Effect of Microiontophoretic Application of Modulators of Noradrenergic Transmission on Impulse Activity of Neurons of the Cat Motor Cortex during Performance of the Reflex to a Complex of Stimuli

On unanesthetized cats, we studied the effects of selective modulators of noradrenergic transmission on the activity of neurons of the cerebral motor cortex in the course of realization of an operant motor reflex to presentation of a complex of stimuli. These modulators were applied using microiontophoretic injections into sites of recording of impulse activity of cortical neurons within the zone of projection of the “working” forelimb. Applications of the α1 receptor agonist Mesaton resulted in significant suppression of background impulsation of the neurons and spiking within the interstimulus interval immediately during realization of the movement. Under the action of the α2 blocker yohimbine, opposite effects were observed. The activity of neurons increased within both background period and other examined time intervals. Mechanisms of the effects of modulation of noradrenergic transmission in the sensorimotor cortex are discussed.     

Effect of stimulation of β adrenoreceptors on conditioned reflex-related spike activity of neurons of the cat somatosensory cortex

Using extracellular recording of impulse activity of pyramidal neurons of the cat somatosensory cortex generated in the course of realization of an operant conditioned reflex, we examined effects of microiontophoretic applications of an agonist of β2 adrenoreceptors, metaproterenol, and of an antagonist of β adrenoreceptors, propranolol, on the frequency of this impulsation. Applications of propranolol induced intensification of both background and reflex-related spiking. The effect of metaproterenol was manifested as moderate intensification of background discharges, a noticeable increase in the frequency of evoked impulsation, and an increase in the latency of impulse reactions. It is supposed that noradrenergic projections to the neocortex intensify neuronal activity via activation of β2 adrenoreceptors and suppress this activity via influencing mostly β1 adrenoreceptors. Such effects of synaptically active agents should probably be taken into account in the treatment of neurological diseases, namely epilepsy, neurodegenerative disorders, psychoemotional shifts, etc., which are accompanied by emotional and cognitive disorders.     

Role of Acetylcholine in the Modulation of Activity of Neocortical Neurons in Awake Animals Performing an Instrumental Conditioned Reflex

We studied modulatory effects of the cholinergic system on the activity of sensorimotor cortex neurons related to realization of an instrumental conditioned placing reflex. Experiments were carried out on awake cats; multibarrel glass microelectrodes were used for extracellular recording of impulse activity of neurons in the sensorimotor cortex and iontophoretic application of synaptically active agents within the recording region. The background and reflex-related activity was recorded in the course of realization of conditioned movements, and then changes of spiking induced by applications of the testing substances were examined. Applications of acetylcholine and carbachol resulted in increases in the intensity of impulse reactions of neocortical neurons evoked by presentation of an acoustic signal and in simultaneous shortening of the response latencies. An agonist of muscarinic receptors, pylocarpine, exerted a similar effect on the evoked activity of sensorimotor cortex neurons. Blockers of muscarinic receptors, atropine and scopolamine, vice versa, sharply suppressed impulse reactions of cortical neurons to afferent stimulation and simultaneously increased latencies of these responses. Applications of an agonist of nicotinic receptors, nicotine, was accompanied by suppression of impulse neuronal responses, an increase in the latency of spike reactions to presentation of a sound signal, and a corresponding increase in the latency of a conditioned motor reaction. In contrast, application of an antagonist of nicotinic receptors, tubocurarine, significantly intensified neuronal spike responses and shortened their latency. The mechanisms underlying the effects of antagonists of membrane muscarinic and nicotinic cholinoreceptors and the role of activation of these receptors in the modulation of activity of pyramidal and non-pyramidal neocortical neurons related to realization of the instrumental motor reflex are discussed.     

Effects of modulation of GABA-and noradrenergic transmission on impulse activity of neurons of the cat motor cortex related to realization of an operant reflex to the action of two signals

On unanesthetized cats trained to perform placing movements to the action of two subsequent signals (warning and imperative stimuli), we examined reflex-related impulse activity (IA) of neurons of the motor cortex (field 4) and simultaneous changes in the “slow” cortical potentials (SCP) in the vertex zone. In almost all cases under study, the shift in the SCP toward negativity was associated with a decrease in the frequency of IA within interstimulus intervals; this corresponded to a period of focusing of the animal’s attention on the expected imperative stimulus. Using a microiontophoretic technique, we tried to elucidate the role of GABA-and adrenergic cerebral systems in the genesis of such inhibitory periods. We conclude that, independently of each other but synchronously, both these systems can be involved in the maintenance of processes of active inhibition in the cerebral cortex under conditions of realization of an operant reflex. Neirofiziologiya/Neurophysiology, Vol. 39, No. 1, pp. 62–68, January–February, 2007.     

Effect of Blocking of Calcium Channels on Cognitive Processes and General Motor Activity in Normal and Stressed Rats

In Wistar rats, we studied the effects of injections of a Ca²⁺ channel blocker, verapamil, on realization of a food-procuring operant conditioned reflex, OCR, and general motor activity within intersignal periods in the norm and under conditions of stress-induced disorders. The OPRs and a few behavioral phenomena (immobilization, grooming, research behavior, orientational and locomotor activity, vertical stands, and intersignal limb movements in a manger) were recorded. The acute stress state was induced by intense acoustic stimulation (a loud ringing sound presented in the course of OCR realization). Inhibition of the conditioned reflex activity (immobilization of the animal within an interstimulus period) and weakening of attention to the manger resulted from stress induction. Stress-related behavioral effects evoked by intense auditory stimulation were eliminated against the background of the action of verapamil, while the OCR and motor activity were not inhibited. Verapamil suppressed reactions of fear and anxiety in a dose-dependent manner and promoted concentration of attention; these effects improved the integrative functions and abilities to adequately estimate the signals in a given situation of the OCR performance. Such effects can be based on weakening of stress-related adrenaline release and certain normalization of the state of the cardiovascular systems due to partial blocking of calcium channels.     

Effects of blockade of noradrenergic and serotonergic transmission in theCM-Pf complex on neuronal activity in the motor thalamus in cats

Effects of injections of blockers of the monoaminergic receptor structures into thecentrum medianum-nucl. parafascicularis (CM-Pf) on the activity of neurons in the motor thalamic nuclei (VA-VL) were studied in chronic experiments on awake cats. The animals were trained to perform an operant placing reflex by the forelimb. Injection of a-adrenoblocker, anapriline, into theCM-Pf resulted in enhancement of background activity of neurons of the motor thalamus and facilitation of their spike responses related to conditioned and unconditioned reflex movements. Application of a blocker of serotonin receptors, lysergoamide, evoked opposite changes in the neuronal activity in theVA-VL nuclei: depression of background activity, facilitation of inhibitory processes, and suppression of evoked activity related to conditioned and unconditioned movements. It is supposed that the monoaminergic system of thelocus coeruleus exerts a suppressing influence on the motor thalamus via theCM-Pf complex, while the system of the raphe nuclei facilitates motor thalamic structures.Neirofiziologiya/Neurophysiology, Vol. 28, No. 6, pp. 305–311, November–December, 1996.     

Somatodendritic α2-Adrenoceptors in the Locus Coeruleus Are Involved in the In Vivo Modulation of Cortical Noradrenaline Release by the Antidepressant Desipramine

Abstract: The effect of the antidepressant and selective noradrenaline reuptake blocker desipramine (DMI) on noradrenergic transmission was evaluated in vivo by dual-probe microdialysis. DMI (1, 3, and 10 mg/kg, i.p.) dose-dependently increased extracellular levels of noradrenaline (NA) in the locus coeruleus (LC) area. In the cingulate cortex (Cg), DMI (3 and 10 mg/kg, i.p.) also increased NA dialysate, but at the lowest dose (1 mg/kg, i.p.) it decreased NA levels. When the α₂-adrenoceptor antagonist RX821002 (1 µ M ) was perfused in the LC, DMI (1 mg/kg, i.p.) no longer decreased but rather increased NA dialysate in the Cg. In electrophysiological experiments, DMI (1 mg/kg, i.p.) inhibited the firing activity of LC neurons by a mechanism reversed by RX821002. Local DMI (0.01–100 µ M ) into the LC increased concentration-dependently NA levels in the LC and simultaneously decreased NA levels in the Cg. This decrease was abolished by local RX821002 administration into the LC. The results demonstrate in vivo that DMI inhibits NA reuptake at somatodendritic and nerve terminal levels of noradrenergic cells. The increased NA dialysate in the LC inhibits noradrenergic activity, which in part counteracts the effects of DMI on the Cg. The modulation of cortical NA release by activity of DMI at the somatodendritic level is mediated through α₂-adrenoceptors located in the LC.     

Dopaminergic modulation of impulse activity of sensorymotor cortex neurons during conditioned reflex

Changes of conditioned impulse reaction of cortical neurons wer studied during microiontophoretic application of agonist and antagonists of glutamate and GABA transmission and their modulation by dopamine. It was shown paradoxal reaction of facilitation of impulse activity during iontophoretic application of ionotropic glutamate antagonist and depressive influences of metabotropic antagonist. Local iontophoretic application of dopamine increased background and evoked impulse activity of pyramidal neurons of deep layers of cortex and eliminated inhibitory influences of glutamate metabotropic antagonist MCPG. It is concluded that DA has stabilizing effects on activity of cortical neurons. It is suppose that these effects of DA realize through system of inhibitory interneurons.     

Thermostimulation-Induced Modulation of Conditioned Reflex Movement-Related Reactions of Cortical Neurons of the Cat

In awake cats trained to perform a food-procuring conditioned operant reflex (placing movement), we studied impulse reactions of 86 neurons of the motor cortex (field 4) related to realization of the above movements. As conditioning stimuli (CS) initiating the reflex, we used either non-noxious electrocutaneous stimulation (ECS) of the contralateral forelimb or an acoustic stimulus (sound click). Impulsation of cortical neurons was recorded under conditions of (i) isolated presentation of the CS (control), (ii) presentation of the CS (either ECS or acoustic stimulus) combined with thermostimulation (heating with a miniature electric bulb) of the skin of the working forelimb, and (iii) the same, but with stimulation of the resting forelimb. When we recorded spike activity of neurons within the projection motor zone of the resting limb subjected to ESC, alternating thermostimulation of both forelimbs resulted in considerable intensification and an increase in the duration of neuronal responses, especially in cases where thermostimulation was applied to the working limb ipsilateral to the recording site (a two- to threefold increase). When spike reactions were recorded within the motor cortex of the working forelimb, thermostimulation resulted in a considerable increase in the intensity of these reactions and a decrease in their latency, but only when such stimulation was applied to the working forelimb. Thermostimulation of the resting (ipsilateral, subjected to ESC) limb evoked opposite effects (the intensity of neuronal reactions dropped). In both situations, placing movements remained within the control limits. When sound click was used as a distant CS, thermostimulation of the working limb enhanced neuronal responses, increased their duration by 50-100%, and also increased the time of forestalling of the movement initiation by spike neuronal reactions. Thermostimulation of the resting forelimb in this situation also suppressed neuronal reactions. We conclude that foreign stimulations directed toward modifications of the receptor model of the operant reflex experimental situation formed in the animal result in a decrease in the intensity of the spike responses of field-4 neurons and prolongation of the latencies of these responses, while stimulations promoting the inflow of afferent information to the cortical projection of the working limb evoke opposite effects, an increase in the intensity of neuronal spike responses and a decrease in their latencies.     

Modulation of EEG Rhythms and Changes in Spike Activity of Noradrenergic Neurons of the <Emphasis Type="Italic">Locus Coeruleus</Emphasis> Related to Feedback Sessions by EEG Characteristics

In chronic experiments on awake cats, we studied the dynamics of the spectral power density (SPD) of the α rhythm vs SPD of the θ rhythm ratio and also of the characteristics of impulse activity generated by supposedly noradrenergic (NA) neurons of the locus coeruleus in the course of feedback (FB) sessions by EEG characteristics (EEG-FB). Trainings were performed using a technique analogous to that in EEG-FB sessions for humans. The level of a sound noise signal presented to the animal decreased with increase in the α/θ SPD ratio in the occipital lead. Changes in the level of the sound signal did not depend on EEG modulation in the control series. The animals were trained to correlate changes in the loudness of the sound signal with the power of EEG rhythms and, in such a way, to control the latter. The α/θ SPD ratio in EEG-FB sessions changed mostly due to a significant increase in the α rhythm power. The frequency of the impulse activity of NA neurons increased in a parallel manner with such EEG modulation. Possible mechanisms of the involvement of the cerebral NA system in the formation of the effects of EEG-FB sessions are discussed.     

Effects of the vitamin derivatives of GABA on inhibitory postsynaptic responses of the rat cortical neurons

With the use of an intracellular recording technique, in experiments on immobilized anesthetized rats, we studied intracortical stimulation (ICS)-evoked responses of the motor cortex neurons before and after applications of pantogam (PG) and GABA ascorbinate (A-GABA) on the cortical surface. Application of PG prolonged the IPSP, suppressed the background spike activity (BA), and increased the membrane potential level of the neurons studied. Applications of A-GABA in low and medium concentrations (below 50 μM) increased the amplitude and duration of inhibitory responses, while that in high concentrations (50 μM and more) evoked depolarization of the neuronal membrane with concurrent intensification of the BA. Probable cellular mechanisms of the effects of the above drugs are discussed.     

Activation of Neurons of the Medullary Centers of the Autonomic Nervous System Related to Motivated Operant Movements Realized by Rats

Using the corresponding techniques, we visualized Fos-immunoreactive (Fos-ir) and NADPH diaphorasereactive (NADPH-dr) neurons in the medullary centers of the autonomic nervous system (ANS) of rats, which performed repetitive operant movements (catching of food globules from the manger by the left forelimb under conditions of high food motivation). Animals were trained to perform operant movements in 30 min-long everyday sessions during 12 days. The duration of a single food-procuring movement was about 600 msec. Realization of the operant reflex was accompanied by clearly expressed motivational/affective reactions. The heart rate (HR) in the course of each operant movement sharply dropped (on the 10th day of training, by 12%, on average) with subsequent recovery of this parameter within 3–4 sec. In the course of 30-min-long training sessions, the mean HR gradually decreased (in the examined group, 7%, on average) within an interval from the 5th to the 20th min with subsequent recovery until the end of the training session. The mean numbers of Fos-ir neurons in the medullary nuclei of the ANS (Sol, IRt, CVL, RVL, Amb, 10, and MdD) of rats performing food-procuring movements (n = 4) were significantly (P < 0.05) greater than those in the control, and the intensities of c-fos expression in these structures corresponded to the following succession: Sol > IRt > CVL+RVL/CVL > RVL. Large Fos-ir neurons were observed in the dorsal motor nucleus of the n. vagus (10) and in the Amb/RAmb nuclei. In a considerable proportion of neurons of the Sol and single cells of the 10 and Amb, we observed double labeling (Fos-ir + NADPH-dr). Thus, operant food-procuring movements are accompanied by episodes of bradycardia related to each separate realization; in addition, a long-lasting tonic decrease in the HR developed. These autonomic reactions are mediated by the abovementioned medullary ANS nuclei. It is supposed that the respective weakening of inhibitory sympathetic effects on spindle receptors of the muscles involved in realization of the above operant movements can provide facilitation of generation of proprioceptive impulsation, facilitation of monosynaptic spinal reflexes, and, finally, an increase in the efficacy of targeted limb movements directed toward food procurement.     

A metabonomic study of inhibition of GABA uptake in the cerebral cortex

GABAergic activity is regulated by rapid, high affinity uptake of GABA from the synapse. Perturbation of GABA reuptake has been implicated in neurological disease and inhibitors of GABA transporters (GAT) have been used therapeutically but little detail is known about the ramifications of GAT inhibition on brain neurochemistry. Here, we incubated Guinea pig cortical tissue slices with [3-¹³C]pyruvate and major, currently available GABA uptake inhibitors. Metabolic fingerprints were generated from these experiments using ¹³C/¹H NMR spectroscopy. These fingerprints were analyzed using multivariate statistical approaches and compared with an existing library of fingerprints of activity at GABA receptors. This approach identified five distinct clusters of metabolic activity induced by blocking GABA uptake. Inhibition of GABA uptake via GAT1 produced patterns similar to activity at mainstream GABAergic synapses in particular those containing α1-subunits but still statistically separable. This indicated that inhibition of GABA uptake, an indirect method of activating GABA receptors, produces different effects to direct receptor activation or to exogenous GABA. The mechanism of inhibitor function also produced different outcomes, with the channel blocker SKF 89976A yielding a unique metabolic response. Blocking GAT1 and GAT3 simultaneously induces a large metabolic response consistent with induction of tonic inhibition via high affinity GABA receptors. Blocking BGT produces patterns similar to activity at less common receptors such as those containing α5 subunits. This approach is useful for determining where in the spectrum of GABAergic responses a particular GABA transport inhibitor is effective.     

Background and reflex activity of guinea pig caudal mesenteric ganglion neurons

The background activity of the guinea pig caudal mesenteric ganglion (CMG) neurons and their reflex reactions to colonic distension were studied on isolated combined preparations including the CMG and a colon segment connected with the lumbar colonic nerves. In the control, 62% of the neurons under study generated background activity, which consisted of irregular or regular “fast” excitatory postsynaptic potentials (fEPSP) and action potentials (AP). In 27% of the CMG neurons called “pacemaker-like neurons” (PLN), the background activity was represented by highly regular AP never observed in the CMG completely isolated from the distal colon. Reflex responses evoked by colonic distension were recorded from 76% of the units studied. The distension evoked fEPSP and AP in “silent” neurons and increased the background activity. Both the background activity and reflex responses were shown to be due to nicotinic cholinergic transmission. In some neurons, reflex responses (regular AP) were generated as superimposed on a slow depolarization; the latter was insensitive to nicotinic antagonists and either sensitive or insensitive to muscarinic antagonists. It has been concluded that CMG neurons receive nicotinic, muscarinic, and, probably, peptidergic afferent inputs from the distal colon. Although there are no true pacemaker neurons in CMG, some neurons generate pacemaker-like activity of a synaptic origin.     

Effects of acetylcholine and cholinergic transmission blockers on neuronal spike activity in the cat motor cortex associated with conditioned reflex

The effects of direct application of acetylcholine (ACh) and m- and n-cholinoreceptor blockers on test cells were investigated in waking cats having developed instrumental lever-pressing conditioned reflex. Changes were recorded in both spontaneous and invoked firing activity in a functionally homogeneous group of motor cortex cells, in which increased discharge rate usually preceded the start of conditioned reflex movements. It was found, however, that ACh increased spontaneous activity considerably in some of the neurons tested and reduced it moderately in others. Atropine sharply reduced background activity in cortical neurons while preserving spike response to presentation of a conditioned stimulus and n-cholino-blockers such as hexonium and (occasionally) tubocurarine inhibited spike response produced by conditioned stimuli; background activity was slightly inhibited by hexonium and reinforced by tubocurarine. It was concluded that ACh put out by cholinergic fibers helps to maintain background firing activity level in cortical neurons under naturally occurring conditions, acting via m-cholinoreceptors, whereas factors influencing generation of spike discharges associated with performance of conditioned reflex movements are mediated by n-cholinoreceptors.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 21, No. 5, pp. 579–589, September–October, 1989.     

Modulation of neuronal impulse activity of the anterior hypothalamus as a functional basis of the mechanisms underlying hypothalamic control

We examined the neuronal activity of hypothalamic neurons in acute experiments on cats under ketamine anesthesia. Using glass microelectrodes, we extracellularly recorded the impulse activity (IA) of neurons of the anterior hypothalamus in the absence of controlled influences (background IA, BIA) and after stimulation of evolutionary heterogeneous zones of the brain cortex projecting to the hypothalamus (hippocampal CA3 area, pyriform, cingular, and proreal gyri). Electrical 5-sec-long stimuli were applied with frequencies of 12, 30, or 100 sec⁻¹. In another experimental series, we recorded changes in the IA of hypothalamic neurons induced by visceral stimuli (heating or cooling by 7°C of the foot pad, cooling of the body of the animal, and infusions of 5% glucose, 0.2% NaCl, 3.0% NaCl, or phenylephrine in the carotid artery), modeling in such a way shifts of the constants of homeostasis within physiological limits. We also compared the parameters of neuronal BIA and stimulation-influenced IA in equal epochs of the analysis and classified the types of BIA. About 50% of the cells of the total studied sampling of hypothalamic neurons responded by a considerable modulation of their BIA with a significant change in the frequency in the course of and after stimulations of the above-mentioned modalities. In some neurons after cortical or visceral stimulation, a significant transformation of the temporal structure of the IA with no changes in the mean frequency occurred. We hypothesize that stimulation-induced transformation of the IA pattern with preservation of the mean discharge frequency can be one of the modes of encoding of information necessary for triggering of one efferent reaction or another, which are controlled by the hypothalamus. Examination of the BIA parameters of subcortical neurons, as well as comparison of the parameters of such an activity with the localization of cells and with the modality of stimulation that leads to modification of the IA, should allow one to reveal reasons for the formation and modification of the IA on neurons of the anterior hypothalamus. Since functional peculiarities of the neurons correlate with their BIA pattern, such data can provide an insight into the functional bases of the neurophysiological mechanisms underlying regulatory functions of the hypothalamus. Neirofiziologiya/Neurophysiology, Vol. 37, Nos. 5/6, pp. 463–474, September–December, 2005.     

Physiological and pharmacological properties of responses to GABA and ACh by abdominal motor neurons in Manduca sexta

1. GABA, ACh, and other agents were applied by pressure ejection to the neuropil of the third abdominal ganglion in the isolated nerve cord of Manduca sexta. Intersegmental muscle motor neurons with dendritic arborizations in the same hemiganglion were inhibited by GABA (Fig. 2) and excited by ACh (Fig. 5).
2. Picrotoxin was a potent antagonist of GABA (Fig. 4A). Bicuculline reduced GABA responses in some motor neurons (Fig. 4C), but had no effect on many other motor neurons. Curare reduced ACh responses (Fig. 6A). Bicuculline was an effective ACh antagonist in most motor neurons tested (Fig. 6B).
3. Motor neurons with dendrites across the ganglion from the ejection pipette exhibited different responses to GABA and ACh. Contralateral motor neurons often showed smaller, delayed hyperpolarizing GABA responses (Fig. 7). On two occasions, contralateral motor neurons had excitatory responses (Fig. 8). Contralateral motor neurons were hyperpolarized by ACh (Fig. 9). The inhibitory responses had only slightly longer latencies than ipsilateral excitatory ACh responses (Fig. 10A). The contralateral inhibitory ACh responses, but not the ipsilateral excitatory ACh responses, were eliminated by TTX (Fig. 10B).
4. A model, which includes inhibitory interneurons that cross the ganglionic midline to inhibit their contralateral homologs and motor neurons (Fig. 11), is proposed to account for contralateral responses to GABA and ACh and antagonistic patterns of activity of motor neurons during mechanosensory reflex responses.

     

State transitions through inhibitory interneurons in a cortical network model

Inhibitory interneurons shape the spiking characteristics and computational properties of cortical networks. Interneuron subtypes can precisely regulate cortical function but the roles of interneuron subtypes for promoting different regimes of cortical activity remains unclear. Therefore, we investigated the impact of fast spiking and non-fast spiking interneuron subtypes on cortical activity using a network model with connectivity and synaptic properties constrained by experimental data. We found that network properties were more sensitive to modulation of the fast spiking population, with reductions of fast spiking excitability generating strong spike correlations and network oscillations. Paradoxically, reduced fast spiking excitability produced a reduction of global excitation-inhibition balance and features of an inhibition stabilised network, in which firing rates were driven by the activity of excitatory neurons within the network. Further analysis revealed that the synaptic interactions and biophysical features associated with fast spiking interneurons, in particular their rapid intrinsic response properties and short synaptic latency, enabled this state transition by enhancing gain within the excitatory population. Therefore, fast spiking interneurons may be uniquely positioned to control the strength of recurrent excitatory connectivity and the transition to an inhibition stabilised regime. Overall, our results suggest that interneuron subtypes can exert selective control over excitatory gain allowing for differential modulation of global network state.     

Neuroplasticity in nucleus tractus solitarius neurons after episodic ozone exposure in infant primates.

Acute ozone exposure evokes adverse respiratory responses, particularly in children. With repeated ozone exposures, however, despite the persistent lung inflammation and increased sensory nerve excitability, the central nervous system reflex responses, i.e., rapid shallow breathing and decreased lung function, adapt, suggesting changes in central nervous system signaling. We determined whether repeated ozone exposures altered the behavior of nucleus tractus solitarius (NTS) neurons where reflex respiratory motor outputs are first coordinated. Whole cell recordings were performed on NTS neurons in brain stem slices from infant monkeys exposed to filtered air or ozone (0.5 ppm, 8 h/day for 5 days every 14 days for 11 episodes). Although episodic ozone exposure depolarized the membrane potential, increased the membrane resistance, and increased neuronal spiking responses to depolarizing current injections (P < 0.05), it decreased the excitability to vagal sensory fiber activation (P < 0.05), suggesting a diminished responsiveness to sensory transmission, despite overall increases in excitability. Substance P, implicated in lung and NTS signaling, contributed to the increased responsiveness to current injections but not to the diminished sensory transmission. The finding that NTS neurons undergo plasticity with repeated ozone exposures may help to explain the adaptation of the respiratory motor responses.