Modulation of Inhibitory Synaptic Transmission in the Cat Motor Cortex Related to Realization of an Operant Reflex Evoked by a Complex of Stimuli

In non-anesthetized cats, we examined the effects of iontophoretic microinjections of GABA, a blocker of GABAergic synaptic transmission, and modulators of noradrenergic transmission on impulse activity (IA) generated by motor cortex neurons in the course of realization of an operant motor reflex to the action of a complex of stimuli (warning and imperative ones). We tried to elucidate the role of different membrane receptors in modulation of spiking of cortical neurons. Microiontophoretic applications of GABA and noradrenaline resulted in decreases in the frequency of background IA of cortical neurons and suppression of their reactions related to realization of the operant reflex. The use of selective adrenoactive substances showed that applications of an α1 agonist, Mezaton, suppressed background spiking and impulsation generated within an interspike interval and in the course of the movement. An α2 blocker, yohimbine, exerted an opposite effect; the neuronal IA was intensified within the background period and other examined time intervals. There are reasons to believe that noradrenergic modulation of IA of cortical neurons is realized via direct effects on pyramidal neurons and also indirectly, through changes in the activity of inhibitory cortical interneurons.     

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 noradrenaline on neuronal response induced in the motor cortex by conditioned stimuli

In chronic experiments on cats, the effects were investigated of iontophoretic application of the adrenomimetic ephedrine and the -blocker obsidan (propranolol) on neuronal response induced in the motor cortex by conditioned stimulus presentation during performances of instrumental lever-pressing response. Inhibition of background firing activity and response in most neurons induced by conditioned stimuli was produced by ephedrine, whereas obsidan application enhanced this activity. It was concluded that steady, tonic inhibitory action of the noradrenergic system on background and induced firing activity in cortical neurons takes place during free-ranging behavior. Temporary reinforcement of noradrenergic influences could be an important element in mechanisms of external inhibition during stressful situations, aversive effects, and distractive stimuli.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 22, No. 5, pp. 680–688, September–October, 1990.     

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.     

Modulating Action of an α2Adrenoreceptor Agonist,Clonidine, on Neuronal Activity and Synaptic Transmission in the Rat Prefrontal Cortex

We studied the action of an α2-adrenoreceptor agonist, clonidine, on impulse activity of neurons of the prefrontal cortex (FRA; the cortical region playing an important role in cognitive processes). The background activity of such neurons and their responses to stereotaxic stimulation of the mediodorsal thalamic nucleus, MDM, directly projecting to FRA were recorded. Clonidine was applied microiontophoretically (50 mM, currents 5 to 40 nA, duration 20 to 30 sec). Applications of clonidine exerted ambivalent effects. A predominantly inhibitory action was manifested at small doses of the agent (currents about 5 nA). The frequency of background activity generated by FRA neurons and reactions of the latter to stimulation of afferent inputs from the thalamic nucleus decreased. With increase in the dose (currents 20-30 nA), the inhibitory effect of clonidine was usually replaced by excitation. These findings may help in the interpretation of a possible mechanism of psychopathological symptoms frequently observed when using α2-adrenoreceptor agonists in the treatment of drug addictions; these results emphasize the necessity of accurate selection of effective doses of such agents.     

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.     

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.     

Role of Alpha-Adrenoreceptors in Cerebello-Cortical Transmission in the Rat

We studied the role of alpha-adrenoreceptors (AR) in the modulation of evoked neuronal activity in the primary motor cortex (PMC). Neurons receiving afferent inputs from the cerebellum were examined using a microiontophoretic technique. Activation of alpha-AR with octopamine resulted in most units (71%) on the intensification of background firing and in a prominent rise (in a dose-dependent manner) in the responsiveness of PMC neurons to stimulation of the superior cerebellar peduncle (SCP). A selective postsynaptic alpha1 antagonist, prazosin, evoked significant dose-dependent suppression of the background and evoked activity in 84% of the tested neurons. A selective presynaptic alpha2 antagonist, yohimbine, provided diverse effects. Its application exerted an excitatory effect in 50% of the studied neurons; however, in 33% of the cells qualitatively opposite alterations were observed: in low doses yohimbine increased the neuronal activity, but in high doses suppressed it. Our findings demonstrate the essential role of alpha-AR in the modulation of cerebro-cortical transmission and suggest their considerable involvement in motor functions.     

Alpha-1 Adrenergic Receptors in the Medial Preoptic Area are Involved in the Induction of Sleep

This paper reviews the recent studies that led to the conclusion that the noradrenergic neurons projecting to the medial preoptic area (mPOA) are hypnogenic and that they mediate this action through α₁ adrenergic receptors. Microinjection of noradrenaline (NA) into the mPOA induced arousal. Studies using α₂ adrenergic drugs showed that the arousal induced by intrapreoptic injection of NA was due to its action on presynaptic α₂ adrenergic receptors. A combination of lesion and chemical stimulation techniques demonstrated that when NA acted on the postsynaptic α₁ receptors in the mPOA, it induced sleep. Intrapreoptic injection of α₁ agonist, methoxamine could induce sleep, when the hypothermia, which was simultaneously produced, was behaviorally compensated for by the animal. Increased arousal produced by the destruction of noradrenergic fibers in the mPOA further confirmed the hypnogenic role of these fibers.     

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.     

Activity of sensorimotor cortex neurons during a dopaminergic transmission block in cats performing conditional reflex

Activity of sensorimotor cortex neurons was recorded in chronic experements on cats trained to perform instrumental conditional reflex; records were made before, during, and after isolated iontophoretic applications of haloperidol or glutamate, or their combined application. Haloperidol was shown either to facilitate or to inhibit the background and evoked (related to acoustic stimulation and motor response) spike activity of cortical neurons. Aftereffects of haloperidol were observed too; they were still expressed 10–15 min after the cessation of the iontophoresis. Combined haloperidol and glutamate application was followed by a sharp suppression of the evoked responses potentiated earlier by glutamate. An adenylatecyclase system is supposed to mediate the facilitation evoked by glutamate application. Some modulators, including dopamine, probably activate adenylatecyclase and in this way ensure facilitation of the glutamate-induced responses.Neirofiziologiya/Neurophysiology, Vol. 26, No. 5, pp. 347–355, September–October, 1994.     

Heterogeneity of neuronal nicotinic acetylcholine receptors: Structural and functional aspects

Decay kinetics of the postsynaptic excitatory currents (EPSC), distribution of the antibodies specific to different α-subunits of neuronal nicotinic acetylcholine receptors (nAChR), and the effects of these antibodies on ACh-induced membrane currents were studied in neurons of different autonomic ganglia of rats. It was shown that α3-, α5- and α7-subunits were present in all studied cultured neurons of the rat superior cervical ganglion (SCG), while the α4-subunit was present only in about half of the neurons; this α-subunit distribution differed from that in cultured intracardial neurons of rats. Two nAChR populations were found in rat SCG neurons, and a series of nAChR populations were found in murine superior mesenteric ganglion neurons; they differed in kinetics of their ion channel activity, voltage dependence and the rate of their open channel blockade. The possible functional role of neuronal nAChR heterogeneity is discussed.     

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.     

Activation of neurons of zone A5 of the rat brain upon hypoxic and thermonociceptive stimulation and switching off of the central respiratory generator

We recorded spike activity of noradrenergic neurons of zone A5 (n = 89) in the brain of anesthetized rats under conditions of hypoxic stimulation (breathing with pure N₂, 10 sec), thermonociceptive stimulation (tail-flick test), and reversible hypothermal blocking of the central respiratory activity. Hypoxic stimulation of peripheral O₂-sensitive chemoreceptors considerably increased the discharge frequency in all the examined neurons and induced tachypnea and a hypotensive reaction. Sixty-nine (77.5%) neurons of the studied group were tested using nociceptive stimulation (thermal stimulation of the tail); such stimulation resulted in a multifold increase in their discharge frequency. This was accompanied by tachypnea and a hypertensive response. Thus, we first demonstrated the role of nociception in the control of activity of noradrenergic neurons in zone A5 and the role of nociceptive afferent signals in the modulation of functions of the respiratory and cardiovascular systems mediated by neurons of the above zone. Under conditions of blocking of the central respiratory activity, we examined 36 (40.4%) neurons of zone A5 and first observed the effect of strong activation of a significant proportion of these cells upon switching off of respiration. This fact shows that there is an activating “respiratory” drive on neurons of zone A5 (probably, from the side of an expiratory neuronal population of the respiratory center) and allows us to hypothesize on the genesis of “respiratory” modulation of these cells. The activity of 16 (18.0%) cells was recorded under conditions of consecutive applications of the above stimuli; all the neurons were activated by the respective afferent influences. The simultaneously induced effects of hypoxic and nociceptive stimulations on the activity of neurons of zone A5 were additive. Thus, we first obtained proofs in favor of the multimodality of noradrenergic neurons of the above zone. This feature is a significant factor providing integrative interaction between the respiratory and cardiovascular systems and the system of nociception. Neirofiziologiya/Neurophysiology, Vol. 38, No. 4, pp. 305–313, July–August, 2006.     

Responses of motor cortex neurons of the cat to auditory stimulation and their role in the instrumental food reflex

The responses of motor cortex neurons in the cat to the presentation of a single auditory click and a series of 10 clicks presented with 1,000/sec frequency were studied under conditions of chronic experiments before and after the development of an instrumental food reflex. After reflex development a single presentation of a positive conditioned stimulus (single click) markedly influenced for 7 sec the appearance of instrumental movements. At the same time, the immediate responses of motor cortex neurons to presentation of the conditioned auditory stimulus had no impact on the appearance in the motor cortex of discharges leading to the realization of instrumental movements. Consequently, motor cortex neurons do not require activation from afferent sensory inputs for the generation of such discharges. The immediate neuronal responses to conditioned stimulation did not inhibit the realization of the instrumental reflex. It is proposed that they are associated with the realization of motor function in the unconditioned defensive response evoked by the presentation of an auditory stimulus. The presence or absence of responses to auditory conditioned stimulation was dependent upon the signal meaning of the stimulus, its physical parameters, and the degree of excitability of the animal.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 17, No. 4, pp. 539–550, July–August, 1985.     

Effects of Bemitil on the Activity of Noradrenergic and Serotonergic Brainstem Neurons and on EEG of Awake Cats

In experiments on five awake cats, we studied the effects of bemitil, a drug possessing psychostimulatory, antidepressive, and actoprotector properties (peroral introduction, 50 mg/kg), on the activity of neurons of the aminergic cerebral systems. Eleven noradrenergic (NA-ergic) neurons of the locus coeruleus (LC) and 11 serotonergic (ST-ergic) neurons of the nuclei raphe (NR) were examined. A control experimental series was carried out on 8 NA-ergic neurons of the LC and 8 ST-ergic neurons of the NR. Bemitil was found to exert opposite effects on the impulse activity of NA-ergic and ST-ergic brainstem neurons; it suppressed impulsation of LC neurons and increased the spiking frequency of NR neurons within certain time intervals after its introduction. Analysis of EEG showed that bemitil decreased the spectral power of the delta and theta activities, which was accompanied by behavioral relaxation. Neirofiziologiya/Neurophysiology, Vol. 37, No. 3, pp. 235–243, May–June, 2005.     

Organization of neocortical neuronal networks

Multiple unit activity in deep layers of the frontal and motor cortices was recorded by chronically implanted semimicroelectrodes in waking cats with different levels of food motivation. From four to seven neuronal spike trains were selected from the recorded multiunit activity. Interactions between neighbouring neurons in the motor and frontal areas of the neocortex (within the local neuronal networks) and between the neurons of these areas (distributed neuronal networks) were estimated by means of statistical crosscorrelation analysis of spike trains within the range of delays from 0 to 100 ms. Neurons in the local networks were divided in two subgroups: the neurons with higher spike amplitudes with the dominance of divergent connections and neurons with lower spike amplitudes with the dominance of convergent connections. Strong monosynaptic connections (discharges with a delay of less than 2 ms) between the neurons with high- and low-amplitude spikes formed the background of the local networks. Connections between low-amplitude neurons in the frontal cortex and high-amplitude neurons in the motor cortex dominated in the distributed networks. A 24-hour food deprivation predominantly altered the late interneuronal crosscorrelations with time delays within the range of 2-100 ms in both local and distributed networks.     

GABAA receptor diversity and pharmacology

Because of its control of spike-timing and oscillatory network activity, γ-aminobutyric acid (GABA)-ergic inhibition is a key element in the central regulation of somatic and mental functions. The recognition of GABA_A receptor diversity has provided molecular tags for the analysis of distinct neuronal networks in the control of specific pharmacological and physiological brain functions. Neurons expressing α₁GABA_A receptors have been found to mediate sedation, whereas those expressing α₂GABA_A receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic α₅GABA_A receptors. In addition, neurons expressing α₃GABA_A receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. Finally, during the postnatal development of the brain, the maturation of GABAergic interneurons seems to provide the trigger for the experience-dependent plasticity of neurons in the visual cortex, with α₁GABA_A receptors setting the time of onset of a critical period of plasticity. Thus, particular neuronal networks defined by respective GABA_A receptor subtypes can now be linked to the regulation of various clearly defined behavioural patterns. These achievements are of obvious relevance for the pharmacotherapy of certain brain disorders, in particular sleep dysfunctions, anxiety disorders, schizophrenia and diseases associated with memory deficits.     

Redundant information encoding in primary motor cortex during natural and prosthetic motor control

Redundant encoding of information facilitates reliable distributed information processing. To explore this hypothesis in the motor system, we applied concepts from information theory to quantify the redundancy of movement-related information encoded in the macaque primary motor cortex (M1) during natural and neuroprosthetic control. Two macaque monkeys were trained to perform a delay center-out reaching task controlling a computer cursor under natural arm movement (manual control, ‘MC’), and using a brain-machine interface (BMI) via volitional control of neural ensemble activity (brain control, ‘BC’). During MC, we found neurons in contralateral M1 to contain higher and more redundant information about target direction than ipsilateral M1 neurons, consistent with the laterality of movement control. During BC, we found that the M1 neurons directly incorporated into the BMI (‘direct’ neurons) contained the highest and most redundant target information compared to neurons that were not incorporated into the BMI (‘indirect’ neurons). This effect was even more significant when comparing to M1 neurons of the opposite hemisphere. Interestingly, when we retrained the BMI to use ipsilateral M1 activity, we found that these neurons were more redundant and contained higher information than contralateral M1 neurons, even though ensembles from this hemisphere were previously less redundant during natural arm movement. These results indicate that ensembles most associated to movement contain highest redundancy and information encoding, which suggests a role for redundancy in proficient natural and prosthetic motor control.