László Détári

Sleep states alter activity of suprachiasmatic nucleus neurons

The timing of sleep and wakefulness in mammals is governed by a sleep homeostatic process and by the circadian clock of the suprachiasmatic nucleus (SCN), which has a molecular basis for rhythm generation. By combining SCN electrical activity recordings with electroencephalogram (EEG) recordings in the same animal (the Wistar rat), we discovered that changes in vigilance states are paralleled by strong changes in SCN electrophysiological activity. During rapid eye movement (REM) sleep, neuronal activity in the SCN was elevated, and during non-REM (NREM) sleep, it was lowered. We also carried out selective sleep deprivation experiments to confirm that changes in SCN electrical activity are caused by changes in vigilance state. Our results indicate that the 24-hour pattern in electrical activity that is controlled by the molecular machinery of the SCN is substantially modified by afferent information from the central nervous system.

The role of basal forebrain neurons in tonic and phasic activation of the cerebral cortex

The basal forebrain and in particular its cholinergic projections to the cerebral cortex have long been implicated in the maintenance of cortical activation. This review summarizes evidence supporting a close link between basal forebrain neuronal activity and the cortical electroencephalogram (EEG). The anatomy of basal forebrain projections and effects of acetylcholine on cortical and thalamic neurons are discussed along with the modulatory inputs to basal forebrain neurons. As both cholinergic and GABAergic basal forebrain neurons project to the cortex, identification of the transmitter specificity of basal forebrain neurons is critical for correlating their activity with the activity of cortical neurons and the EEG. Characteristics of the different basal forebrain neurons from in vitro and in vivo studies are summarized which might make it possible to identify different neuronal types. Recent evidence suggests that basal forebrain neurons activate the cortex not only tonically, as previously shown, but also phasically. Data on basal forebrain neuronal activity are presented, clearly showing that there are strong tonic and phasic correlations between the firing of individual basal forebrain cells and the cortical activity. Close analysis of temporal correlation indicates that changes in basal forebrain neuronal activity precede those in the cortex. While correlational, these data, together with the anatomical and pharmacological findings, suggest that the basal forebrain has an important role in regulating both the tonic and the phasic functioning of the cortex.

Firing properties of cat basal forebrain neurones during sleep-wakefulness cycle.

Neuronal activity was studied in the basal forebrain area (BFA) of freely moving cats during wakefulness (W), slow wave sleep (SWS) and paradoxical sleep (PS). Two classically synchronizing and hypnogenic regions, the preoptic area (POA) and the olfactory tubercle (OT) were explored by microelectrodes. Compared to W, the discharge rate in most of the POA cells was not modified or was slightly reduced by SWS, but it was increased by PS. Half of the OT cells increased slightly their firing frequency during falling asleep. A great proportion of OT neurones showed facilitation of activity during PS also, which in half of the cells started already in the last seconds of SWS. The results are discussed from the point of view of the synchronizing and hypnogenic influence attributed to POA and OT.

Phasic relationship between the activity of basal forebrain neurons and cortical EEG in urethane-anesthetized rat

Previous studies have shown that a large number of neurons in the basal forebrain have higher firing rates when the cortical electroencephalogram (EEG) is characterized by low-voltage fast activity compared to states characterized by slow waves. A smaller number of cells with increased discharge rates during slow waves have also been observed. This putative ascending effect is thought to be tonic, but no attempt has been made to analyze a closer temporal correlation between the activity of basal forebrain neurons and the cortical EEG. Recordings were made from single units in the basal forebrain concurrently with the cortical EEG in urethane-anesthetized rats. A total of 52 neurons consistently showed higher firing during low-voltage fast activity (F-cells), whereas 14 neurons were consistently more active during cortical slow waves (S-cells). In most of the F- (90%) and S-cells (86%) the change in firing rate occurred prior to the change in the EEG. The average delay was 300-400 ms. At a deep level of anesthesia, the EEG was characterized by an alternation of flat periods and large waves. Most F-cells became active near the start of the first large wave, which is known to correspond to the onset of depolarization of cortical pyramidal neurons. In contrast, most S-cells were less active during the large waves. These data show that the activity of basal forebrain neurons is phasically correlated with the EEG in addition to the tonic correlation that has been demonstrated previously. Both types of basal forebrain neurons change their firing rate prior to the change in cortical EEG, suggesting that the basal forebrain neurons may have a regulatory influence on the EEG.

Tonic and phasic influence of basal forebrain unit activity on the cortical EEG

Changes in arousal levels are normally accompanied by modification of gross electrical activity (EEG) in the cortex, with low amplitude fast waves characterizing high levels and large slow waves low levels of arousal. These changes in cortical EEG patterns depend mainly on two factors: on the input from the thalamus and on the state of various membrane channels in the cortical pyramidal cells, which are both regulated by ascending modulatory systems. Several lines of evidence indicate that of the activating systems the cholinergic is the most effective in activating the cortex. Its blockade with atropine induces large slow waves in the EEG, while inhibition of other systems has no such profound effect. The effect of atropine can be mimicked by lesioning the basal forebrain. Neurons in this area show very close tonic and phasic correlation with the cortical EEG, further supporting the suggestion that projections of these neurons have a special role in the regulation of cortical activity. However, there is a discrepancy between the effects of excitotoxic and selective cholinotoxic lesions of the basal forebrain. The immunohistochemical diversity of the corticopetal basal forebrain projection and the electrophysiological heterogeneity of the neurons also indicate that, in addition to cholinergic cells, other types of neurons do also participate in the regulation of cortical activity from this area. To understand the intimate details the activity of identified basal forebrain neurons must be recorded and correlated with cortical events.

Neuronal firing in the pallidal region: firing patterns during sleep-wakefulness cycle in cats.

Neuronal activity was investigated by extracellular microelectrodes in the pallidal region of freely moving cats during wakefulness (W), slow-wave sleep (SWS) and paradoxical sleep (PS). The firing of 150 units from 35 points was examined. On the basis of the modifications of firing rates and patterns during the sleep-wakefulness cycle, 5 groups of neurons were distinguished. Two of these groups were characterized by strong increase of firing rate in W and PS and in one of them this increase preceded the cortical activation at the SWS-PS transition by an average of 26 sec. The role played by the basal forebrain area in the regulation of the sleep-wakefulness cycle is discussed.

Circadian rhythm in light response in suprachiasmatic nucleus neurons of freely moving rats.

Long-term recordings of single SCN units were performed in freely moving rats simultaneously with multiunit recordings and evidence is presented for a daily change in light-responsiveness. SCN light response is high during the night and low during the day. We conclude that this difference is caused by a change in sensitivity, with higher sensitivities at night. Moreover, we demonstrate that the circadian rhythm in SCN light response is the result of the integrated behaviour of similarly behaving single SCN units.

Responses of Cortical EEG‐related Basal Forebrain Neurons to Brainstem and Sensory Stimulation in Urethane‐anaesthetized Rats

The basal forebrain can be considered to be a rostral extension of the ascending reticular activating system. A large number of neurons in the basal forebrain have been shown to display higher firing rates when low‐voltage fast activity is present in the cortical EEG as opposed to states characterized by large slow waves in both unanaesthetized and anaesthetized animals. However, a smaller number of cells with increased discharge rate during slow waves was also observed in most of these studies. While it is likely that these two types of neurons have opposite roles in the regulation of cortical activation, it is not known how they respond to inputs from the brainstem or the periphery. In the present study, extracellular recordings were made in the basal forebrain of urethane‐anaesthetized rats. A total of 52 neurons were studied in which the firing rate was significantly higher during fast cortical EEG waves (F‐cells), and 14 neurons in which activity was significantly greater during slow waves (S‐cells). The two cell types responded differently to stimulation of the pedunculopontine tegmental nucleus (PPT) and dorsal raphe nucleus (DRN) with short (0.5–1 s) trains of pulses and to noxious sensory stimuli (tail pinch). These stimulations excited most F‐cells (80–96%) and inhibited the majority of S‐cells (55–67%). In the few F‐cells that were inhibited by stimulation, the response varied with the background firing rate of the cell: the higher the firing rate at the time of stimulation, the higher the probability of observing an inhibitory response. In contrast, single electrical pulses delivered to the PPT and DRN excited the majority (72%) of both F‐ and S‐cells. Previous in vitro studies have shown that the application of acetylcholine or serotonin has predominantly inhibitory effects on basal forebrain cholinergic neurons. The predominantly excitatory effect of noxious, PPT and DRN stimulation on F‐cells therefore suggests that glutamatergic or other excitatory afferents play a more dominant role in regulating basal forebrain neurons. We have previously shown that F‐cells are more prevalent than S‐cells. In combination, these findings suggest that basal forebrain neurons, and F‐cells in particular, are important in mediating the ascending excitatory drive from the brainstem to the cerebral cortex.

Comparison of spontaneous and evoked epileptiform activity in three in vitro epilepsy models

Rat neocortical slices express spontaneous epileptiform activity after incubation with GABA(A) receptor blocker bicuculline (BIC, 20 microM), with potassium channel blocker 4-aminopyridine (4-AP, 50 microM) or in Mg(2+)-free medium (LMG). Various parameters of spontaneous and evoked epileptiform discharges and their pharmacological sensitivity were analysed using extracellular field potential recordings in this comparative in vitro study. All types of convulsant solution induced spontaneous epileptiform activity, however, the analysed parameters showed that characteristics of epileptiform discharges are rather different in the three models. The longest duration of discharges was recorded in LMG, while the highest frequency of spontaneous events was detected in 4-AP. The epileptiform field responses elicited by electrical stimulation appeared in an all-or-none manner in BIC. On the contrary, in 4-AP and in LMG the amplitude of the responses increased gradually with increasing stimulation intensities. The NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid (APV, 25 microM) abolished the LMG induced spontaneous epileptiform activity and significantly reduced the frequency of the epileptiform discharges in BIC and 4-AP. Blocking the AMPA type of glutamate transmission with 1-(aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466, 40 microM) rapidly abolished BIC-induced spontaneous epileptiform activity and caused a significant decrease in the frequency of 4-AP induced spontaneous epileptiform discharges. However, it had only a weak effect on the LMG-induced epileptiform activity. We conclude that the contribution of NMDA and AMPA types of glutamate receptors to the development and maintenance of epileptiform activity in cortical cell assemblies is different in the three models. There are significant alterations in contribution of NMDA and AMPA types of glutamate receptors to the above-mentioned processes in the different convulsants. In BIC the synchronisation is mainly due to the altered network properties, namely inhibition is reduced in the local circuits. Although inhibition is reduced in the local circuits, the AMPA receptor antagonist relatively easily blocked the synchronised excitation. In 4-AP, and especially in LMG, changes in the membrane characteristics of neurones play a crucial role in the increased excitability. In this case the AMPA antagonist was less effective.

Morphological characterization of electrophysiologically and immunohistochemically identified basal forebrain cholinergic and neuropeptide Y-containing neurons

The basal forebrain (BF) contains cholinergic as well as different types of non-cholinergic corticopetal neurons and interneurons, including neuropeptide Y (NPY) containing cells. BF corticopetal neurons constitute an extrathalamic route to the cortex and their activity is associated with an increase in cortical release of the neurotransmitter acetylcholine, concomitant with low voltage fast cortical EEG activity. It has been shown in previous studies (Duque et al. in J Neurophysiol 84:1627–1635, 2000) that in anesthetized rats BF cholinergic neurons fire mostly during low voltage fast cortical EEG epochs, while increased NPY neuronal firing is accompanied by cortical slow waves. In this paper, electrophysiologically and neurochemically characterized cholinergic and NPY-containing neurons were 3D reconstructed from serial sections and morphometrically analyzed. Cholinergic and NPY-containing neurons, although having roughly the same dendritic surface areas and lengths, were found to differ in dendritic thickness and branching structure. They also have distinct patterns of dendritic endings. The subtle differences in dendritic arborization pattern may have an impact on how synaptic integration takes place in these functionally distinct neuronal populations. Cholinergic neurons exhibited cortically projecting axons and extensive local axon collaterals. Elaborate local axonal arbors confined to the BF also originated from NPY-containing neurons. The presence of local axon collaterals in both cholinergic and NPY neurons indicates that the BF is not a mere conduit for various brainstem inputs to the cortex, but a site where substantial local processing must take place.