Discharge Patterns Of Neurons Research Articles

Morphological and physiological identification of medulla interneurons in the visual system of the tiger beetle larva.

The morphology of visual interneurons in the tiger beetle larva was identified after recording their responses. Stained neurons were designated as either medulla or protocerebral neurons according to the location of their cell bodies. Medulla neurons were further subdivided into three groups. Afferent medulla neurons extended processes distally in the medulla neuropil and a single axon to the brain through the optic nerve. They received their main input from stemmata on the ipsilateral side. Two distance-sensitive neurons, near-by sensitive and far-sensitive neurons, were also identified. Atypical medulla neurons extended their neurites distally in the medulla and proximally to the brain, as afferent medulla neurons, but their input patterns and the shapes of their spikes differed from afferent neurons. Protocerebral neurons sent a single axon to the medulla neuropil. They spread collateral branches in the posterior region of the protocerebrum on its way to the medulla neuropil. They received main input from stemmata on the contralateral side. Medulla intrinsic neurons did not extend an axon to the brain, and received either bilateral or contralateral stemmata input only. The input patterns and discharge patterns of medulla neurons are discussed with reference to their morphology.

Discharge patterns of preganglionic neurones with axons in a cardiac vagal branch in the rat.

The fibre types that run in a vagal branch projecting to the rat heart are described in this study. In order to obtain spontaneous discharge in this vagal branch and optimal recording conditions, we compared the decerebrate state to urethane, urethane-chloralose and pentobarbital-chloralose anaesthesia with regard to level of chronotropic cardiac vagal tone. Administration of atropine (2 mg kg(-1), I.V.) significantly decreased baseline cardiac interval only in the decerebrate and urethane-anaesthetised rat (by 0.018 +/- 0.001 s and 0.019 +/- 0.002 s, respectively). As a result of these experiments, urethane was chosen as the anaesthetic for all subsequent studies. Using a heart rate signal-averaging method we demonstrated that rat cardiac vagal preganglionic neurones innervating the sinoatrial node should have an expiratory discharge pattern, as reported in other species. However, only 5 % of chronotropic vagal tone was found to be subject to respiratory sinus arrhythmia. A suction microelectrode method, combined with spike-triggered averaging, was employed to record activity from a total of 58 vagal afferents that had axons in this branch. Approximately 75 % of these latter sensory fibres displayed cardiac rhythm. In a separate study we also recorded 318 preganglionic neurones with axons in the right cardiac vagal branch of the rat. Respiratory-modulated preganglionic units were statistically less common than tonically firing units. Six preganglionic subtypes were categorised according to conduction velocity and respiratory discharge pattern. Myelinated B-fibre and unmyelinated C-fibre types were found to be equally prevalent and equally likely to be reflexly excited during the pulmonary chemoreflex and the peripheral arterial chemoreflexes. The electrophysiological analysis has shown how diverse the discharge patterns of the preganglionic neurones or interneurones are whose axons course in the right cardiac vagal branch of the rat. The results of these experiments demonstrate the usefulness of combining spike discrimination with multiple spike-triggered averaging to simultaneously record B and C centrifugal vagal efferents.

Discharge Patterns of Cerebellar Output Neurons in the Caudal Fastigial Nucleus during Head‐Free Gaze Shifts in Primates

Lesion studies in both human and non-human primates indicate that the cerebellum is important for accurate and stereotyped saccadic eye movements. Based on single-unit recordings and pharmacological inactivations in head-fixed monkeys, we suggested that the caudal fastigial nucleus (CFN) provides the brainstem saccade generator with a burst that helps accelerate contraversive saccades and decelerate ipsiversive ones. Here we examine this suggestion during head-free gaze shifts where there can be a 10-fold difference in saccade duration. First, the timing of the burst does not depend on whether the gaze shift has a head component. When a family of either ipsiversive or contraversive gaze shifts with a variety of saccadic durations is aligned on gaze onset, the high-frequency burst in the associated rasters occurs progressively later as saccade duration increases. Realignment of the same rasters with the end of the saccade reveals a tight timing of burst end with saccade end for all 10 CFN burst neurons studied. The delayed bursts for contraversive saccades were unexpected based on the early burst illustrated in the published head-fixed data. One hypothesis is that the late activity helps terminate contraversive as well as ipsiversive gaze shifts. An alternative explanation is that the late CFN burst could still be used as an excitatory drive to promote the late reacceleration or prolonged velocity plateau that is present during large gaze shifts.

Discharge Patterns of Cerebellar Output Neurons in the Caudal Fastigial Nucleus during Head-Free Gaze Shifts in Primates

Discharge Patterns of Cerebellar Output Neurons in the Caudal Fastigial Nucleus during Head-Free Gaze Shifts in Primates

Kinetic analyses of three distinct potassium conductances in ventral cochlear nucleus neurons.

Neurons in the ventral cochlear nucleus (VCN) express three distinct K+ currents that differ in their voltage and time dependence, and in their inactivation behavior. In the present study, we quantitatively analyze the voltage-dependent kinetics of these three currents to gain further insight into how they regulate the discharge patterns of VCN neurons and to provide supporting data for the identification of their channel components. We find the transient A-type K+ current (IA) exhibits fourth-order activation kinetics (a4), and inactivates with one or two time constants. A second inactivation rate (leading to an a4bc kinetic description) is required to explain its recovery from inactivation. The dendrotoxin-sensitive low-threshold K+ current (ILT) also activates with fourth-order kinetics (w4) but shows slower, incomplete inactivation. The high-threshold K+ current (IHT) appears to consist of two kinetically distinct components (n2 + p). The first component activates approximately 10 mV positive to the second and has second-order kinetics. The second component activates with first-order kinetics. These two components also contribute to two kinetically distinct currents upon deactivation. The kinetic behavior of IHT was indistinguishable amongst cell types, suggesting the current is mediated by the same K+ channels amongst VCN neurons. Together these results provide a basis for more realistic modeling of VCN neurons, and provide clues regarding the molecular basis of the three K+ currents.

Altered spontaneous discharge rate and pattern of basal ganglia output neurons in the circling ( ci2) rat mutant

The circling rat is an autosomal recessive mutant (homozygous ci2/ ci2) characterized by lateralized rotational behavior, locomotor hyperactivity, ataxia, stereotypic head movements, and deafness. Previous neurochemical investigations showed that ci2 rats of both genders have a lower tissue content of dopamine in the striatum ipsilateral to the preferred direction of circling. For further evaluation as to whether this striatal imbalance has functional consequences within basal ganglia structures, the spontaneous extracellular single unit activity of GABAergic neurons located in the striatum and, downstream to the dopaminergic nigrostriatal system, the substantia nigra pars reticulata (SNr) was recorded bilaterally in anesthetized ci2 rats. Heterozygous ( ci2/+) littermates that display normal behavior, and rats from the background strain (LEW/Ztm) served as controls. No significant hemispheric imbalances in striatal discharge rate and firing pattern were evident in ci2 rats. Furthermore, there were no significant intergroup differences in striatal activity. However, the mean spontaneous discharge rate of SNr neurons was significantly increased in both brain sides, and there was a significant shift toward rhythmic burst-like firing in ci2 mutants. Again, no hemispheric differences were detected. The data substantiate previous findings of altered basal ganglia function in ci2 rats. The abnormal basal ganglia output activity, i.e. of the SNr, is likely to contribute to the complex behavioral disturbances seen in ci2 rats.

Changes in neuronal activity of the inferior colliculus in rat after temporal inactivation of the auditory cortex.

The role of cortico-tectal pathways in auditory signal processing was studied in anesthetized rats by comparing the extracellular single unit activity in the inferior colliculus (IC) before and after functional ablation of the auditory cortex (AC) by tetrodotoxin (TTX). The responses of several IC neurons to sound stimuli were simultaneously recorded with a 16-channel electrode probe introduced into the IC. Click-evoked middle latency responses (MLR) recorded from the AC were suppressed for several hours after TTX injection. During AC inactivation the firing rate of IC neurons increased (40 % of neurons), decreased (44 %) or did not change (16 %) in comparison with control conditions. In several IC neurons, TTX injection resulted in alterations in the shape of the rate-level functions. Response thresholds, tuning properties and the type of discharge pattern of IC neurons were not altered during AC inactivation. However, in one-third of the neurons, the initial part of the response was less altered than the later, sustained part. In two-thirds of neuronal pairs, functional decortication resulted in a change in the cross-correlation coefficient. The results reveal the complex changes that appear in IC neuronal activity after functional ablation of the ipsilateral auditory cortex.

Medullary raphe neuron activity is altered during fictive cough in the decerebrate cat.

Chemical lesions in the medullary raphe nuclei region influence cough. This study examined whether firing patterns of caudal medullary midline neurons were altered during cough. Extracellular neuron activity was recorded with microelectrode arrays in decerebrated, neuromuscular-blocked, ventilated cats. Cough-like motor patterns (fictive cough) in phrenic and lumbar nerves were elicited by mechanical stimulation of the intrathoracic trachea. Discharge patterns of respiratory and nonrespiratory-modulated neurons were altered during cough cycles (58/133); 45 increased and 13 decreased activity. Fourteen cells changed firing rate during the inspiratory and/or expiratory phases of cough. Altered patterns in 43 cells were associated with the duration of, or extended beyond, the cough episodes. The different response categories suggest that multiple factors influence the discharge patterns during coughing: e.g., respiratory-modulated and tonic inputs and intrinsic connections. These results suggest involvement of midline neurons (i.e., raphe nuclei) in the cough reflex.

Determination and quantification of pharmacological, physiological, or behavioral manipulations on ensembles of simultaneously recorded neurons in functionally related neural circuits

The present report describes methods for evaluating the impact of physiological, pharmacological or behavioral manipulations on simultaneously recorded single neurons within a functional sensory network of the awake, freely moving rat. Surgical techniques were developed to implant a subcutaneous electrode at the base of a single facial whisker (mystacial vibrissae) so that uniform electrical stimuli could be routinely delivered to a discrete region of the whisker pad in the awake and freely moving animal. Multi-channel extracellular recording was used to monitor the spike train activity from ensembles of single neurons in whisker-related regions of the thalamus and neocortex. Algorithms were developed to verify the stability of individual cell recordings during extended experimental sessions. Additional analysis procedures and criteria were established for identifying and evaluating the treatment-specific changes in single neuron discharge patterns that are likely to occur under these experimental conditions. Finally, analyses for evaluating the impact of experimental manipulations on sensory representations distributed over populations of neurons are discussed. The development of these techniques has provided us with the means to investigate the influence of systemically administered drugs or broadly projecting monoamine pathways on single neurons and local circuits within primary sensory networks of the awake or anesthetized mammalian brain.

FM signals produce a robust paradoxical latency shift that is important for coding of target range in the bat inferior colliculus

Echolocating bats utilize the time delay between an outgoing ultrasonic pulse and its echo to determine target range. Many neurons at the inferior colliculus (IC) and above are tuned to time delays between these sound pulses of unequal amplitudes. Sullivan previously proposed that paradoxical latency shift (PLS), characterized by a quantal increase in firing latency to loud sounds, is important for this attribute because PLS permits coincidence detection that is important for the creation of delay-tuned responses. In the IC of little brown bats, Galazyuk and Feng recently reported that, in response to tone pulses, the proportion of neurons showing PLS was low (<20%). This study was undertaken to determine whether PLS is a function of the acoustic stimulus. For this, the temporal discharge patterns of single IC neurons were investigated over a broad range of sound levels, using tone pulses at CF as well as FM sound pulses that mimicked bats’ ultrasonic cry as stimuli. For many IC neurons, tone pulses did not elicit PLS but FM sound pulses produced robust PLS. This result showed that PLS is stimulus dependent and that the bat’s auditory system is optimal for processing FM sounds employed during echolocation. [Work supported by NIH R01DC04998.]

Chemical activation of C1–C2 spinal neurons modulates activity of thoracic respiratory interneurons in rats

Discharge patterns of thoracic dorsal horn neurons are influenced by chemical activation of cell bodies in cervical spinal segments C(1)-C(2). The present aim was to examine whether such activation would specifically affect thoracic respiratory interneurons (TRINs) of the deep dorsal horn and intermediate zone in pentobarbital sodium-anesthetized, paralyzed, artificially ventilated rats. We also characterized discharge patterns and pathways of TRIN activation in rats. A total of 77 cells were classified as TRINs by location, continued burst activity related to phrenic discharge when the respirator was stopped, and lack of antidromic response from selected pathways. A variety of respiration-phased discharge patterns was documented whose pathways were interrupted by ipsilateral C(1) transection. Glutamate pledgets (1 M, 1 min) on the dorsal surface of the spinal cord inhibited 22/49, excited 15/49, or excited/inhibited 3/49 tested cells. Incidence of responses did not depend on whether the phase of TRIN discharge was inspiratory, expiratory, or biphasic. Phrenic nerve activity was unaffected by chemical activation of C(1)-C(2) in this preparation. Besides supraspinal input, TRIN activity may be influenced by upper cervical modulatory pathways.

Cortical processing of temporal modulations

Temporal modulations are fundamental components of human speech and animal communication sounds. Understanding their representations in the auditory cortex is a crucial step towards our understanding of brain mechanisms underlying speech processing. While modulated signals have long been used as experimental stimuli, their cortical representations are not completely understood, particularly for rapid modulations. Known physiological data do not adequately explain psychophysical observations on the perception of rapid modulations, largely due to slow stimulus-synchronized temporal discharge patterns of cortical neurons. In this article, we summarize recent findings from our laboratory on temporal processing mechanisms in the auditory cortex. These findings show that the auditory cortex represents slow modulations explicitly using a temporal code and fast modulations implicitly by a discharge rate code. Rapidly modulated signals within a short-time window (∼20–30 ms) are integrated and transformed into a discharge rate-based representation. The findings also indicate that there is a shared representation of temporal modulations by cortical neurons that encodes the temporal profile embedded in complex sounds of various spectral contents. Our results suggest that cortical processing of sound streams operates on a “segment-by-segment” basis with a temporal integration window on the order of ∼20–30 ms.

Altered Discharge Pattern of Basal Ganglia Output Neurons in an Animal Model of Idiopathic Dystonia

A decreased activity of basal ganglia output neurons is thought to underlie idiopathic dystonias and other hyperkinetic movement disorders. We found recently a reduced spontaneous discharge rate of entopeduncular neurons (internal globus pallidus in primates) in<i>dt</i>^<i>sz</i> hamsters, an unique model for idiopathic paroxysmal dystonia in which stress-inducible attacks show an age-dependent severity. Otherwise, it has been suggested that an altered discharge pattern may be more important for the occurrence of dystonia than a reduced discharge rate. Based on qualitative and computerized quantitative evaluations of interspike interval histograms and spike trains of extracellularly recorded single neurons, we investigated the spontaneous discharge pattern of GABAergic entopeduncular and nigral neurons in<i>dt^sz</i> hamsters at different ages. The discharge pattern of entopeduncular neurons was highly irregular and showed an altered burst-like firing in<i>dt^sz</i> hamsters at the age of the most marked expression of dystonia when compared with age-matched nondystonic controls. In line with a recently reported normalization of discharge rates after age-dependent disappearance of dystonia, we found an almost complete normalization of the discharge pattern of entopeduncular neurons after remission of dystonia in<i>dt^sz</i> hamsters. Investigations of GABAergic nigral neurons, reported recently to have the same spontaneous discharge rates in dystonic and nondystonic hamsters, did not show an altered firing pattern in<i>dt^sz</i> hamsters. The present data clearly indicate the fundamental importance of an altered discharge pattern of entopeduncular neurons for the expression of paroxysmal dystonia, and probably also for other dyskinesias, and may explain the improvements obtained by pallidotomy in dystonic patients despite an obviously reduced pallidal output.

Altered discharge pattern of basal ganglia output neurons in an animal model of idiopathic dystonia.

A decreased activity of basal ganglia output neurons is thought to underlie idiopathic dystonias and other hyperkinetic movement disorders. We found recently a reduced spontaneous discharge rate of entopeduncular neurons (internal globus pallidus in primates) in dt(sz) hamsters, an unique model for idiopathic paroxysmal dystonia in which stress-inducible attacks show an age-dependent severity. Otherwise, it has been suggested that an altered discharge pattern may be more important for the occurrence of dystonia than a reduced discharge rate. Based on qualitative and computerized quantitative evaluations of interspike interval histograms and spike trains of extracellularly recorded single neurons, we investigated the spontaneous discharge pattern of GABAergic entopeduncular and nigral neurons in dt(sz) hamsters at different ages. The discharge pattern of entopeduncular neurons was highly irregular and showed an altered burst-like firing in dt(sz) hamsters at the age of the most marked expression of dystonia when compared with age-matched nondystonic controls. In line with a recently reported normalization of discharge rates after age-dependent disappearance of dystonia, we found an almost complete normalization of the discharge pattern of entopeduncular neurons after remission of dystonia in dt(sz) hamsters. Investigations of GABAergic nigral neurons, reported recently to have the same spontaneous discharge rates in dystonic and nondystonic hamsters, did not show an altered firing pattern in dt(sz) hamsters. The present data clearly indicate the fundamental importance of an altered discharge pattern of entopeduncular neurons for the expression of paroxysmal dystonia, and probably also for other dyskinesias, and may explain the improvements obtained by pallidotomy in dystonic patients despite an obviously reduced pallidal output.

What can be learned about motoneurone properties from studying firing patterns?

The discharge patterns of tonically-firing neurones are influenced by both the characteristics of their presynaptic input and their intrinsic properties. The regularity of the discharge of motoneurones is thought to reflect their prominent post-spike afterhyperpolarization (AHP). When a motoneurone fires at steady mean rate, the distribution of interspike intervals is determined by the amplitude and frequency content of the synaptic noise together with the decrease in excitability following a spike due to AHP. This paper considers how motoneurone discharge statistics can be used to estimate AHP trajectories as well as a motoneurone's sensitivity to excitatory input.

Sleep-waking discharge patterns of neurons recorded in the rat perifornical lateral hypothalamic area.

The perifornical lateral hypothalamic area (PF-LHA) has been implicated in the control of several waking behaviours, including feeding, motor activity and arousal. Several cell types are located in the PF-LHA, including projection neurons that contain the hypocretin peptides (also known as orexins). Recent findings suggest that hypocretin neurons are involved in sleep-wake regulation. Loss of hypocretin neurons in the human disorder narcolepsy is associated with excessive somnolence, cataplexy and increased propensity for rapid eye movement (REM) sleep. However, the relationship of PF-LHA neuronal activity to different arousal states is unknown. We recorded neuronal activity in the PF-LHA of rats during natural sleep and waking. Neuronal discharge rates were calculated during active waking (waking accompanied by movement), quiet waking, non-REM sleep and REM sleep. Fifty-six of 106 neurons (53 %) were classified as wake/REM-related. These neurons exhibited peak discharge rates during waking and REM sleep and reduced discharge rates during non-REM sleep. Wake-related neurons (38 %) exhibited reduced discharge rates during both non-REM and REM sleep when compared to that during waking. Wake-related neurons exhibited significantly higher discharge rates during active waking than during quiet waking. The discharge of wake-related neurons was positively correlated with muscle activity across all sleep-waking states. Recording sites were located within the hypocretin-immunoreactive neuronal field of the PF-LHA. Although the neurotransmitter phenotype of recorded cells was not determined, the prevalence of neurons with wake-related discharge patterns is consistent with the hypothesis that the PF-LHA participates in the regulation of arousal, muscle activity and sleep-waking states.

Cutaneous sympathetic motor rhythms during a fever-like response induced by prostaglandin E 1

Neuronal population discharges within the CNS and in somatic and sympathetic motor nerves often display oscillations. Peripheral oscillations may provide a window into central mechanisms, as they often show coherence with population activity of subsets of central neurones. The reduction in heat loss through the cutaneous circulation during fever may be mediated via sympathetic premotor neurones not utilised during normal temperature regulation. Consequently, here we assessed, in anaesthetised rats, whether the frequency signature of population sympathetic discharge observed in neurones innervating the tail (thermoregulatory) circulation changed during a fever-like response induced by intracerebroventricular injection of prostaglandin E 1. We found that when core temperature was raised to 38.8–40.5°C sympathetic activity was abolished. Following administration of prostaglandin (400 ng or 1 μg per rat), activity was restored to levels seen prior to heating (154±53.5%; n=10). Injection of vehicle had no effect ( n=7). Prior to heating when most animals were in central apnoea (14/18) two peaks were observed in autospectra of sympathetic activity: one at 0.68–0.93 Hz (T-peak) and another at the frequency of ventilation (2 Hz). Central respiratory drive was recruited during hyperthermia where it was 1:2 locked to the frequency of ventilation and following prostaglandin administration, an additional peak in sympathetic autospectra was seen at this frequency. Time-evolving spectra indicated that this peak resulted from the dynamic locking of the ‘T-peak’ to central respiratory drive. Our data show that during a fever-like response the dominant oscillations in sympathetic activity controlling a thermoregulatory circulation and their dynamic coupling to respiratory-related inputs are similar to those seen under normal conditions. Therefore, during this fever-like response, the neural substrate(s) underlying the oscillations is not reconfigured and remains capable of sculpturing the pattern of sympathetic neuronal discharge that may be regulated by several descending pathways.

Discharge of primate magnocellular red nucleus neurons during reaching to grasp in different spatial locations.

Reaching to grasp is of fundamental importance to primate motor behavior. One descending motor pathway that contributes to the control of this behavior is the rubrospinal tract. An important source of origin of the rubrospinal tract is the magnocellular red nucleus (RNm). Forelimb RNm neurons discharge vigorously during reach-to-grasp movements. RNm discharge is important for hand use, as coordinated whole-limb movements without hand use are not associated with strong discharge. Because RNm is functionally linked to muscles of the entire forelimb, RNm discharge may also contribute to use of the proximal limb that accompanies hand use. If RNm contributes to proximal limb use, we predict discharge to differ for reaches that differ in proximal limb involvement but require the same grasp. We tested this prediction by measuring discharge of individual RNm neurons while monkeys reached to grasp objects in four spatial locations in front of them. The animals reached from the waist to locations to the left, right, above, and below the shoulder of the "reaching" limb. RNm neurons of our sample were activated strongly during reach-to-grasp, and discharge of a third of the neurons tested depended on the spatial location of the object grasped. Discharge of RNm neurons and EMG activity of many of the distal and proximal forelimb muscles we tested were larger for reaching to grasp in the upper and/or right than lower and left target locations. Based on comparisons of each individual neuron's discharge patterns during reaches with and without preshaping the hand, we conclude that target location-dependent modulations in discharge rate of the majority of RNm neurons whose discharge differed for reaching to grasp in the four target locations contributed to aspects of hand preshaping that covaried with reach direction.

Discharge patterns of neurons in the medial pontobulbar reticular formation during fictive mastication in the rabbit.

In this study, we describe functional characteristics of neurons forming networks generating oral ingestive motor behaviours. Neurons in medial reticular nuclei on the right side of the brainstem between the trigeminal and hypoglossal motor nuclei were recorded in anaesthetized and paralysed rabbits during two types of masticatory-like motor patterns induced by electrical stimulation of the left (contralateral) or right (ipsilateral) cortical masticatory areas. Sixty-seven neurons in nucleus reticularis pontis caudalis (nPontc), nucleus reticularis parvocellularis (nParv), and nucleus reticularis gigantocellularis (Rgc) were studied. These were classified as phasic or tonic depending on their firing pattern during the fictive jaw movement cycle. Phasic neurons located in the dorsal part of nPontc were active during the jaw opening phase, whilst those in dorsal nParv tended to fire during the closing phase. In most neurons, burst duration and firing frequency changed between the two motor patterns, but there was little change in phase of firing. Tonic units were mainly recorded in the ventral half of nPontc, and at the junction between Rgc and caudal nParv. Cortical inputs with short latency from the contralateral masticatory area were more frequent in phasic (82%) than tonic (44%) neurons, whilst inputs from the ipsilateral cortex were equal in the two subgroups (57% and 56%). Phasic neurons had significantly shorter mean contralateral than ipsilateral cortical latencies, whilst there was no difference among tonic neurons. Intra- and perioral primary afferent inputs activated both types of neurons at oligo-synaptic latencies. Our results show that subpopulations of neurons in medial reticular nuclei extending from the caudal part of the trigeminal motor nucleus to the rostral third of the hypoglossal motor nucleus are active during the fictive masticatory motor behaviour. Unlike masticatory neurons in the lateral tegmentum, the medial subpopulations are spatially organized according to discharge pattern.

Differential modulation of respiratory neuronal discharge patterns by GABA(A) receptor and apamin-sensitive K(+) channel antagonism.

The discharge patterns of respiratory neurons of the caudal ventral respiratory group (cVRG) appear to be subject to potent GABAergic gain modulation. Local application of the GABA(A) receptor antagonist bicuculline methochloride amplifies the underlying discharge frequency (F(n)) patterns mediated by endogenous excitatory and inhibitory synaptic inputs. Gain modulation can also be produced by alterations in the amplitude of spike afterhyperpolarizations (AHPs) mediated by apamin-sensitive small-conductance Ca(2+)-activated K(+) (SK) channels. Since methyl derivatives of bicuculline (BICm) also have been shown to reduce the amplitude of AHPs, in vitro, it is possible that the BICm-induced gain modulation is due to a block of SK channels. The purpose of these studies was to determine the mechanisms by which BICm produces gain modulation and to characterize the influence of SK channels in the control of respiratory neuron discharge. Six protocols were used in this in vivo study of cVRG inspiratory (I) and expiratory (E) neurons in decerebrate, paralyzed, ventilated dogs. The protocols included characterizations of the neuronal responses to 1) BICm and apamin on the same neuron, 2) BICm during maximum apamin-induced block of AHPs, 3) apamin during maximum BICm-induced gain modulatory responses, 4) the specific GABA(A) receptor antagonist, (+)beta-hydrastine, 5) the specific GABA(A) receptor agonist, muscimol, and 6) the GABA uptake inhibitor, nipecotic acid. For protocols 3, 5, and 6, only E neurons were studied. Four-barrel micropipettes were used for extracellular single neuron recording and pressure ejection of drugs. Cycle-triggered histograms were used to quantify the F(n) patterns and to determine the drug-induced changes in the gain (slope) and offset of the F(n) patterns. Compared to apamin at maximum effective dose rates, BICm produced a 2.1-fold greater increase in peak F(n) and a 3.1-fold greater increase in average F(n). BICm and apamin produced similar increases in gain, but the offsets due to apamin were more negative. The responses to hydrastine were similar to BICm. During maximum apamin block, BICm produced an additional 112 +/- 22% increase in peak F(n). Conversely, apamin produced an additional 176 +/- 74% increase in peak F(n) during the maximum BICm-induced response. Muscimol and nipecotic acid both decreased the gain and offset of the discharge patterns. Taken together, these results suggest that the gain modulatory effect of BICm is due to a reduction of GABA(A)-ergic shunting inhibition rather than a reduction in AHPs by block of SK channels in canine cVRG neurons.