Skip to main content Accessibility help
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 2
  • Print publication year: 2011
  • Online publication date: September 2011

11 - Preoptic and basal forebrain modulation of REM sleep

from Section III - Neuronal regulation



Although the basic mechanisms of REM sleep regulation are thought to reside in the brain stem, considerable evidence suggests that the forebrain, including the preoptic area and the adjacent basal forebrain (BF) as well as the hypothalamus, participates in the regulation of REM sleep. In this review we will first discuss findings that support the role of the preoptic area (POA) in REM sleep, with special focus on the ventrolateral preoptic nucleus (VLPO) and the median preoptic nucleus (MnPO). We will then review evidence for a role of the BF in REM sleep regulation and briefly discuss the role of the suprachiasmatic nucleus (SCN) in the circadian pattern of REM sleep. We will conclude with a view that the POA and BF house a continuum of distinct sleep–wake regulatory neurons with descending and ascending projections that interact with neurons in the posterior hypothalamus, brain stem, and cortex to regulate sleep and wakefulness, including REM sleep.

Since early transection studies, basic neural mechanisms responsible for the occurrence of REM sleep have been thought to reside in the pons, wherein the cyclic occurrence of REM sleep has been postulated to be controlled through the interaction between neurons that execute (REM-on) and those that block (REM-off) REM sleep. The ideas about the identity of these neurons have gone through several revisions. The current reciprocal interaction model focuses on cholinergic REM-on and monoaminergic REM-off neurons (Pace-Schott and Hobson, 2002), whereas the flip-flop model (Lu et al., 2006) and a similar model (Sapin et al., 2009) emphasize GABAergic/glutamatergic REM-on neurons in the sublaterodorsal nucleus and GABAergic REM-off neurons in the ventrolateral periaqueductal gray. Despite this focus on the brain stem for executive mechanisms of REM sleep, there is considerable evidence to suggest that the forebrain, in particular the hypothalamus as well as the POA and the adjacent BF, participates in REM sleep regulation. This review will focus on the role of the POA, including the VLPO and MnPO, and the BF in REM sleep regulation. The role of the SCN of the hypothalamus in the circadian pattern of REM sleep is also discussed briefly. According to the common usage, the BF here refers to those ventral forebrain regions that contain magnocellular cholinergic neurons (Semba, 2000).

Related content

Powered by UNSILO
Alam, M. N. & Mallick, B. N. (1990) Differential acute influence of medial and lateral preoptic areas on sleep-wakefulness in freely moving rats. Brain Res 525: –8.
Baghdoyan, H. A., Spotts, J. L. & Snyder, S. G. (1993) Simultaneous pontine and basal forebrain microinjections of carbachol suppresses REM sleep. J Neurosci 13: –42.
Basheer, R., Strecker, R., Thakkar, M. . (2004) Adenosine and sleep-wake regulation. Prog Neurobiol 73: –96.
Buijs, R. M., la Fleur, S. E., Wortel, J. . (2003) The suprachiasmatic nucleus balances sympathetic and parasympathetic output to peripheral organs through separate preautonomic neurons. J Comp Neurol 464: –48.
Cape, E. G. & Jones, B. E. (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: –66.
Cape, E. G. & Jones, B. E. (2000) Effects of glutamate agonist versus procaine microinjections into the basal forebrain cholinergic cell area upon gamma and theta EEG activity and sleep-wake state. Eur J Neurosci 12: –84.
Cape, E. G., Manns, I. D., Alonso, A. . (2000) Neurotensin-induced bursting of cholinergic basal forebrain neurons promotes gamma and theta cortical activity together with waking and paradoxical sleep. J Neurosci 20: –61.
Cerri, M., Ocampo-Garces, A., Amici, R. . (2005) Cold exposure and sleep in the rat: effects on sleep architecture and the electroencephalogram. Sleep 28: –705.
Chou, T. C., Bjorkum, A. A., Gaus, S. E. . (2002) Afferents to the ventrolateral preoptic nucleus. J Neurosci 22: –90.
de Andrés, I., Garzón, M. & Villablanca, J. R. (2003) The disconnected brain stem does not support rapid eye movement sleep rebound following selective deprivation. Sleep 26: –25.
Deurveilher, S. & Semba, K. (2005) Indirect projections from the suprachiasmatic nucleus to major arousal-promoting cell groups in rat: implications for the circadian control of behavioural state. Neuroscience 130: –83.
Deurveilher, S. & Semba, K. (2006) Mapping sleep–wake control with the transcription factor c-Fos. In Immediate Early Genes in Sensory Processing, Cognitive Performance and Neurological Disorders, eds. Pinaud, R. & Tremere, L. A.. New York: Springer, pp. 113–36.
España, R. A., Baldo, B. A., Kelley, A. E. . (2001) Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience 106: –715.
Gong, H., Szymusiak, R., King, J. . (2000) Sleep-related c-Fos protein expression in the preoptic hypothalamus: effects of ambient warming. Am J Physiol 279: –88.
Gvilia, I., Angara, C., McGinty, D. . (2005) Different neuronal populations of the rat median preoptic nucleus express c-fos during sleep and in response to hypertonic saline or angiotensin-II. J Physiol 569: –99.
Gvilia, I., Xu, F., McGinty, D. . (2006a) Preoptic area neurons and the homeostatic regulation of rapid eye movement sleep. J Neurosci 26: –44.
Gvilia, I., Xu, F., McGinty, D. . (2006b) Homeostatic regulation of sleep: a role for preoptic area neurons. J Neurosci 26: –33.
Hassani, O., Lee, M., Henny, P. . (2009) Discharge profiles of identified GABAergic in comparison to cholinerigc and putative glutamatergic basal forebrain neurons across the sleep-wake cycle. J Neurosci 29: –40.
Hernández-Peón, R., Chávez-Ibarra, G., Morgane, P. . (1963) Limbic cholinergic pathways involved in sleep and emotional behavior. Exp Neurol 8: –111.
Kalinchuk, A., Porkka-Heiskanen, T. & McCarley, R. (2006a) Basal forebrain and saporin cholinergic lesions: the devil dwells in delivery details. Sleep 29:–7.
Kalinchuk, A., Stenberg, D., Rosenberg, P. . (2006b) Inducible and neuronal nitric oxide synthases (NOS) have complementary roles in recovery sleep induction. Eur J Neurosci 24: –56.
Kalinchuk, A., Lu, Y., Stenberg, D. . (2006c) Nitric oxide production in the basal forebrain is required for recovery sleep. J Neurochem 99: –98.
Kalinchuk, A., McCarley, R. D. S. . (2008) The role of cholinergic basal forebrain neurons in adenosine-mediated homeostatic control of sleep: lessons from 192 IgG-saporin lesions. Neuroscience 157: –53.
Kaur, S., Junek, A., Black, M. A. . (2008) Effects of ibotenate and 192IgG-saporin lesions of the nucleus basalis magnocellularis/substantia innominata on spontaneous sleep and wake states and on recovery sleep after sleep deprivation in rats. J Neurosci 28: –504.
Koyama, Y. & Hayaishi, O. (1994) Firing of neurons in the preoptic/anterior hypothalamic areas in rat: its possible involvement in slow wave sleep and paradoxical sleep. Neurosci Res 19: –8.
Lee, M., Manns, I. D., Alonso, A. . (2004) Sleep–wake related discharge properties of basal forebrain neurons recorded with micropipettes in head-fixed rats. J Neurophysiol 92: –98.
Lee, M., Hassani, O., Alonso, A. . (2005) Cholinergic basal forebrain neurons burst with theta during waking and paradoxical sleep. J Neurosci 25: –9.
Lee, M., Swanson, B. & de la Iglesia, H. (2009) Circadian timing of REM sleep is coupled to an oscillator within the dorsomedial suprachiasmatic nucleus. Curr Biol 19: –52.
Lu, J., Greco, M. N., Shiromani, P. . (2000) Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. J Neurosci 20: –42.
Lu, J., Bjorkum, A., Xu, M. . (2002) Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep. J Neurosci 22: –76.
Lu, J., Sherman, D., Devor, M. . (2006) A putative flip-flop switch for control of REM sleep. Nature 441: –94.
Mallick, B. N., Thankachan, S. & Islam, F. (2004) Influence of hypnogenic brain areas on wakefulness- and rapid-eye-movement sleep-related neurons in the brainstem of freely moving cats. J Neurosci Res 75: –42.
Manfridi, A. & Mancia, M. (1996) Desynchronized (REM) sleep inhibition induced by carbachol microinjections into the nucleus basalis of Meynert is mediated by the glutamatergic system. Exp Brain Res 109: –8.
Manfridi, A., Brambilla, D. & Mancia, M. (2001) Sleep is differently modulated by basal forebrain GABA(A) and GABA(B) receptors. Am J Physiol Regul Integr Comp Physiol 281: –5.
McKenna, J., Cordeira, J., Jeffrey, B. . (2009) c-Fos protein expression is increased in cholinergic neurons of the rodent basal forebrain during spontaneous and induced wakefulness. Brain Res Bull 80: –8.
Mistlberger, R. E., Antle, M. C., Glass, J. D. . (2000) Behavioral and serotonergic regulation of circadian rhythms. Biol Rhythm Res 31: –83.
Modirrousta, M., Mainville, L. & Jones, B. (2004) GABAergic neurons with alpha2-adrenergic receptors in basal forebrain and preoptic area express c-Fos during sleep. Neuroscience 129: –10.
Nishino, S., Tafti, M., Reid, M. S. . (1995) Muscle atonia is triggered by cholinergic stimulation of the basal forebrain: implication for the pathophysiology of canine narcolepsy. J Neurosci 15: –14.
Pace-Schott, E. & Hobson, J. (2002) The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 3: –605.
Porkka-Heiskanen, T., Kalinchuk, A., Alanko, L. . (2003) Adenosine, energy metabolism, and sleep. Scientific World Journal 3: –8.
Ramesh, V., Thakkar, M., Strecker, R. . (2004) Wakefulness-inducing effects of histamine in the basal forebrain of freely moving rats. Behav Brain Res 152: –8.
Saper, C. B., Chou, T. C. & Scammell, T. E. (2001) The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 24: –31.
Saper, C. B., Lu, J., Chou, T. C. . (2005) The hypothalamic integration for circadian rhythms. Trends Neurosci 28: –7.
Sapin, E., Lapray, D., Bérod, A. . (2009) Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep. PLoS One 4: .
Schmidt, M. H., Valatx, J.-L., Sakai, K. . (2000) Role of the lateral preoptic area in sleep-related erectile mechanisms and sleep generation in the rat. J Neurosci 20: –7.
Semba, K. (1991) The cholinergic basal forebrain: a critical role in cortical arousal. In The Basal Forebrain. Anatomy and Function, eds. T.C. Napier, , Kalivas, P. W. & Hanin, I. New York: Plenum, pp. 197–218.
Semba, K. (2000) Multiple output pathways of the basal forebrain: organization, chemical heterogeneity, and roles in vigilance. Behav Brain Res 115: –41.
Sherin, J. E., Shiromani, P. J., McCarley, R. W. . (1996) Activation of ventrolateral preoptic neurons during sleep. Science 271: –19.
Sherin, J. E., Elmquist, J. K., Torrealba, F. . (1998) Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci 18: –21.
Srividya, R., Mallick, H. & Kumar, V (2006) Differences in the effects of medial and lateral preoptic lesions on thermoregulation and sleep in rats. Neuroscience 139: –64.
Steininger, T. L., Gong, H., McGinty, D. . (2001) Subregional organization of preoptic area/anterior hypothalamic projections to arousal related monoaminergic cell groups. J Comp Neurol 429: –53.
Stewart, D. J., MacFabe, D. F. & Vanderwolf, C. H. (1984) Cholinergic activation of the electrocorticogram: role of the substantia innominata and effects of atropine and quinuclidinyl benzilate. Brain Res 322: –32.
Suntsova, N. & Dergacheva, O. (2004) The role of the medial preoptic area of the hypothalamus in organizing the paradoxical phase of sleep. Neurosci Behav Physiol 34: –35.
Suntsova, N., Szymusiak, R., Alam, M. . (2002) Sleep–waking discharge patterns of median preoptic nucleus neurons in rats. J Physiol 543: –77.
Suntsova, N., Guzman-Marin, R., Kumar, S. . (2007) The median preoptic nucleus reciprocally modulates activity of arousal-related and sleep-related neurons in the perifornical lateral hypothalamus. J Neurosci 27: –30.
Szymusiak, R. & McGinty, D. (1986) Sleep suppression following kainic acid-induced lesions of the basal forebrain. Exp Neurol 94: –614.
Szymusiak, R. & McGinty, D. (1989) Sleep–waking discharge of basal forebrain projection neurons in cats. Brain Res Bull 22: –30.
Szymusiak, R., McGinty, D. (2008) Hypothalamic regulation of sleep and arousal. Ann N Y Acad Sci 1129: –86.
Szymusiak, R., Alam, N., Steiniger, T. L. . (1998) Sleep–waking discharge patterns of ventrolateral preoptic/anterior hypothalamic neurons in rats. Brain Res 803: –88.
Szymusiak, R., Gvilia, I., McGinty, D. (2007) Hypothalamic control of sleep. Sleep Med 8: –301.
Takahashi, K., Lin, J. & Sakai, K. (2009) Characterization and mapping of sleep–waking specific neurons in the basal forebrain and preoptic hypothalamus in mice. Neuroscience 161: –92.
Uschakov, A., Gong, H., McGinty, D. . (2006) Sleep-active neurons in the preoptic area project to the hypothalamic paraventricular nucleus and perifornical lateral hypothalamus. Eur J Neurosci 23: –96.
Uschakov, A., Gong, H., McGinty, D. . (2007) Efferent projections from the median preoptic nucleus to sleep- and arousal-regulatory nuclei in the rat brain. Neuroscience 150: –20.
Vazquez, J. & Baghdoyan, H. (2001) Basal forebrain acetylcholine release during REM sleep is significantly greater than during waking. Am J Physiol Regul Integr Comp Physiol 280: –601.
von Economo, C. (1930) Sleep as a problem of localization. J Nerv Ment Dis 71: –59.
Wigren, H., Schepens, M., Matto, V. . (2007) Glutamatergic stimulation of the basal forebrain elevates extracellular adenosine and increases the subsequent sleep. Neuroscience 147: –23.
Yang, Q. Z. & Hatton, G. I. (1997) Electrophysiology of excitatory and inhibitory afferents to rat histaminergic tuberomammillary nucleus neurons from hypothalamic and forebrain sites. Brain Res 773: –72.