Invited Symposium: Role of the Basal Forebrain Neurons in Cortical Activation and Behavioural State Regulation
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Sleep- and Arousal- Regulating Functions of the Basal Forebrain
The basal forebrain (BF) has long been implicated in the control of behavioral state. Initially, the focus was on the BF as the site of a sleep-promoting (hypnogenic) mechanism. Low and high frequency trains of electrical stimulation delivered to the BF of cats elicit sleep with neocortical EEG synchrony (Sterman, Clemente, 1962). Electrolytic or neurotoxin lesions centered in the midline preoptic area or more laterally in magnocellular regions of the BF cause insomnia (McGinty, Sterman, 1968; Szymusiak, McGinty, 1986b). Localized thermal or chemical stimulation of the BF can also be sleep-promoting (Roberts, Robinson, 1969; Ticho, Radulovacki, 1991; Ueno et al., 1982).
With the discovery that the major cholinergic innervation of the limbic telencephalon and the neocortex originates within magnocellular regions of the BF, the recent emphasis has been on the role of this region in neocortical arousal and/or cognition.
The seemingly conflicting roles of the BF as the site of a cholinergic arousal system and of a sleep-promoting mechanism can be reconciled by the experimental evidence that these two functions are, at least partially, anatomically segregated within the BF. Much of the experimental evidence for a BF hypnogenic mechanism derives from manipulations (e.g., lesion, stimulation) of the midline preoptic area and rostral hypothalamus. For example, insomnia-producing lesions characterized as being within the "basal forebrain", were centered in the medial preoptic area and caused little or no damage to magnocellular BF cholinergic neurons (McGinty, Sterman, 1968; Szymusiak, Satinoff, 1984). Cell groups exhibiting comparatively selective activation during sleep, as assessed by single unit recording and/or immediate-early gene expression, have been found within the medial preoptic/anterior hypothalamic area and within the ventrolateral preoptic region (Alam et al., 1995; Sherin et al., 1996; Szymusiak et al., 1998). These brain regions do not contain cortically-projecting cholinergic neurons. Within the magnocellular BF, most neurons with sleep-related discharge are localized ventral to the highest concentrations of cholinergic neurons, although there is partial overlap of sleep-related and arousal-related cell types (Szymusiak, McGinty, 1989).
Sleep-Wake Discharge Patterns of Cholinergic Basal Forebrain Neurons
A role for the magnocellular BF cholinergic system in the regulation of arousal should be reflected in the electrophysiological activity of these neurons during natural wakefulness and sleep. In fact, within cholinergic regions of the BF, neurons that discharge in association with behavioral and EEG arousal can be easily found. In our initial study of BF neuronal discharge patterns in unanesthetized, freely-moving cats, the most commonly encountered cell type (~50% of the sample,) displayed elevated discharge rates in waking and rapid-eye-movement (REM) sleep, with significantly diminished activity during sleep with EEG synchrony, i.e., nonREM sleep (Szymusiak, McGinty, 1986a). An even higher proportion of arousal-related cell types had been previously described in the BF of cats (Detari et al., 1984). In a subsequent study, we were able to identify a subset of these waking-REM sleep active neurons as cortically projecting, using antidromic techniques (Szymusiak, McGinty, 1989).
Thus, in the cat, the discharge of putative BF cholinergic neurons was characterized by phasic activation during waking accompanied by movement. Discharge rates remained low during both light and deep nonREM sleep, but increased during REM sleep, with rates during phasic REM sleep events (bursts of eye movements, clusters of ponto-geniculo-occipital waves, phasic muscle activation) being similar to those observed during waking movements. Furthermore, BF waking/REM-active neurons typically exhibited short latency orthodromic excitatory responses to single-pulse stimulation of the midbrain and pontine reticular formation. Neurons within cholinergic BF regions in rats, some identified as cortically projecting, were shown to exhibit peak rates while animals were awake and moving; discharge rates during nonREM and REM sleep were not examined (Buzsaki et al., 1988). We have subsequently examined neuronal discharge in the cholinergic BF of freely-moving rats (principally in the horizontal limb of the diagonal bands of Broca and in the magnocellular preoptic area), and have observed neurons with peak discharge rates during waking movement and REM sleep, similar to those seen in the cat (unpublished observations). These findings of movement related discharge among neurons recorded in cholinergic regions of the BF is consistent with findings that release of acetylcholine in the neocortex and hippocampus in rats is highest during waking movement (Day et al., 1991; Kurosawa et al., 1993).
Definitive categorization of any BF neuron recorded with extracellular techniques as cholinergic is problematic. Throughout the magnocellular BF, cholinergic neurons are interspersed with noncholinergic cell types. Both cholinergic and noncholinergic neurons project to neocortex, so antidromic activation with cortical stimulation does not constitute definitive evidence.
With these concerns in mind, it would seem that BF neurons displaying waking/REM sleep discharge, or at least a subset of these neurons, are the ones most likely to be cholinergic. A common feature of these neurons is activation during waking movements and during phasic events of REM sleep, a feature that is consistent with the behavioral correlates of acetylcholine release in brain regions to which BF cholinergic neurons directly project. These findings, combined with the ability of muscarinic receptor activation to evoke depolarizing responses in cortical neurons (McCormick, 1989), suggests that the BF cholinergic system participates in phasic aspects of neocortical arousal during waking and REM sleep.
A role for BF cholinergic neurons as a source of a generalized neocortical arousal does not preclude a more specific role in modulating cortical activation in response to particular environmental stimuli and contingencies. Neurophysiological evidence indicates that activation of the BF cholinergic system can produce regional enhancement of sensory processing within the cortex (Rasmusson, Dykes, 1988; Webster et al., 1991; Metherate, Ashe, 1993; Hars et al., 1993). Putative cholinergic neurons recorded in the primate nucleus basalis of Meynert are activated in response to the delivery of reinforcement or to stimuli that are associated with reward (Wilson, Rolls, 1990; Richardson, DeLong, 1991). Therefore, coordinated activation of the BF cholinergic system during waking movement could contribute to the maintenance of generalized neocortical arousal during the waking state. Sensory modality- or contingency-specific activation of subsets of cholinergic neurons could further increase acetylcholine release in selected cortical regions, thereby enhancing the cortical representation of specific sensory information.
Regulation of the State-Dependent Activity of BF Cholinergic Neurons
What factors are responsible for regulating the excitability of the BF cholinergic system across the sleep-waking cycle? Current evidence suggests that several mechanisms are involved. All portions of the BF cholinergic system receive projections from the midbrain and pontine reticular formation. Electrical stimulation of these brainstem sites can evoke short-latency excitation of putative BF cholinergic neurons (Szymusiak, McGinty, 1989). Microinfusion of excitatory amino acid receptor antagonists into the BF can inhibit increases in neocortical acetylcholine release evoked by brainstem stimulation (Rasmusson et al., 1994).
Thus, glutamatergic input from neurons in the midbrain and pontine reticular core appear to be an important source of excitatory input. Since many reticular formation neurons are active during waking movement and phasic REM sleep events (Siegel, McGinty, 1977), they may convey this pattern of state-dependent discharge to BF cholinergic neurons. Reductions of reticular formation activity during nonREM sleep could result in generalized disfacilitation of the BF cholinergic system during this state.
It has recently been shown that local BF microinfusion of the endogenous somnogen adenosine, can evoke enhanced neocortical EEG synchrony and sleep in cats (Porkka-Heiskanen et al., 1997). Extracellular levels of adenosine within the BF are elevated in response to sleep deprivation. Adenosine exerts inhibitory effects on BF neurons in vitro (Rannie et al., 1994). Based on these findings, it has been hypothesized that endogenous adenosine functions to promote sleep via inhibition of the BF cholinergic system (Porkka-Heiskanen et al., 1997). We have examined the effects of adenosine analogs on the state-dependent discharge pattern of putative BF cholinergic neurons (i.e., those with waking/REM sleep-related discharge) in rats (Alam et al., 1998b). For these studies, adenosine analogs were delivered via a microdialysis probe located within 500 µ of the microwire bundle used for neuronal recordings. Microinfusion of adenosine or of the adenosine transport blocker nitrobenzyl-6-thionosine, evoked suppression of waking discharge in putative cholinergic neurons, consistent with the sleep-promoting effects of these agents described in cats. Infusion of the adenosine A1 receptor antagonist 8-cylopentyl-1,3-dipropylxanthine (CPDX), evoked increased neuronal discharge during both waking and nonREM sleep.
While discharge rates were increased in response to CPDX, the neurons still exhibited sleep/wake state dependent modulation of activity, with higher discharge rates in waking compared to nonREM sleep. The finding that CPDX leads to increases in neuronal discharge in both waking and sleep suggests that BF neurons are subject to tonic inhibition by endogenous adenosine across the sleep-waking cycle. The finding that neuronal discharge remains sleep/wake state-dependent in the presence of CPDX suggests that other neurotransmitters/neuromodulators contribute to the state-dependent activity of putative BF cholinergic neurons.
Changes in gamma-amino butyric acid (GABA)-mediated inhibition also appear to be involved in regulating the state-dependent excitability of putative BF cholinergic neurons. Using the microdialysis/unit recording methodology described above, we examined the effects of GABAergic agonists and antagonists on the discharge of BF neurons in rats (Alam et al., 1998a). Microperfusion of the GABA-A receptor agonist, muscimol, suppressed neuronal discharge during waking and nonREM sleep, but the magnitude of this discharge suppression was largest during waking. Administration of bicuculline, a GABA-A antagonist, had little effect on discharge rate during waking in a subset of putative cholinergic neurons. However, bicuculline significantly antagonized the decline in discharge rate normally observed in these neurons during transitions from waking to sleep. These findings suggest that increased GABA-mediated inhibition contributes to sleep-related reduction in activity in BF neurons. GABAergic mechanisms have also been implicated in modulating behavioral and cognitive functions of BF cholinergic neurons (Dudchenko, Sarter, 1991; Shreve, Uretsky, 1991).
GABAergic neurons are a major type of noncholinergic neuron within the BF (Gritti et al., 1993). Cortically-projecting BF cholinergic neurons are contacted by significant numbers of GABA-containing nerve terminals (Zaborszky et al., 1986). Sources of GABAergic afferents to cholinergic neurons include local interneurons within magnocellular BF regions and more medial sites in the preoptic area (Cullinan, Zaborszky, 1991; Fort et al., 1998). These areas also contain neurons that discharge in association with nonREM sleep, but display little activation during waking (Alam et al., 1995; Sherin et al., 1996; Szymusiak et al., 1998; Szymusiak, McGinty, 1989). Therefore, a subset of the GABAergic neurons localized to these regions can be hypothesized to display sleep-related discharge, and exert inhibitory effects on BF cholinergic neurons during transitions from wakefulness to nonREM sleep.
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