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


Section 1

Section 2

Section 3

Section 4

Section 5


INABIS '98 Home Page Your Session Symposia & Poster Sessions Plenary Sessions Exhibitors' Foyer Personal Itinerary New Search

The basal forebrain cholinergic system: direct cortical activator and mediator of activation induced by excitation of secondary brain systems

Contact Person: C. Dringenberg (dringenb@psyc.queensu.ca)

Cholinergic projections as EEG activator

Electrophysiologists in the first quarter of the 20th century observed that extracellular field potentials generated by neocortical neurons show characteristic changes that correlate tightly with the behavioral state in humans and experimental animals: often, active waking states seemed to be associated with high frequency, low amplitude activity patterns, while sleep appeared to be accompanied by a pattern of low frequency, high amplitude activity (1).

Subsequent work has focused on developing a more complete understanding of the neuroanatomical and neurochemical systems that produce different types of electroencephalographic activity and especially the waking-related activated, desynchronized state of cortical processing. Classic experiments by Moruzzi and Magoun (2) suggested that an ascending system originating in the brainstem reticular formation plays a critical role in the induction of cortical activation. However, Moruzzi and Magoun did not specify which neurotransmitters may be involved in mediating the interaction between the ascending reticular projection system and its target neurons in the neocortex.

In 1965, Kanai and Szerb (3) published experiments, subsequently replicated by Herbert Jasper and others (4) demonstrating that the release of acetylcholine (ACh) from the cortex of experimental animals is tightly linked to the state of the electroencephalogram (EEG): ACh release is high during periods of EEG activation and decreases during periods of synchronized, deactivated EEG activity. These data confirmed pharmacological evidence indicating that EEG activation can be induced by cholinergic agonists, and reduced or abolished by cholinergic antagonists (5). In addition, Kanai and Szerb’s work (3) showed that ACh may promote activation by a local, direct action on cortical neurons, rather than by stimulating other subcortical brain regions that, in turn, act as a final effector in the induction of activation.

Interestingly, Kanai and Szerb (3) used electrical stimulation of the brainstem reticular formation to modulate EEG activity and ACh release during their experiments. The fact that this reticular stimulation induced activation and concurrent ACh release appeared to suggest that there is an ascending cholinergic pathway to cortex, originating perhaps in the brainstem, that permits the widespread release of ACh in cortex, thus inducing EEG activation. However, anatomical studies that employed selective markers for cholinergic neurons (the enzymes acetylcholinesterase or choline acetyltransferase) demonstrated that there are no substantial cholinergic brainstem-cortical projections that could account for the diffuse, widespread release of ACh in cortex during EEG activation. Rather than in the brainstem, the cholinergic innervation of the cortical mantle originates in cell groups of the basal forebrain that include the substantia innominata, globus pallidus, and nucleus basalis (6). Electrical stimulation of the basal forebrain mimics the effects of reticular stimulation to induce cortical ACh release and EEG activation; the EEG effect, but not the release of ACh, is abolished by blocking cortical cholinergic-muscarinic receptors (7). These data, together with additional evidence from basal forebrain lesion experiments, suggest that the intracortical release of ACh is directly involved in producing cortical activation by a local action on cortical neurons. Further, given the lack of substantial midbrain-cortical cholinergic projections, it now appears that the ACh release and EEG activation produced by reticular stimulation is mediated by an excitation of basal forebrain, cortically-projecting ACh neurons, and not by other (direct or indirect) pathways that connect midbrain and cortex.

The hypothesis that ACh exerts a direct, local action on cortical cells to induce EEG activation also receives support from intracellular recording experiments. Synchronized, deactivated EEG activity is related to the appearance of a discontinuous, burst-suppression mode of firing in cortical pyramidal cells (8). Intracellular recordings show that large numbers of cortical pyramidal cells are hyperpolarized during periods of discharge suppression and hyperpolarizing outward currents from these cells summate to produce the large amplitude, low frequency extracellular field potentials typical of synchronized EEG activity (9). Acetylcholine, acting on cortical pyramidal cells, can block the summation of (inhibitory) extracellular currents and the appearance of synchronized EEG waves by: (a) producing membrane depolarizations, possibly by blocking outward potassium currents; (b) increasing the frequency of intracellular membrane oscillations; and (c) reducing inhibitory after-hyperpolarization after discharge (10). These cellular events act to increase neuronal responsiveness and continuous firing in pyramidal cells, and favor the appearance of desynchronized EEG activity.

Back to the top.

Basal forebrain as activation-mediator

As mentioned, a reinterpretation of Kanai and Szerb’s experiments suggests that the EEG activation produced by midbrain stimulation is mediated by an excitation of the basal forebrain ACh input to the cortex, rather than by other pathways between midbrain and cortex. Recent experiments have shown that, indeed, the basal forebrain functions as a ‘final common pathway’ through which other brain systems can act to modulate cortical EEG activity indirectly.

Electrical or chemical stimulation of numerous sites outside the midbrain reticular formation or cholinergic basal forebrain (e.g. amygdala, locus coeruleus, orbitofrontal and cingulate cortex, superior colliculus) can induce cortical activation in anesthetized preparations (11 for review). However, activation induced by stimulation of many of these sites (amygdala, locus coeruleus, orbitofrontal cortex) is abolished by systemic treatment with muscarinic antagonists (12), suggesting that these activating responses also depend critically on the central cholinergic system (peripheral antimuscarinics are not effective). Subsequent experiments supported this hypothesis by showing that: (a) activation induced by amygdala stimulation is abolished by inactivation of the basal forebrain (by local lidocaine infusions), and (b) many basal forebrain cells that contribute to activation (as suggested by their higher discharge rates during activation relative to EEG synchronization) are excited by electrical stimulation of the amygdala or locus coeruleus area (12).

Further, basal forebrain cells that do not appear to contribute to activation (i.e. that discharge at higher rates during synchronization relative to activation) are often inhibited by amygdala or locus coeruleus stimulation (12). The fact that infusions of noradrenaline into the basal forebrain promote cortical activation (13) supports the notion that the locus coeruleus-noradrenergic system produces activation through the basal forebrain cholinergic system, rather than through direct noradrenergic projections to cortex. Excitation of basal forebrain neurons is also produced by stimulation of the brainstem core (pedunculopontine and dorsal raphe nuclei; 14), further implicating the basal forebrain as a mediator of EEG activation induced by stimulation of the midbrain reticular system. Together these data suggest that several brain systems known to induce EEG activation appear to do so by acting through the basal forebrain cholinergic system, rather than by their direct efferent connections to cortex; the fact that muscarinic antagonists completely abolish activation produced by stimulation of many forebrain and brainstem sites is consistent with this hypothesis.

Results consistent with those outlined above have been obtained with biochemical studies that measure the release of ACh in cortex. Dopaminergic receptor blockade can decrease the release of ACh in cortex, while dopamine agonists increase it (15). Stimulation of dopaminergic transmission with various agonists (e.g. l-DOPA, amphetamine) can produce EEG activation, but this effect is blocked by muscarinic antagonists (16). Thus, ACh release is a critical step in activation due to enhanced dopaminergic activity, suggesting that dopamine itself, like the other brain systems mentioned above, functions as an indirect modulator of cortical EEG activation (11).

The data summarized above suggest that the basal forebrain cholinergic system not only acts as a direct activator of cortex, but also functions as a ‘final common pathway’ through which other brain systems can act to modulate cortical activity by stimulating the cholinergic input to cortex. Thus, the effect of many brain lesions or pharmacological antagonists to reduce EEG activation may largely reflect the loss of excitatory inputs to the basal forebrain and, consequently, a reduction in cortical ACh release.

Back to the top.

Non-essential role of the thalamus

In addition to the cortical projection system, basal forebrain cholinergic efferents also innervate the thalamus and, thus, are in a position to modulate the cortical EEG indirectly by altering activity in thalamo-cortical systems. Neurons in the reticular thalamic nucleus show rhythmic pacemaker properties that impose highly regular, oscillatory activity patterns on thalamo-cortical projection neurons and, subsequently, on large populations of cortical pyramidal cells, resulting in the appearance of cortical synchronized, high voltage spindle activity (17). The release of ACh in the thalamus suppresses the regular, oscillatory activity of reticular pacemaker cells and synchronized spindle activity in cortex (18). This indirect suppression of EEG synchronization by ACh via the thalamus may normally aid in the appearance of activated cortical EEG activity.

There is little evidence, however, to support the notion that the release of ACh in thalamus is a necessary step in maintaining cortical activation. Numerous studies have shown that large lesions of the thalamus abolish cortical spindle activity, but not cortical activation (19). Further, blockade of muscarinic receptors in cortex abolishes activation (see above), even though the effects of ACh release in the thalamus presumably remain intact. Thus, the integrity of the basal forebrain-thalamic projection system is neither necessary nor sufficient for the maintenance of normal cortical activation, even though it may normally contribute to activation by reducing synchronous activity in large populations of cortical neurons.

Back to the top.

Non-cholinergic EEG activation

The last question to be addressed in this review is the following: is all activation critically dependent on the release of ACh from cortical terminals ? Numerous experiments monitoring cortical EEG activity in freely-moving rats have provided a clear answer to this question. The cortex of freely-moving rats treated with large doses of antimuscarinic drugs or basal forebrain lesions displays deactivated, synchronized activity whenever rats remain motionless. However, when these rats start to walk or rear, EEG activity reverses back to the desynchronized, activated state (20). These observations suggest that ACh is critical for activating the cortex during behavioral immobility, but other, non-cholinergic systems can maintain activation during movement even after cholinergic inputs to the cortex have been eliminated.

A long series of experiments has provided evidence that activation that occurs during movement and that is resistant to cholinergic blockade is abolished by removing the serotonergic input from the midbrain raphe nuclei to neocortex by various means (e.g., depleting serotonin with systemic administration of reserpine or p-chlorophenylalanine, neurotoxic raphe lesions with 5,7-dihydroxytryptamine) (21); the effect of reserpine is reversed by serotonergic agonists, but not by catecholamine precursors or agonists (22). Also, the effect of serotonin blockade to abolish non-cholinergic EEG activation is not mimicked by removal of the dopaminergic, noradrenergic, or histaminergic inputs to the cortex (see (11) for review). Finally, direct, intracortical administration of 5-HT2 receptor antagonists can abolish cortical activation (23). Thus, 5-HT can induce activation by a local action on cortical neurons, rather by an indirect action that is mediated by cholinergic mechanisms. The fact that 5-HT application into the basal forebrain reduces high frequency (30-70 Hz) EEG activity, perhaps by inhibiting ACh neurons (24), suggests that ACh and 5-HT activating pathways normally are in a state of ‘competition’ such that high levels of serotonergic activity not only activate the cortex directly, but also reduce cholinergic transmission between basal forebrain and cortex. This state of ‘competition’ between cholinergic and serotonergic systems may be related to the preferential expression of different types of behavior and cognitive events controlled by these two cortical activating pathways.

Back to the top.


(1) Berger H (1929) Arch f Psychiat 87:527-570;

(2) Moruzzi G (1972) Ergeb Physiol 64:1-165; Moruzzi G, Magoun HW (1949) Electroenceph clin Neurophysiol 1:455-473;

(3) Kanai T, Szerb JC (1965) Nature 205:80-82;

(4) Celesia GG, Jasper HH (1966) Neurology 16:1053-1063; Jasper HH, Tessier J (1971) Science 172:601-602;

(5) Bremer F, Chatonnet J (1949) Arch Int Physiol 57:106-109; Funderburk WH, Case TJ (1951) Electroenceph clin Neurophysiol 3:213-233; Longo VG (1966) Pharmacol Rev 18:965-996; Wikler A (1952) Proceed Society Exp Biol and Med 79:261-265;

(6) Bigl V et al (1982) Brain Res Bull 8:727-749; Mesulam MM et al (1983) Neuroscience 10:1185-1201; Saper CB (1984) J Comp Neurol 222:313-342; Semba K, Fibiger HC (1989) Prog Brain Res 79:37-63; Woolf N (1991)) Prog Neurobiol 37:475-524;

(7) Belardetti F et al (1977) Electroenceph clin Neurophysiol 42:213-235; Casamenti F et al (1986) Brain Res Bull 16:689-695; Metherate R, Ashe JH (1991) Brain Res 559:163-167; Metherate R et al (1992) J Neurosci 12:4701-4711;

(8) Calvet J et al (1973) Brain Res 52:173-187; Creutzfeld O et al (1966) Electroenceph clin Neurophysiol 20:19-37; Vanderwolf CH (1988) Int Rev Neurobiol 30:225-340;

(9) Amzica F, Steriade M (1998) Electroenceph clin Neurophysiol 107:69-83; Buzsaki G, Gage FH (1989) in Central Cholinergic Synaptic Transmission, Basel, Birkhauser, pp 159-171; Calvet J et al (1964) Electroenceph clin Neurophysiol 17:109-125; Pedley TA, Traub RD (1990) in Daly DD, Pedley TA Current Practice of Clinical Electroencephalography, 2nd ed, New York, Raven Press, pp 107-137;

(10) Buzsaki G, Gage FH (1989) in Central Cholinergic Synaptic Transmission, Basel, Birkhauser, pp 159-171; Cole AE, Nicoll RA (1984) J Physiol (Lond) 352:173-188; Cole AE, Nicoll RA (1984) Brain Res 305:283-290; Krnjevic K et al (1971) J Physiol (Lond) 215:247-268; McCormick DA, Prince DA (1986) J Physiol (Lond) 375:169-194; Metherate R et al (1992) J Neurosci 12:4701-4711;

(11) Dringenberg HC, Vanderwolf CH (1998) Neurosci Biobehav Rev 22:243-257;

(12) Dringenberg HC, Vanderwolf CH (1996) Exp Brain Res 108:285-296; Dringenberg HC, Vanderwolf CH (1997) Exp Brain Res 116:160-174;

(13) Cape EG, Jones BE (1998) J Neurosci 18:2653-2666;

(14) Detari L et al (1997) Eur J Neurosci 9:1153-1161;

(15) Day J, Fibiger HC (1993) Neuroscience 54:643-648; Pepeu G (1973) Prog Neurobiol 2:257-288; Pepeu G, Bartolini A (1968) Eur J Pharmacol 4:254-263;

(16) Vanderwolf CH et al (1980) Brain Res 202:65-77;

(17) Andersen P, Andersson SA (1968) Physiological Basis of the alpha rhythm, New York, Appleton-Century-Crofts; Steriade M, Deschenes M (1984) Brain Res Rev 8:1-63; Steriade M, Llinas RR (1988) Physiol Rev 68:649-742;

(18) Buzsaki G, Gage FH (1989) see (10); Puoliväli J et al (1998) NeuroReport 9:1685-1689;

(19) Buzsaki G et al (1988) J Neurosci 8:4007-4026; Vanderwolf CH, Stewart DJ (1988) Brain Res Bull 20:529-538;

(20) Vanderwolf CH (1975) J Comp Physiol Psychol 88:300-323; Vanderwolf (1988) see (8);

(21) Vanderwolf CH, Baker GB (1986) Brain Res 374:342-356; Vanderwolf CH et al (1989) Brain Res 504:181-191; Vanderwolf CH et al (1980) Brain Res 202:65-77;

(22) Dringenberg HC, Vanderwolf CH (1996) Brain Res 728:181-187; Vanderwolf CH et al (1980) Brain Res 202:65-77;

(23) Neuman RS, Zebrowska G (1992) Can J Physiol Pharmacol 70:1604-1609;

(24) Cape EG, Jones BE (1998) see (13).

Back to the top.

| Discussion Board | Previous Page | Your Symposium |
Dringenberg, H.C.; (1998). The basal forebrain cholinergic system: direct cortical activator and mediator of activation induced by excitation of secondary brain systems. 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/dringenberg0136/index.html
© 1998 Author(s) Hold Copyright