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


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Why and How Is the Basal Forebrain Important for Modulating Cortical Activity across the Sleep-Waking Cycle?

Contact Person: Barbara E. Jones (mcbj@musica.mcgill.ca)


As an anatomical term, the basal forebrain originally referred to the entire basal telencephalon, including the preoptic area, in addition to the medial septum, diagonal band nuclei and substantia innominata (see for review and references: Jones, In press #1622; Jones, 1998 #1613; Jones, 1993 #1234; Jones, 1995 #1136]. It is in the latter regions where the magnocellular neurons which project to the cerebral cortex are located and where, as constituents of that cell system, the cholinergic neurons are situated. This region of the basal forebrain has long been known to be characterized by isodendritic neurons, that is neurons, like neurons of the brainstem reticular formation, with long radiating dendrites which extend out through the passing fibers of the medial forebrain bundle within which they lie. In this position, they appear to receive ascending input from neurons of the brainstem reticular formation. This input comes from glutamate-containing neurons of the reticular formation and also from monoamine-containing neurons of the brainstem. They are also situated in a manner to receive input from descending fiber pathways from cortical regions and importantly from olfactory structures.

From both the early anatomical and physiological studies, the importance of the basal forebrain in the transmission of ascending activating impulses from the brainstem reticular formation to the cerebral cortex was known. The basal forebrain represents the ventral extra-thalamic relay of the ascending reticular activating system. It comprises a parallel pathway to the dorsal thalamic relay, which involves the non-specific thalamo-cortical projection system of the midline and intralaminar thalamic nuclei (see Steriade, this symposium). Both the non-specific thalamo-cortical and the basalo-cortical systems have widespread projections to the cerebral cortex, even though each has a degree of topographic organization. Accordingly as the early physiological studies showed, stimulation of the reticular formation evoked widespread and long-lasting activation of the cerebral cortex. This activation could be produced following ablation of the thalamus, via the ventral extra-thalamic relay through the basal forebrain.

In early lesion studies, the importance of the brainstem reticular formation in cortical activation was evident following extensive lesions of it or transections in front of it. In such preparations, however, cortical activation returned in the chronic course and could always be evoked by olfactory stimulation, indicating the existence of an autochthonous activating system in the forebrain, which was undoubtedly the basalo-cortical system.

Interestingly, relatively early studies also showed that the basal forebrain played a role in de-activation of the cerebral cortex and thus in the onset and maintenance of slow wave sleep. Stimulation of particular sites in the basal forebrain could elicit slow wave activity and behavioral sleep. These results indicated many years ago that this region may exert fundamental control over cortical activity across the sleep-waking cycle, evoking and maintaining activation during waking and paradoxical sleep (also known as rapid eye movement, REM, sleep) and dampening that activation during slow wave sleep.

Thus, as the rostral-most extension of the reticular core of the brain, the basal forebrain, including the cholinergic neurons therein, serves as the important ventral extra-thalamic relay from the brainstem reticular formation to the cerebral cortex, yet also represents an autochthonous forebrain activating system, responsive to olfactory input, and moreover a sleep-wake modulatory system that may determine the state of cortical and subcortical activity across the sleep-waking cycle.

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1. Cholinergic, GABAergic and other neurons. From extensive work over many years, it is known that the magnocellular basal forebrain neurons are comprised in significant part by acetylcholine (ACh)-synthesizing and releasing, or cholinergic, neurons (see for review and references: (Jones, 1993; Jones, 1995; Jones, 1998; Jones, In press; Jones and Muhlethaler, In press) and also Semba, this symposium). It is also well known that ACh release is greater in association with cortical activation, during waking and paradoxical sleep, than with slow wave activity during slow wave sleep. However, in addition to the cholinergic neurons, it is now evident that GABA-synthesizing neurons also comprise a portion of the magnocellular neurons and project to the cerebral cortex in parallel with the cholinergic cells (Gritti et al., 1997). For both, the cortical projection is a widespread one, apparently through scattered thin collaterals extending beyond topographically organized, focussed axonal projections. In addition to the cholinergic and GABAergic basalo-cortical magnocellular projection neurons, there appears to be another contingent of cortically projecting neurons, for which the neurotransmitter remains to be identified but could be glutamate. Accordingly, other non-cholinergic neurons may influence the cortex in different ways from the cholinergic cells.

In addition to the cortically projecting neurons, there are smaller, caudally projecting neurons in the basal forebrain, some projecting to the posterior hypothalamus (Gritti et al., 1993; Gritti et al., 1994). Interestingly, few of these are cholinergic, whereas a significant number are GABAergic neurons. Such cells may influence ascending activating systems by dampening their activity and promoting slow wave sleep, or they may influence descending systems involved in control of behavior and muscle tone.

Finally, there are also a large number of small GABAergic neurons in the basal forebrain which may serve as local interneurons. The cholinergic neurons are surrounded by GABAergic terminals and thereby under the potential control of such cells across the sleep-waking cycle.

Thus, cholinergic, GABAergic and as-yet-unidentified other non-cholinergic neurons contribute to the basalo-cortical projection system, and to descending and local projections, providing the possibility for modulation of cortical and subcortical activity in different ways across the sleep-waking cycle.

2. Different in vitro electrophysiological properties of cholinergic and non-cholinergic neurons. In vitro studies have revealed cell types within the basal forebrain with distinct intrinsic properties (see for review, (Jones and Muhlethaler, In press). Neurons identified by dual staining for biocytin and choline acetyl transferase (ChAT) as cholinergic, display two modes of firing, a tonic mode and burst mode (Khateb et al., 1992). Dependent upon low threshold calcium spikes, which subtend high frequency bursts (100-200 Hz), bursting can recur rhythmically in relatively low frequencies and could thus modulate cortical activity in a slow rhythmic manner (1-5 Hz, in vitro), in addition to a slow tonic manner (up to 15 Hz). Non-cholinergic neurons also display rhythmic discharge, but through an entirely different mechanism and in a resulting entirely different pattern (Alonso et al., 1996). They discharge in clusters of spikes with an interspike interval corresponding often to 20-80 Hz and with an inter-cluster interval corresponding often to a theta rhythmicity. These non-cholinergic neurons could thus influence cortical activity in both a rapid and slow rhythmic manner, perhaps pacing gamma and theta activity.

Thus, cholinergic and possibly GABAergic or other, non-cholinergic neurons display distinct electrophysiological properties such that they may each modulate cortical activity in a differential yet commonly rhythmic manner.

3. Different in vivo discharge properties of possible cholinergic and non-cholinergic neurons. In vivo studies of neurons in the basal forebrain have revealed different discharge patterns, responses to stimulation and activity profiles across the sleep-waking cycle (see Detari and Syzmusiak, this symposium and (Jones and Muhlethaler, In press), for review). In recent in vivo recording studies in urethane-anesthized rats, using juxtacellular neurobiotin labelling for identification of the recorded cells (and ultimately their neurotransmitter and projections), basal forebrain neurons have been identified which share characteristics with those of cells identified in vitro (Manns et al., 1998).

Accordingly, a significant proportion of cells display high frequency bursts (>100 Hz). These neurons are excited by stimulation of the reticular formation or pinching of the tail and shift their discharge pattern from a slow irregular tonic discharge to a regular bursting discharge in association with a shift from irregular slow activity to rhythmic slow activity in limbic cortical EEG. The rhythmic bursting is correlated with the rhythmic EEG activity, suggesting that the burst discharge may provide a rhythmic modulation to cortical activity during cortical activation typified by theta in limbic cortex. These burst discharge units were relatively large, multipolar or fusiform cells with long radiating dendrites. They are very likely cholinergic cells. Another major proportion of cells discharged in a cluster pattern, showing interspike intervals corresponding to 20-60 Hz and inter-cluster intervals corresponding to theta frequencies in the urethane-anesthetized animal when stimulated. The cluster cells, which increased their discharge and rhythmicity with stimulation, were also relatively large, multipolar or fusiform, isodendritic neurons that are most likely non-cholinergic. From these discharge properties, the possibly cholinergic and non-cholinergic cells could act in a complimentary fashion to stimulate cortical activation in a rhythmic manner and accordingly pace theta-like activity across cortical regions during waking and paradoxical sleep. Such rhythmic cortical activity can provide a temporal coordination for coherent activation across spatially separated cortical regions.

In addition to cells which discharged in a rhythmic patterned fashion, other, on average smaller, cells in the basal forebrain discharged tonically (20-60 Hz). Across the different cell types, the majority of cells were excited and increased their discharge with stimulation. However, another proportion decreased their rate of discharge. Such cells could potentially exert a dampening influence upon cortical activation through a direct action upon cortical neurons, since some of these could be antidromically activated from the cortex, or more predominantly by an action upon caudally or locally situated activating neurons, since the majority of these cells could not be antidromically activated from the cortex.

Thus, different cell types, including possibly cholinergic and non-cholinergic neurons, are present in the basal forebrain which according to their burst or cluster discharge patterns and characteristics can stimulate cortical activation in response to activation of the reticular formation and modulate rhythmic cortical activity in this process. Other cells which are inhibited by reticular activation may conversely attenuate cortical activation particularly through subcortical projections.

4. Influence of basalo-cortical system on cortical activity and sleep-wake states. Multiple lesion and pharmacological studies have indicated that the basal forebrain plays an important role in modulating cortical activity and sleep-wake state (see Semba, Detari, Syzmusiak this symposium and (Jones, 1993; Jones, 1998; Jones, In press; Jones and Muhlethaler, In press), for references and review). In vitro pharmacological studies of the action of neurotransmitters contained in afferents to the basal forebrain upon cholinergic and non-cholinergic neurons has allowed a more specific pharmacological study of the influence of basalo-cortical systems on cortical activity and sleep-wake state.

First, noradrenaline which depolarizes and excites cholinergic neurons and the majority of non-cholinergic neurons (Fort et al., 1995; Fort et al., 1998), when microinjected into the basal forebrain evokes increases in gamma EEG activity (30-60 Hz) associated with a behaviorally awake state (Cape and Jones, 1998). It is of note that noradrenaline also hyperpolarizes and inhibits a minor number of non-cholinergic neurons, which have been hypothesized to be potentially sleep-active neurons. In contrast, serotonin, which hyperpolarizes and inhibits cholinergic neurons and the majority of non-cholinergic neurons (Khateb et al., 1993), when mciroinjected into the basal forebrain decreases gamma EEG activity and does not interfere with slow wave sleep and activity during the day when rats sleep the majority of the time. Second, glutamate agonists which depolarize and excite cholinergic neurons (Khateb et al., 1995), when microinjected into the basal forebrain, promote cortical activation, characterized by increased high frequency gamma activity and a behaviorally awake state (Cape and Jones, 1994). In addition, NMDA which promotes bursting in the cholinergic neurons (Khateb et al., 1995), significantly increases theta activity in limbic cortex, suggesting that bursting by the cholinergic cells stimulates rhythmic activity in the cortex (Cape and Jones, In preparation). Conversely, procaine microinjections, which would inactivate basal forebrain neurons, lead to a decrease in both gamma and theta, and to the occurence of irregular slow wave activity on the cortex.

Third, neurotensin which promotes bursting in the cholinergic neurons and is selectively bound and internalized by the cholinergic cells (Alonso et al., 1994), when injected into the basal forebrain promotes increases in both gamma and theta limbic cortical activity and an alternation of waking and paradoxical sleep states with a diminution of slow wave sleep (Cape et al., 1996; Cape et al., 1998). These results suggest that excitation of cholinergic neurons stimulates high frequency gamma activity, but that promotion of bursting activity in the cholinergic neurons by stimulation of NMDA or neurotensin receptors also stimulates rhythmic cortical activity, characterized by theta in limbic cortex. The rhythmic cortical activity may also involve co-activation of non-cholinergic cells which can act in concert with the cholinergic neurons. Inhibition of the cholinergic neurons, along with other non-cholinergic cells, decreases both gamma and theta cortical activity. The predominant influence of the basal forebrain cholinergic and non-cholinergic cell populations upon cortical activity and sleep-wake state is thus promoting cortical activation with rhythmic modulation during waking and paradoxical sleep. Such rhythmic modulation may provide the basis for coherent activation across distant cortical regions during these states.

With regard to the influence of basal forebrain neurons upon sleep, certain effects of the microinjections reveal the importance of some neurons, at least, upon the sleep cycle. Procaine microinjections decrease both gamma and theta EEG activity, but they also result in an increase of a behaviorally awake state, characterized by quiet waking with eyes open. Muscle tonus is often high and despite the occurence of slow wave sleep, paradoxical sleep is virtually absent. These results suggest that in addition to a perhaps minimal direct dampening influence by basal forebrain neurons upon cortical activity, there is an important descending influence from the basal forebrain involved in behavioral changes including decreased muscle tonus that characterize slow wave sleep and the culmination of the sleep cycle in paradoxical sleep. Such influences could be exerted by caudally projecting basal forebrain neurons, which include GABAergic cells.

Thus, the predominant influence of basal forebrain neurons, attributable to the major cholinergic and non-cholinergic cell populations, is to promote cortical activation characterized by gamma and also rhythmic theta activity during the states of waking and paradoxical sleep. In addition, more minor non-cholinergic cell groups may dampen cortical activation by direct attenuation of cortical activity or by inhibition of local activating neurons, but most importantly must act to diminish muscle tonus and behavioral arousal to allow the natural sleep cycle to occur.

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Summary and Conclusions

In summary, the basal forebrain represents an important relay to the cerebral cortex from the ascending reticular activating system but also represents an autochthonous forebrain activating system linked to olfactory inputs and a modulatory system that may be important for the occurence of sleep as well as waking across the sleep-waking cycle. These different roles are fulfilled by different cell groups in the basal forebrain. The cholinergic neurons act to stimulate cortical activation by release of ACh in the cortex, eliciting a depolarization and tonic discharge of cortical neurons. Increased discharge by cholinergic neurons stimulated by neurotransmitters such as noradrenaline or glutamate that are contained in brainstem afferents stimulates high frequency gamma activity in cortical EEG. Cholinergic neurons and other non-cholinergic basalo-cortical neurons also discharge in a rhythmic phasic manner, characterized respectively by burst or cluster discharge and may promote in turn rhythmic cortical activity.

Stimulation of burst discharge in cholinergic neurons by NMDA or neurotensin promotes theta activity in limbic cortical EEG. Accordingly, cholinergic together with non-cholinergic basalo-cortical neurons may promote rhythmic cortical activity and provide for coherent cortical activation during waking and paradoxical sleep. Finally, other basal forebrain neurons, including locally and caudally projecting cells, may be responsible for inhibiting the cholinergic and non-cholinergic activating neurons in the basal forebrain, as well as in the posterior hypothalamus or brainstem and thus periodically dampening cortical activation and decreasing muscle tonus to allow sleep to occur. Together, the cholinergic and non-cholinergic basal forebrain cell populations have the capacity to control cortical activity and the behavioral state of the animal across the sleep-waking cycle.

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  1. Alonso A, Faure M-P, Beaudet A (1994) Neurotensin promotes oscillatory bursting behavior and is internalized in basal forebrain cholinergic neurons. J Neurosci 14:5778-5792.
  2. Alonso A, Khateb A, Fort P, Jones BE, Muhlethaler M (1996) Differential oscillatory properties of cholinergic and non-cholinergic nucleus Basalis neurons in guinea pig brain slice. Eur J Neurosci 8:169-182.
  3. Cape E, Jones BE (1994) Modulation of sleep-wake state and cortical activity following injection of agonists into the region of cholinergic basal forebrain neurons. Soc Neurosci Abst 20:156.
  4. Cape E, Jones BE (In preparation) Effects of glutamate agonist versus procaine microinjections into the basal forebrain upon gamma and theta cortical EEG activity and sleep-wake state.
  5. Cape EG, Alonso A, Beaudet A, Jones BE (1996) Neurotensin micro-injections into the basal forebrain promote cortical activation associated with the states of wake and PS in the rat. Soc Neurosci Abst 22:149.
  6. Cape EG, Beaudet A, Jones BE (1998) Binding and internalization of fluorescent neurotensin in basal forebrian neurons is associated with cortical activation, waking and paradoxical sleep. Soc Neurosci Abst
  7. Cape EG, Jones BE (1998) Differential modulation of high frequency gamma electroencephalogram activity and sleep-wake state by noradrenaline and serotonin microinjections into the region of cholinergic basalis neurons. J Neurosci 18:2653-2666.
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  21. Manns ID, Alonso A, Jones BE (1998) Characterization of juxtacellularly recorded and labelled basal forebrain units in relation to cortical EEG activity. Soc Neurosci Abst

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Jones, B.E.; (1998). Why and How Is the Basal Forebrain Important for Modulating Cortical Activity across the Sleep-Waking Cycle?. 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/jones0891/index.html
© 1998 Author(s) Hold Copyright