics underlie excitability (Rinzel & Ermentrout, 1989). We present a canonical model for type I membranes, the theta-neuron. The theta-neuron is a phase model whose dynamics reflect salient features of type I membranes. This model generates spike trains with coefficient of variation (CV) above 0.6 when brought to firing by noisy inputs. This happens because the timing of spikes for a type I excitable cell is exquisitely sensitive to the amplitude of the suprathreshold stimulus pulses. A noisy input current, giving random amplitude "kicks" to the cell, evokes highly irregular firing across a wide range of firing rates; an intrinsically oscillating cell gives regular spike trains. We corroborate the results with simulations of the Morris-Lecar (M-L) neural model with random synaptic inputs: type I M-L yields high CVs. When this model is modified to have type II dynamics (periodicity arises via a Hopf bifurcation), however, it gives regular spike trains (CV below 0.3). Our results suggest that the high CV values such as those observed in cortical spike trains are an intrinsic characteristic of type I membranes driven to firing by "random" inputs. In contrast, neural oscillators or neurons exhibiting type II excitability should produce regular spike trains.     

The intracellular domain of p55 tumor necrosis factor receptor induces apoptosis which requires different caspases in naive and neuronal PC12 cells

There is growing evidence that prenatal protein malnutrition alters the development of the hippocampal formation in rats (Morgane et al., 1993; Galler et al., 1996; Almeida et al., 1996, for reviews). Little is known, however, of the possible functional consequences of prenatal malnutrition on the physiology of principal cells in the hippocampus. We have addressed this issue by comparing the electrophysiological properties of hippocampal neurons (dentate granule cells and CA1 pyramidal cells) in slices prepared from control and from prenatally protein malnourished adult male and female Sprague-Dawley rats. We found no significant effect of the prenatal protein malnutrition insult upon a number of intrinsic membrane properties measured with whole-cell current clamp recordings, including: resting membrane potential, input resistance, and membrane time constant, or on action potential characteristics such as threshold, amplitude, and/or firing frequency. Additionally, we saw no effect of prenatal malnutrition upon extracellular measures of glutamatergic synaptic transmission such as the presynaptic fiber volley, excitatory postsynaptic potential or population spike amplitude at the perforant path to dentate granule cell synapse or at the Schaffer collateral to CA1 pyramidal cell synapse. In conclusion, we have demonstrated that prenatal protein malnutrition does not result in significant alterations of the cellular physiological properties of these two types of principal neurons in the adult rat hippocampus.     

Bursting and tonic discharges in two classes of reticular thalamic neurons

1. Two types of cat reticular (RE) thalamic cells were disclosed by means of intracellular recordings under urethan anesthesia. The RE neurons were identified by their typical depolarizing spindle oscillations in response to synchronous stimulation of the internal capsule. 2. In type I neurons (n = 41), depolarizing current pulses induced tonic firing at the resting or slightly depolarized membrane potential (Vm) and triggered high-frequency spike bursts at a Vm more negative than -75 mV. As well, these cells discharged rebound bursts at the break of a hyperpolarizing current pulse. Internal capsule stimulation elicited spindle sequences made off by depolarizing waves giving rise to spike bursts. 3. Type II cells (n = 9) did not discharge spike bursts to large depolarizing current pulses even when the Vm reached -100 mV, nor did they fire rebound bursts after long-lasting hyperpolarizing current pulses or spike bursts riding on the rhythmic depolarizing components of spindle sequences. 4. Compared with type I cells, type II cells showed less frequency accommodation during tonic firing. The latter neuronal class discharged at high frequencies (40 Hz) with slight DC depolarization, approximately 8-10 Hz at the resting Vm, and no underlying synaptic or subthreshold oscillatory events could be detected when the firing was blocked by DC hyperpolarization. 5. The presence of two cell classes in the RE nucleus challenges the common view that this nucleus consists of a single neuronal class. We suggest that a different set of conductances is present in type II RE neurons, thus preventing the low-threshold Ca2+ current from dominating the behavior of these cells.     

Cholinergic contribution to excitation in a spinal locomotor central pattern generator in Xenopus embryos

1. We have investigated whether in Xenopus embryos, spinal interneurons of the central pattern generator (CPG) receive cholinergic or electrical excitatory input during swimming. The functions of cholinergic excitation during swimming were also investigated. 2. Intracellular recordings were made from rhythmically active presumed premotor interneurons in the dorsal third of the spinal cord. After locally blocking inhibitory potentials with 2 microM strychnine and 40 microM bicuculline, the reliability of spike firing and the amplitude of fast, on-cycle, excitatory postsynaptic potentials (EPSPs) underlying the single on-cycle spikes were measured during fictive swimming. 3. The nicotinic antagonists d-tubocurarine and dihydro-beta-erythroidine (DH beta E, both 10 microM) reversibly reduced the reliability of the spike firing during swimming and reduced the amplitude of the on-cycle EPSP by 16%. DH beta E also reduced the EPSP amplitude in spinalized embryos by 22%. These results indicate that interneurons receive rhythmic cholinergic excitation from a source within the spinal cord. 4. Combined applications of nicotinic and excitatory amino acid (EAA) antagonists or cadmium (Cd2+, 100-200 microM) resulted in complete block of the fast EPSP, suggesting that interneurons do not receive electrical excitation. 5. The nicotinic antagonists mecamylamine and d-tubocurarine (both 5 microM) reduced the duration of episodes of fictive swimming recorded from the ventral roots, in spinal embryos. When applied in the middle of a long episode, d-tubocurarine decreased the swimming frequency, ruling out an effect on the initiation pathway. The cholinesterase inhibitor eserine (10 microM) increased the duration of swimming episodes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brain stem reticular units: synaptic responses to stimulation within the ascending reticular pathways

When the ascending reticular axonal system is stimulated, the responses of distal structures (e.g., the cerebral cortex) appear to outlast the stimulus; these longlasting effects could reflect the intrinsic nature of the distal structure, or the response could reflect an interaction among the reticular cells which tends to prolong the effects of stimulation. To examine the latter hypothesis, single units with ascending axons (projecting units) were recorded in the cat rostral rhombencephalon in acute experiments conducted under halothane-nitrous oxide anesthesia. Stimulation of areas to or through which axons of reticular neurons projected (midbrain tegmentum and lower tectum, medial thalamus, and basal forebrain) produced a consistent and specific response which was elicited only from these areas: suppression of spontaneous activity which was typically elicited from several areas having ascending axons. One-half of these responses were accompanied by a short latency-single spike synaptic excitation. Stimulating areas more than 1.0 mm from the ascending trajectory never produced this response, whereas the number of responses was directly related to the number of projecting axons identified in any one experiment from a given site. Thus, the predominant effect of stimulating within the ascending axonal trajectory was suppression of spontaneous activity in the projecting units, not an 'en cascade' activation of these units; on the contrary, the only type of excitation encountered was a single, short latency spike. Therefore, any effects of stimulation within the ascending reticular pathway which appear to outlast the stimulus (as previously described in the literature) cannot be ascribed to a reverberating (excitatory) circuit among projecting units. A possible source of the synaptic responses of projecting units is a retrograde activation of collaterals interconnecting the reticular cells. If such interaction exists, it is specifically distributed among cells with ascending axons, as the responses were only observed in a very few units not identified by antidromic excitation; however, other evidence is adduced to support the belief that these few units were projecting units whose axons were beyond the reach of the stimulating electrodes. Futhermore, the axons may be bundled such that units with axons nearest that of a given projecting unit give rise to the most extensive synaptic interactions; the activation of these nearby axons suppresses spontaneous activity, while axons farther away have a greater possibility of being excitatory in nature. Should such a medium for interaction exist, reticular collateral interactions might be seen to exist specifically for the purpose of decreasing the activity of cells destined for similar rostral target structures.     

A model of visuospatial working memory in prefrontal cortex: recurrent network and cellular bistability

We report a computer simulation of the visuospatial delayed-response experiments of Funahashi et al. (1989), using a firing-rate model that combines intrinsic cellular bistability with the recurrent local network architecture of the neocortex. In our model, the visuospatial working memory is stored in the form of a continuum of network activity profiles that coexist with a spontaneous activity state. These neuronal firing patterns provide a population code for the cue position in a graded manner. We show that neuronal persistent activity and tuning curves of delay-period activity (memory fields) can be generated by an excitatory feedback circuit and recurrent synaptic inhibition. However, if the memory fields are constructed solely by network mechanisms, noise may induce a random drift over time in the encoded cue position, so that the working memory storage becomes unreliable. Furthermore, a "distraction" stimulus presented during the delay period produces a systematic shift in the encoded cue position. We found that the working memory performance can be rendered robust against noise and distraction stimuli if single neurons are endowed with cellular bistability (presumably due to intrinsic ion channel mechanisms) that is conditional and realized only with sustained synaptic inputs from the recurrent network. We discuss how cellular bistability at the single cell level may be detected by analysis of spike trains recorded during delay-period activity and how local modulation of intrinsic cell properties and/or synaptic transmission can alter the memory fields of individual neurons in the prefrontal cortex.     

Synaptic current at the rat ganglionic synapse and its interactions with the neuronal voltage-dependent currents

The membrane current activated by fast nicotinic excitation of intact and mature rat sympathetic neurons was studied at 37 degrees C, by using the two-microelectrode voltage-clamp technique. The excitatory postsynaptic current (EPSC) was modeled as the difference between two exponentials. A fast time constant (tau2; mean value 0.57 ms), which proves to be virtually voltage-independent, governs the current rise phase and a longer time constant (tau1; range 5.2-6.8 ms in 2 mM Ca2+) describes the current decay and shows a small negative voltage dependence. A mean peak synaptic conductance of 0.58 muS per neuron is measured after activation of the whole presynaptic input in 5 mM Ca2+ external solution (0.40 muS in 2 mM Ca2+). The miniature EPSCs also rise and decay with exponential time constants very similar to those of the compound EPSC recorded at the same voltage. A mean peak conductance of 4.04 nS is estimated for the unitary event. Deconvolution procedures were employed to decompose evoked macrocurrents. It is shown that under appropriate conditions the duration of the driving function describing quantal secretion can be reduced to <1 ms. The shape of the EPSC is accurately mimicked by a complete mathematical model of the sympathetic neuron incorporating the kinetic properties of five different voltage-dependent current types, which were characterized in a previous work. We show that IA channels are opened by depolarizing voltage steps or by synaptic potentials in the subthreshold voltage range, provided that the starting holding voltage is sufficiently negative to remove IA steady-state inactivation (less than -50 mV) and the voltage trajectories are sufficiently large to enter the IA activation range (greater than -65 mV). Under current-clamp conditions, this gives rise to an additional fast component in the early phase of membrane repolarization-in response to voltage pulses-and to a consistent distortion of the excitatory postsynaptic potential (EPSP) time course around its peak-in response to the synaptic signal. When the stimulation initiates an action potential, IA is shown to significantly increase the synaptic threshold conductance (up to a factor of 2 when IA is fully deinactivated), compared with that required when IA is omitted. The voltage dependence of this effect is consistent with the IA steady-state inactivation curve. It is concluded that IA, in addition to speeding up the spike repolarization process, also shunts the excitatory drive and delays or prevents the firing of the neuron action potential.     

Cholinergic excitation of dendrites in neocortical neurons

Discharge patterns were studied in response to iontophoretic application of acetylcholine to the soma and dendrites of 128 neocortical pyramidal neurons of layer V. Extracellular recordings were obtained from slices of the guinea-pig parietal cortex. All responses found were excitatory and were better expressed in spontaneously firing cells than in silent ones. Sensitivity to acetylcholine was approximately the same at somatic and dendritic sites in all the cells. Activation of muscarinic receptors gave rise to firing patterns with equal latencies and intensities when applied to both soma and dendrites. The latter suggests that membrane excitation elicited in dendrites by binding of acetylcholine to muscarinic cholinoreceptors is likely to propagate towards the soma through intracellular biochemical processes. Modulating effect of acetylcholine on output firing patterns, elicited by dendritic application of excitatory amino acids, included shortening of the somatic response latency and increase of response intensity and duration. We propose that, in contrast to glutamatergic excitation, the spread of cholinergic excitation along dendrites involves intra-cellular chemical signalling and results in changing the electrical properties of dendrites all over their length.     

Simulated responses of cerebellar Purkinje cells are independent of the dendritic location of granule cell synaptic inputs

Cerebellar Purkinje cell responses to granule cell synaptic inputs were examined with a computer model including active dendritic conductances. Dendritic P-type Ca2+ channels amplified postsynaptic responses when the model was firing at a physiological rate. Small synchronous excitatory inputs applied distally on the large dendritic tree resulted in somatic responses of similar size to those generated by more proximal inputs. In contrast, in a passive model the somatic postsynaptic potentials to distal inputs were 76% smaller. The model predicts that the somatic firing response of Purkinje cells is relatively insensitive to the exact dendritic location of synaptic inputs. We describe a mechanism of Ca2+-mediated synaptic amplification, based on the subspiking threshold recruitment of P-type Ca2+ channels in the dendritic branches surrounding the input site.     

Intracellular recordings in response to monaural and binaural stimulation of neurons in the inferior colliculus of the cat

The inferior colliculus (IC) is a major auditory structure that integrates synaptic inputs from ascending, descending, and intrinsic sources. Intracellular recording in situ allows direct examination of synaptic inputs to the IC in response to acoustic stimulation. Using this technique and monaural or binaural stimulation, responses in the IC that reflect input from a lower center can be distinguished from responses that reflect synaptic integration within the IC. Our results indicate that many IC neurons receive synaptic inputs from multiple sources. Few, if any, IC neurons acted as simple relay cells. Responses often displayed complex interactions between excitatory and inhibitory sources, such that different synaptic mechanisms could underlie similar response patterns. Thus, it may be an oversimplification to classify the responses of IC neurons as simply excitatory or inhibitory, as is done in many studies. In addition, inhibition and intrinsic membrane properties appeared to play key roles in creating de novo temporal response patterns in the IC.     

Central vestibular networks in the guinea-pig: functional characterization in the isolated whole brain in vitro

The isolated, in vitro whole brain of guinea-pig was used to assess some of the main physiological and pharmacological properties of the vestibulo-ocular pathways in this species. Extracellular and intracellular recordings were obtained from the vestibular, abducens and oculomotor nuclei, as well as from the abducens and oculomotor nerves, while inputs from the vestibular afferents, the visual pathways and the spinal cord were activated. The three main types of medial vestibular nucleus neurons (A, B and B+LTS), previously described on slices, were also identified in the isolated brain. They had similar membrane properties in both preparations. Eighty-five per cent of cells recorded in the vestibular nucleus responded with monosynaptic, excitatory postsynaptic potentials (latency 1.05-1.9 ms) to stimulation of the ipsilateral vestibular nerve, and were thus identified as second-order vestibular neurons. In addition, stimulation of the contralateral vestibular afferents revealed in most cases a disynaptic or trisynaptic, commissural inhibition. Second-order vestibular neurons displayed in the isolated brain a high degree of variability of their spontaneous activity, as in alert guinea-pigs. Type A neurons always exhibited a regular firing, while type B and B+LTS cells could have very irregular patterns of spontaneous discharge. Thus, type A and type B neurons might correspond, respectively, to the tonic and phasic vestibular neurons described in vivo. The regularity of spontaneous discharge was positively correlated with the amplitude of spike after hyperpolarization, and there was a trend for irregular neurons to be excited from ipsilateral vestibular afferents at shorter latencies than regular units. Synaptic activation could trigger subthreshold plateau potentials and low-threshold spikes in some of the second-order vestibular neurons. As a second step, the pharmacology of the synaptic transmission between primary vestibular afferents and second-order neurons was assessed using specific antagonists of the glutamatergic receptors. Both the synaptic field potentials and excitatory postsynaptic potentials elicited in the medial vestibular nucleus by single shock stimulation of the ipsilateral vestibular nerve were largely or, sometimes, totally blocked by 6-cyano-7-nitroquinoxaline-2,3-dione, indicating a dominating role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated glutamatergic transmission. The remaining component of the responses was completely or partially suppressed by DL-2-amino-5-phosphonovaleric acid in 35% of the cases, suggesting a concomitant, moderate involvement of N-methyl-D-asparate receptors. In addition, a synaptic response resistant to both antagonists, but sensitive to a zero Ca2+/high Mg(2+)-containing solution, was often observed. Finally, recordings from abducens and oculomotor complexes confirmed the existence in the guinea-pig of strong bilateral, disynaptic excitatory and inhibitory inputs from vestibular afferents to motoneurons of extraocular muscles, which contribute to generation of the vestibulo-ocular reflex. The functional integrity of vestibular-related pathways in the isolated brain was additionally checked by stimulation of the spinal cord and optic tract. Stimulation of the spinal cord evoked, in addition to antidromic responses in the vestibular nucleus, short-latency synaptic responses in both the vestibular nucleus and abducens motoneurons, suggesting possible recruitment of spinal afferents. Activation of visual pathways at the level of the optic chiasm often induced long latency responses in the various structures under study. These results demonstrate that the in vitro isolated brain can be readily used for detailed, functional studies of the neuronal networks underlying gaze and posture control.     

Mechanisms of the cochlear nucleus octopus cell's onset response: synaptic effectiveness and threshold

Octopus cells are one of the principal cell types in the mammalian posteroventral cochlear nucleus. These cells respond to the onset of a toneburst with a precisely timed spike followed by little, if any, sustained activity. While experimental studies have partially characterized the cell, the mechanisms of this onset response are not well understood. The present study involved a model-based investigation that analyzed the responses of a compartmental model of the octopus cell in terms of synaptic effectiveness and dynamic spike threshold. The simulations demonstrate that properties of the onset response (first-spike latency, temporal precision of the first spike, and sustained firing rate) can be predicted from the values of these cell properties for a wide range of model configurations. These relationships were further analyzed through the development of mathematical expressions for synaptic effectiveness and dynamic spike threshold. This computational analysis resulted in a relatively simple explanation of the onset response, as well as predictions of the responses of octopus cells to nontonal, complex stimuli.     

Noradrenaline modifies the spontaneous spiking activity of red nucleus neurons in the rat by activation of alpha 2- and beta-adrenoceptors

We have investigated the effects of noradrenaline (NA) on the spontaneous firing activity of red nucleus (RN) neurons recorded extracellularly in anesthetized rats by using an in vivo electrophysiological technique. Microiontophoretic applications of NA (5-100 nA for 30 s) modified the background firing rate in 99 out of 124 neurons and three different patterns of response were observed in distinct cells. In 61% of the responding neurons NA decreased the mean firing rate, whereas 22% of the neurons responded to NA application with an increase of their spiking activity; in a smaller group of cells (17%) NA exerted a biphasic inhibitory/excitatory effect on the spontaneous firing rate. The effects of NA were reversible and dose-dependent. From histological examination, the neurons responding to NA with a purely inhibitory effect were scattered throughout the RN. On the other hand, the neurons responding to NA with an excitation were found to be more numerous in the dorso-medial part of the RN, whereas the neurons in which NA induced biphasic effects appeared to be segregated in the outer lateral portion of the RN. The alpha 2-adrenoceptor antagonist yohimbine completely blocked the inhibitory effect of NA but was unable to antagonize the excitatory response. In addition, the inhibitory effect of NA was mimicked by clonidine, a selective agonist of alpha 2-adrenoceptors; clonidine had no effect on those cells which responded to NA with an increase of the mean firing rate. The excitatory effect of NA was mimicked by the beta-receptor agonist isoprenaline and was antagonized by timolol, a selective antagonist of beta-adrenoceptors. Isoprenaline was ineffective in those cells in which NA exerted inhibitory responses. Taken together, our results indicate that the inhibitory effect of NA on the firing activity of rat RN neurons were mediated by alpha 2-adrenoceptors, whereas beta-adrenoceptors were responsible for the excitatory effects.