Invited Symposium: Role of the Basal Forebrain Neurons in Cortical Activation and Behavioural State Regulation


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Tonic and Phasic Influence of Basal Forebrain Unit Activity on the Cortical EEG

Contact Person: Laszlo Detari (detarineu@ludens.elte.hu)

Cortical EEG reflects vigilance level

In addition to sensory and motor functions, regulation of the vigilance level, the alternation of sleep and wakefulness is probably the most basic brain function that all of us experience every day. Electric activity of the cerebral cortex (EEG) changes characteristically during transitions from one vigilance level to the other. Mechanisms of these EEG waves are more or less well understood now. EEG reflects the sum of membrane potential changes in cortical pyramidal cells forming a layer of dipoles aligned in parallel with each other. Simultaneous changes in a large number of neurons sum up causing large EEG waves, while their asynchronous occurrence results in low voltage fast waves. The membrane potential changes are brought about by synaptic inputs, but endogenous ion currents, e.g. long afterhyperpolarizations following bursts of spikes (Buzsáki and Traub, 1997) may also contribute.

The most important external source of synaptic input to the cortex is the thalamus. It has been shown that due to the presence of special ion currents in the membrane of thalamic neurons and to the interconnections between thalamic reticular and relay cells the thalamus can work in two different modes (for a recent review see McCormick and Bal, 1997). In the oscillatory mode, rhythmic bursts of spikes are generated by the thalamic relay cells due to the internal characteristics of the thalamic neurons and networks. Transmission of sensory information is attenuated. In the transfer mode, relay cells are depolarized close to spike threshold and sensory information can easily pass through the thalamus to the cortex. The transfer mode corresponds to low voltage fast waves in the EEG, while the rhythmically arriving thalamic bursts in the oscillatory mode induce large potential changes in the pyramidal cells in the alpha-, and theta-ranges.

Switching between the two modes of the thalamus depends on the membrane potential of the reticular and relay cells. The low-threshold Ca-spike mechanism, necessary for the generation of the rhythmic bursts, is inactivated at the resting or slightly depolarized membrane potential level. For its deinactivation mild hyperpolarization is needed which develops with the withdrawal of the ascending activating affects as the vigilance level decreases during drowsiness. A similar decrease of the activating effects in the cortex enables low-threshold Ca-spike mechanisms and ion currents producing long afterhyperpolarizations in the pyramidal cells. These changes contribute to the development of spindle oscillations in the EEG. At an even lower level of ascending activation, delta-waves are generated mainly cortical, but partly also by thalamic mechanisms in a less well understood manner. It has been recently suggested that all these waveforms are grouped into complex sequences by a cortically generated slow oscillation built up by the alternation of prolonged depolarizations and hyperpolarizations (Steriade and Amzica, 1998).

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Cholinergic projection is the most important activating system

There are several ascending transmitter systems that promote transfer mode in the thalamus and enhance cortical activation. Cholinergic, noradrenergic, serotoninergic neurons from the brainstem, histaminergic neurons from the posterior hypothalamus and both cholinergic and GABAergic neurons from the basal forebrain project to the thalamus and to widespread areas of the cortex. All these projections are capable to induce activation (McCormick, 1992), but it seems, that the cholinergic one is of outmost importance. This claim is supported by several observations.

  1. Systemic administration of muscarinergic antagonists (atropine or scopolamine) induces large slow waves very similar to delta waves seen during deep sleep. In rats, these waves temporarily disappear during voluntary behaviors, but it is the only system that maintains cortical activation during quiet wakefulness (Vanderwolf and Robinson, 1981).
  2. During REM sleep noradrenergic, serotoninergic, histaminergic systems are all silent (Steriade and McCarley, 1990; McCormick, 1992) and the cholinergic one alone is sufficient to induce and maintain a very strong activation.
Of the two components of the cholinergic activating system it seems that the basal forebrain part is more important than its brainstem counterpart.
  1. Restricted excitotoxic lesions in the basal forebrain result in slowing of the EEG limited to that part of the cortex, which received its innervation from the damaged area (Buzsáki et al., 1988).
  2. Similarly, lesioning of the basal forebrain in one side of the brain leads to asymmetric cortical EEG: large waves on the lesioned side and normal EEG contralaterally in quiet wakefulness. (Stewart et al., 1984)
  3. At last, in a recent study basal forebrain infusion of serotonin inhibited fast cortical activity and induced similar dissociation between EEG and behavior as atropine with delta waves present in wakefulness in half of the animals examined (Cape and Jones, 1998). Serotonin has been shown to inhibit cholinergic cells in vitro (Khateb et al., 1993).
The fact that these manipulations are able to induce their effects while all other activating systems including brainstem cholinergic system and thalamocortical as well as cortico-cortical connections remain intact and functioning clearly indicates the importance of the basal forebrain cholinergic system.

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The cholinergic system has tonic and phasic influence on EEG

Recording of unit activity from the basal forebrain further corroborates the importance of the cholinergic projection in the induction and maintenance of cortical activation. Basal forebrain neurons displaying a very strong, 4-5-fold activation during cortical activation compared to periods when slow waves are present in the cortex were found in freely moving cats (Détári et al., 1987), rabbits (Whalen et al., 1994) and anesthetized rats (Détári and Vanderwolf, 1987) as well. It has to be admitted however, that the cholinergic nature of these neurons has not been proved directly. Nevertheless, these cells were recorded from that part of the basal forebrain where the large cholinergic cells are abundant, and these neurons should increase their firing considerably during low voltage fast cortical activity. Acetylcholine release in cortex has been shown to greatly increase during cortical activation (Kanai and Szerb, 1965) and the basal forebrain is practically the only source of this transmitter in the cortex. In addition, in some cases indirect proofs - such as the antidromic activation from the cortex, or the ability to produce short, high frequency bursts - also support the cholinergic nature of the recorded neurons. High frequency bursts were found in basal forebrain slices exclusively in cholinergic neurons (Alonso et al., 1996). Cortical projection was accepted until recently as an almost unequivocal proof for the cholinergic nature of a basal forebrain cell, at least in the neocortically projecting part of this area (Woolf et al., 1983; Wahle et al., 1984).

In view of the prominent role of the basal forebrain cholinergic system in the tonic modulation of the thalamocortical activity, it can be expected that this projection has strong phasic influence on the EEG as well. Following the description of the Ca-spike mechanism in identified cholinergic cells in vitro (Khateb et al., 1992) it was suggested that the short rhythmic bursts could participate in the generation of different EEG patterns. However, there are relatively few studies analyzing the phasic correlation between basal forebrain unit activity and cortical EEG. Nunez (1996) reported in urethane anesthetized rats that basal forebrain neurons displaying fast bursts during slow waves fired preferentially during positive EEG peaks. It was suggested that the bursts were induced in the supposedly cholinergic cells by cortical input despite fact that there is only a very limited projection from the cortex to the basal forebrain.

In another study in urethane anesthetized rats (Détári et al., 1997), a group of basal forebrain neurons (52 out of 169) were shown to be activated with an average time lag of about 400 ms before low voltage fast activity developed in the cortical EEG. The correlation was especially strong when few-second long epochs of slow waves and fast waves alternated rhythmically. The same neurons were also activated during the active period of the "burst-suppression" pattern that developed at the deepest level of anesthesia. It was concluded that these neurons were probably cholinergic and their short-term activity changes strongly influenced cortical activity and EEG.

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Some well-known EEG events might have cholinergic background

Both EEG phenomena described in the previous paragraph had similar repetition rate as the slow cortical oscillation, which was claimed to group other waveforms generated by the thalamus and cortex (see above). The source of this oscillation was suggested to be in the cortex as it persisted following thalamic lesions (Steriade et al., 1993b). An alternate possibility is however that the rhythmic depolarizing-hyperpolarizing sequences are caused in the cortex by a fluctuation of the basal forebrain cholinergic input. This possibility is supported by the fact that firing changes in the basal forebrain preceded the EEG changes when epochs of slow waves and fast waves alternated in the urethane-anesthetized rats (Détári et al., 1997). While it could not be established whether changes in neuronal firing preceded EEG changes during "burst-suppression" as well, there is only a limited projection from the cortex to the basal forebrain, thus it is improbable that changes in basal forebrain unit activity were induced by cortical events. A further possibility is that the ultimate source of the slow oscillation resides in the brainstem ascending systems reaching the basal forebrain and the cortex via the thalamus through parallel pathways. However, in that case it should persist in the thalamus after cortical lesions, but it disappears in decorticated animals (Timofeev and Steriade, 1996).

Rhythmic hyperpolarizations in the cortex have been completely or partially explained by a non-synaptic increase of K+-conductance (Metherate and Ashe, 1993; Steriade et al., 1993a) Acetylcholine blocks at least three K+-currents in the cortex through muscarinergic mechanisms. In addition, muscarinergic mechanisms might also influence the membrane potential of cortical pyramidal cells by activating a nonselective cation current (Haj-Dahmane and Andrade, 1996). In either case, fluctuations of neuronal activity in cholinergic basal forebrain neurons can rhythmically depolarize and hyperpolarize cortical neurons. Basal forebrain cholinergic cells are able to produce complex bursting in vitro with a frequency closely matching that of the slow cortical rhythm (Alonso et al., 1994) further supporting the assumption that they participate in the generation of this EEG phenomenon.

There are other phasic EEG events in which the contribution of a cholinergic mechanism can be suggested. For example, it was shown that basal forebrain neurons in monkeys, trained in an operant conditioning situation, started to respond to neutral stimuli if they became important because of their association with the delivery of reward (Richardson and DeLong, 1988). The appearance of a prominent event related potential peak (ERP) P300 has similar prerequisite (Squires et al., 1975). The peak, which was described both in humans and animals, can be seen in responses to rare target stimuli that are important for the subject even if their physical parameters differ only slightly from those of the more frequent neutral stimuli. The latency of the basal forebrain activation was 150-200 ms in the monkey experiments, which is in good agreement with the latency of the P300 if the slow action of the muscarinergic transmission is also taken into account. P300 is abolished by scopolamine and in a recent paper electrolytic lesion of the basal forebrain in rabbits have also been shown to eliminate this peak (Wang et al., 1997). All these data suggest that cholinergic mechanisms may participate in the generation of this ERP peak.

To summarize, the basal forebrain cholinergic system has a strong tonic and phasic influence on the functioning and on the electrical activity of the cortex. Changes in the activity of these neurons through the consequent modification in cortical acetylcholine release can participate in the generation of several short term EEG phenomena. Analysis of these possibilities can give further insight into the functions of the cholinergic system in the regulation of wakefulness and cognitive processes.

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Detari, L.; (1998). Tonic and Phasic Influence of Basal Forebrain Unit Activity on the Cortical EEG. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/semba/detari0367/index.html
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