Multiple Arousal Systems Research Articles

Neurobiology of Arousal and Sleep: Updates and Insights Into Neurological Disorders

Brain activation during wakefulness is sustained by multiple arousal systems. Dysfunction of one or more arousal systems is a feature of neurological disorders associated with hypersomnolence and/or sleep-wake cycle disturbance. Narcolepsy, Alzheimer’s disease (AD), Parkinson’s disease (PD), and traumatic brain injury appear to involve hypocretin (HCT) and possibly histamine insufficiency as a mechanism related to excessive daytime sleepiness. Loss of cholinergic neurons in AD and of dopamine neurons in PD contributes to sleep-wake disturbance. GABAergic neurons in the preoptic hypothalamus and rostral medulla promote sleep through inhibition of arousal systems. Pathology of preoptic sleep regulatory circuits is correlated with sleep disturbance in AD. An unidentified endogenous somnogen that potentiates the actions of gamma-aminobutyric acid (GABA) is present in the cerebrospinal fluid (CSF) of patients with primary hypersomnia. Descending pathways from the dorsal lateral pons to the ventral medulla and spinal cord are responsible for the inhibition of spinal motoneurons during rapid eye movement (REM) sleep and are implicated in human REM sleep behavior disorder.

Comment: Where is the Theory? A Critical Comment on Multiple Arousal Theory

Multiple arousal theory suggests that there is more than one arousal system and that the activity of the multiple arousal systems can be observed using electrodermal measures at various body sites. The ideas expressed by multiple arousal theory are interesting but they do not constitute a theory. The absence of a specific definition of arousal and the lack of testable predictions prevent multiple arousal theory from constituting a useful theoretical framework for focussed empirical research.

Social and environmental contexts modulate sleep deprivation-induced c-Fos activation in rats

People often sleep deprive themselves voluntarily for social and lifestyle reasons. Animals also appear to stay awake longer as a result of their natural curiosity to explore novel environments and interact socially with conspecifics. Although multiple arousal systems in the brain are known to act jointly to promote and maintain wakefulness, it remains unclear whether these systems are similarly engaged during voluntary vs. forced wakefulness. Using c-Fos immunohistochemistry, we compared neuronal responses in rats deprived of sleep for 2h by gentle sensory stimulation, exploration under social isolation, or exploration with social interaction, and rats under undisturbed control conditions. In many arousal, limbic, and autonomic nuclei examined (e.g., anterior cingulate cortex and locus coeruleus), the two sleep deprivation procedures involving exploration were similarly effective, and both were more effective than sleep deprivation with sensory stimulation, in increasing the number of c-Fos immunoreactive neurons. However, some nuclei (e.g., paraventricular hypothalamic nucleus and select amygdala nuclei) were more responsive to exploration with social interaction, while others (e.g., histaminergic tuberomammillary nucleus) responded more strongly to exploration in social isolation. In the rostral basal forebrain, cholinergic and GABAergic neurons responded preferentially to exploration with social interaction, whereas resident neurons in general responded most strongly to exploration without social interaction. These results indicate that voluntary exploration with/without social interaction is more effective than forced sleep deprivation with gentle sensory stimulation for inducing c-Fos in arousal and limbic/autonomic brain regions, and suggest that these nuclei participate in different aspects of arousal during sustained voluntary wakefulness.

Inactivation of median preoptic nucleus causes c-Fos expression in hypocretin- and serotonin-containing neurons in anesthetized rat

The median preoptic nucleus (MnPN) of the hypothalamus contains sleep-active neurons including sleep-active GABAergic neurons and is involved in the regulation of nonREM/REM sleep. The hypocretinergic (HCRT) neurons of the perifornical-lateral hypothalamic area (PF-LHA) and serotonergic (5-HT) neurons of the dorsal raphe nucleus (DRN) are mostly active during waking and have been implicated in the regulation of arousal. MnPN GABAergic neurons project to the PF-LHA and DRN. It is hypothesized that MnPN promotes sleep by inhibiting multiple arousal systems including HCRT and other wake-active neurons within the PF-LHA and 5-HT neurons in the DRN. We examined the effects of inactivation of MnPN neurons by locally microinjecting 0.2 µl of 1 mM or 10 mM solutions of a GABA A receptor agonist, muscimol, into the MnPN on Fos expression (Fos-IR) in the PF-LHA neurons including HCRT neurons and 5-HT neurons in the DRN in anesthetized rats. Compared to artificial cerebrospinal fluid control, microinjection of muscimol into the MnPN resulted in significantly higher percentages of HCRT and non-HCRT neurons in the PF-LHA and 5-HT neurons in the DRN that exhibited Fos-IR. The percentage of melanin-concentrating hormone (MCH)+/Fos+ neurons in the PF-LHA did not change after muscimol treatments. These results support a hypothesis that the activation of MnPN neurons contributes to the suppression of wake-promoting systems including HCRT and other unidentified neurons in the PF-LHA and 5-HT neurons in the DRN. These results also suggest that MCH neurons may not be under MnPN inhibitory control. These findings are consistent with a hypothesized role of MnPN in sleep regulation.

Hypothalamic Regulation of Sleep and Arousal

Normal waking is associated with neuronal activity in several chemically defined ascending arousal systems. These include monoaminergic neurons in the brainstem and posterior hypothalamus, cholinergic neurons in the brainstem and basal forebrain, and hypocretin (orexin) neurons in the lateral hypothalamus. Collectively, these systems impart tonic activation to their neuronal targets in the diencephalon and neocortex that is reflected in the low-voltage fast-frequency electroencephalogram patterns of wakefulness. Neuronal discharge in these arousal systems declines rapidly at sleep onset. Transitions from waking to sleep, therefore, involve coordinated inhibition of multiple arousal systems. An important source of sleep-related inhibition of arousal arises from neurons located in the preoptic hypothalamus. These preoptic neurons are strongly activated during sleep, exhibiting sleep/waking state-dependent discharge patterns that are the reciprocal of that observed in the arousal systems. The majority of preoptic sleep regulatory neurons synthesize the inhibitory neurotransmitter GABA. Anatomical and functional evidence supports the hypothesis that GABAergic neurons in the median preoptic nucleus (MnPN) and ventrolateral preoptic area (VLPO) exert inhibitory control over the monoaminergic systems and the hypocretin system during sleep. Recent findings indicate that MnPN and VLPO neurons integrate homeostatic aspects of sleep regulation and are important targets for endogenous sleep factors, such as adenosine and growth hormone releasing hormone.

Hypothalamic control of sleep

A sleep-promoting function for the rostral hypothalamus was initially inferred from the presence of chronic insomnia following damage to this brain region. Subsequently, it was determined that a unique feature of the preoptic hypothalamus and adjacent basal forebrain is the presence of neurons that are activated during sleep compared to waking. Preoptic area “sleep-active” neurons have been identified by single and multiple-unit recordings and by the presence of the protein product of the c-Fos gene in the neurons of sleeping animals. Sleep-active neurons are located in several subregions of the preoptic area, occurring with high density in the ventrolateral preoptic area (vlPOA) and the median preoptic nucleus (MnPN). Neurons in the vlPOA contain the inhibitory neuromodulator, galanin, and the inhibitory neurotransmitter, GABA. A majority of MnPN neurons activated during sleep contain GABA. Anatomical tracer studies reveal projections from the vlPOA and MnPN to multiple arousal-regulatory systems in the posterior and lateral hypothalamus and the rostral brainstem. Cumulative evidence indicates that preoptic area neurons function to promote sleep onset and sleep maintenance by inhibitory modulation of multiple arousal systems. Recent studies suggest a role for preoptic area neurons in the homeostatic aspects of the regulation of both rapid eye movement (REM) and non-REM (NREM) sleep and as a potential target for endogenous somnongens, such as cytokines and adenosine.

Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle.

Although maintained by multiple arousal systems, wakefulness falters if orexin (hypocretin), orexin receptors, or orexin neurons are deficient; narcolepsy results with hypersomnolence or sudden onset of rapid eye movement sleep [or paradoxical sleep (PS)] and loss of muscle tonus. To learn how orexin neurons maintain wakefulness, we recorded neurons in head-fixed rats across the sleep-waking cycle and then labeled them with Neurobiotin to identify them by immunohistochemistry. We show that identified orexin neurons discharge during active waking, when postural muscle tone is high in association with movement, decrease discharge during quiet waking in absence of movement, and virtually cease firing during sleep, when postural muscle tone is low or absent. During PS, they remain relatively silent in association with postural muscle atonia and most often despite phasic muscular twitches. They increase firing before the end of PS and thereby herald by several seconds the return of waking and muscle tone. The orexin neurons would thus stimulate arousal, while antagonizing sleep and muscle atonia.

Arousal systems.

The brain contains autochthonous neural systems that evoke waking from sleep in response to sensory stimuli, prolong or enhance arousal in response to special stimuli, and also generate and maintain wakefulness regardless of sensory stimuli during the active part of the day. Through ascending projections to the cortex, these arousal systems stimulate cortical activation, characterized by high frequency gamma and low frequency rhythmic theta activity, and through descending projections to the spinal cord, they stimulate muscle tonus along with sensory-motor responsiveness and activity. They are comprised of neuronal aggregates within the brainstem reticular formation, thalamus, posterior hypothalamus and basal forebrain, and they utilize multiple different neurotransmitters. Within the brainstem, neurons of the reticular formation, which predominantly utilize glutamate as a neurotransmitter, stimulate cortical activation by exciting the widespread projecting neurons of the nonspecific thalamo-cortical projection system, which similarly utilize glutamate, and neurons of the ventral extra-thalamic relay systems located in the posterior hypothalamus and basal forebrain, many of which also utilize glutamate. In addition, these systems have descending projections by which they can enhance or modulate muscle tonus and activity. Articulating with these are cholinergic neurons of the ponto-mesencephalic tegmentum and basal forebrain that promote cortical activation during waking and also during rapid eye movement sleep (REMS), in association therein with muscle atonia. Dopaminergic ventral mesencephalic neurons stimulate a highly motivated and positively rewarding state during waking and may also do so during REMS. In contrast, noradrenergic locus coeruleus neurons promote an aroused waking state and prevent REMS as well as slow wave sleep (SWS). Serotonergic raphe neurons promote a seemingly quiet or satiated waking state, which though exclusive of REMS, can actually be conducive to SWS. Histaminergic neurons of the posterior hypothalamus act like noradrenergic neurons in enforcing waking and are joined by neurons in the region that contain orexin, a neuropeptide recently shown to maintain waking and in absentia to be responsible for narcolepsy, or the inability to maintain wakefulness. These multiple arousal systems are grossly redundant, since no one system is absolutely necessary for the occurrence of waking; yet they are differentiated, since each plays a special role in waking and sleep. During SWS, they are submitted to an inhibitory influence arising in part at least from particular GABAergic neurons co-distributed with many neurons of the arousal systems and also concentrated within the basal forebrain and adjacent preoptic region.

Preoptic area sleep-regulating mechanisms.

Evidence is summarized for the existence of a sleep-regulating mechanism within the preoptic area of the hypothalamus, including the results of lesion, stimulation, and neuronal recording studies. Recent findings employing the c-fos protein immunohistochemical method, have localized putative sleep-regulatory neurons to the ventrolateral preoptic area (vlPOA) and the median preoptic nucleus (MnPn). Electrophysiological studies have confirmed the presence of neurons with sleep-related discharge in the vlPOA. Neurons in the vlPOA that exhibit c-fos protein immunoreactivity during sleep contain the inhibitory neuromodulators galanin and gamma-aminobutyric acid (GABA). These neurons also project to monoaminergic arousal systems, particularly the histaminergic cell groups in the posterior hypothalamus. POA neurons can be hypothesized to provide sleep-related inhibitory control over multiple arousal systems in the forebrain and brainstem.

Discharge modulation of rat dorsal raphe neurons during sleep and waking: effects of preoptic/basal forebrain warming

In cats, putative serotonergic neurons (PSNs) recorded from the dorsal raphe nucleus (DRN) across the sleep-wake cycle exhibit the so-called rapid eye movement sleep-off (REM-off) discharge pattern. Since, the sleep-wake discharge patterns of DRN neurons in behaving rats is poorly known, the present study examined this neuronal populations. The PSNs recorded in this study exhibited: (1) progressive decrease in discharge rate from waking to NREM to REM sleep; (2) long action potential duration, and (3) reduction of discharge rate after systemic administration of a selective 5-HT 1A agonist, (±)-8-hydroxy-2-(di- n-propylamino) tetralin hydrobromide (8-OH-DPAT). Evidence supports the hypothesis that NREM sleep is modulated by thermoregulatory mechanisms localized in the preoptic area and adjacent basal forebrain (POA/BF). We previously reported that POA/BF warming suppresses the discharge of wake-promoting neurons in the posterior hypothalamus and the basal forebrain. Since the DRN is one component of the brainstem arousal system and receives projections from POA/BF, we examined the effects of local POA/BF warming by 1.5–2.0°C during waking on the discharge of DRN neurons. POA/BF warming reduced the discharge in 14 of 19 PSNs and in 12 of 17 other wake-related neurons in the DRN. DRN neuronal discharge reduction occurred without accompanying EEG frequency or behavioral changes. These results suggest that PSNs recorded in DRN in unrestrained and unanesthetized rats exhibit a “wake-active REM-off” discharge pattern and further support the hypothesis that the POA/BF warm-sensitive hypnogenic system induces sleep by a coordinated inhibition of multiple arousal systems including that modulated by the DRN.

Appraisal of Mood and Personality During Hypoglycaemia in Human Subjects

McCRIMMON, R. J., B. M. FRIER AND I. J. DEARY. Appraisal of mood and personality during hypoglycaemia in human subjects. PHYSIOL BEHAV 67(1)27–33, 1999.—This study used the biological model of experimental hypoglycaemia to examine the effect of a manipulation in mood-state on appraisal. Controlled hypoglycaemia was achieved using the hyperinsulinaemic glucose clamp technique. Mood, appraisal, and personality traits were assessed using well validated questionnaires. Our findings 1) reaffirm the existence of multiple arousal systems in the generation of moods, 2) show that the induction of a negative mood state does lead to more negative appraisals of a life situation, and 3) show that personality traits remain stable during the experience of negative emotions and cognitions. We conclude that hypoglycaemia, by inducing a state of tense tiredness in some individuals, may lead to more negative appraisals of a life situation but does not alter people's reporting of behavioural dispositions.

The personality theories of H.J. Eysenck and J.A. Gray: a comparative review

Hans J. Eysenck and Jeffrey A. Gray have proposed influential theories of the biological bases of personality traits. Eysenck's theory concerns the extraversion, neuroticism and psychoticism traits, whereas Gray proposes the use of new, rotated axes of impulsivity and anxiety. Eysenck uses multiple arousal systems as the central explanatory constructs, whereas Gray describes more specific systems related to behavioural inhibition and activation. This article reviews the evidence relating to these theories provided by studies of c.n.s. and a.n.s. psychophysiology, subjective affect, conditioning and attention and performance. It discusses key predictive successes and failures and methodological problems which may impede theory-testing. It is concluded that there is a solid core of predictive support for the Eysenck theory in some paradigms, such as the moderator effect of stimulation level on individual differences in phasic electrodermal response and eyelid conditioning. In other settings, the theory fails to explain empirical data adequately, especially in studies of subjective response and attention and performance. Gray's theory has advanced research through stimulating interest in moderation of personality effects by motivational variables. It also provides a better explanation than Eysenck's theory for certain data, such as instrumental conditioning to reward stimuli and the positive affectivity of extraverts. Overall, however, Gray's theory explains a narrower range of findings than Eysenck's. There is little evidence that Gray's revised personality axes are generally more predictive of psychophysiological and performance criteria than Eysenck's original dimensions. Finally, it is suggested that the assumptions of the biological approach to personality are in need of reassessment. It is possible that the biological theories may be improved through developments in methodology or through discriminating multiple systems underpinning traits. For example, extraversion may have distinct “reticulo–cortical” and “dopaminergic” aspects. Alternatively, the biological approach may not in fact be adequate for explaining behavioural correlates of traits. In this case, trait research should place more emphasis on cognitive or social bases for personality.

Studies on the sleep-promoting mechanisms mediated by adenosine A 2A receptors

Daily cycles of wakefulness and sleep are regulated by coordinated interactions between wakefulness- and sleep-regulating neural circuitry. Wakefulness is associated with neuronal activity in cholinergic neurons in the brainstem and basal forebrain, monoaminergic neurons in the brainstem and posterior hypothalamus, and hypocretin (orexin) neurons in the lateral hypothalamus that act in a coordinated manner to stimulate cortical activation on the one hand and behavioral arousal on the other hand. Each of these neuronal groups subserves distinct aspects of wakefulness-related functions of the brain. Normal transitions from wakefulness to sleep involve sleep-related inhibition and/or disfacilitation of the multiple arousal systems. The cell groups that shut off the network of arousal systems, at sleep onset, occur with high density in the ventral lateral preoptic area (VLPO) and the median preoptic nucleus (MnPN) of the hypothalamus. Preoptic neurons are activated during sleep and exhibit sleep--wake state-dependent discharge patterns that are reciprocal of that observed in several arousal systems. Neurons in the VLPO contain the inhibitory neuromodulator, galanin, and the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). The majority of MnPN sleep-active neurons synthesize GABA. VLPO and MnPN neurons are sources of projections to arousal-regulatory systems in the posterior and lateral hypothalamus and the rostral brainstem. Mechanisms of sleep induction by these nuclei are hypothesized to involve GABA-mediated inhibition of multiple arousal systems. Normal cycling between discrete behavioral states is mediated by the combined influence of a sleep need that increases with continued wakefulness and an intrinsic circadian oscillation. This chapter will review anatomical and functional properties of populations of sleep- /wake-regulating neurons, focusing on recent findings supporting functional significance of the VLPO and MnPN in the regulation of sleep--wake homeostasis. Evidence indicating that MnPN and VLPO neurons have different, but complementary sleep regulatory functions will be summarized. Potential mechanisms that function to couple activity in these two sleep-regulatory neurons will be discussed.

One or many arousal systems? Reflections on some of Giuseppe Moruzzi's foresights and insights about the intrinsic regulation of brain activity.

Soon after the birth of the hypothesis of the ascending brainstem activating system, Giuseppe Moruzzi considered the possibility that a fractionated and differentiated arousing action of the reticular formation is required for effective behavior and cognition. Current knowledge about the chemically tagged brainstem systems which project diffusely to thalamus, neocortex and limbic structures has justified the assumption of the existence of multiple arousal systems. Combined changes in the activities of these systems are responsible for the sleep-wake cycle and the modulation of the reactivity of the brain to environmental inputs. There remains the physiological problem--one which has always been foremost in Moruzzi's thinking about the intrinsic regulation of brain activity--of how the separate actions of the different arousal systems are brought together into a functional whole. This problem still awaits experimental answers.