, Volume 186, Issue 3, pp 402–413 | Cite as

Neurosteroids and cholinergic systems: implications for sleep and cognitive processes and potential role of age-related changes

  • Olivier George
  • Monique Vallée
  • Michel Le Moal
  • Willy Mayo



The neurosteroids pregnenolone sulfate (PREGS), dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone (3α,5α THPROG) have been implicated as powerful modulators of memory processes and sleep states in young and aged subjects with memory impairment. As these processes depend on the integrity of cholinergic systems, a specific effect of neurosteroids on these systems may account for their effects on sleep and memory.


To review the evidence for a specific and differential effect of neurosteroids on cholinergic systems.


We carried out keyword searches in “Medline” to identify articles concerning (1) the effects of neurosteroids on cholinergic systems, sleep and memory processes, and (2) changes in neurosteroid concentrations during aging. Few results are available for humans. Most data concerned rodents.


Peripheral and central administrations of PREGS, DHEAS, and 3α,5α THPROG modulate the basal forebrain and brainstem projection cholinergic neurons but not striatal cholinergic interneurons. Local administration of neurosteroids to the basal forebrain and brainstem cholinergic neurons alters sleep and memory in rodents. There are a few conflicting reports concerning the effects of aging on neurosteroid concentrations in normal and pathological conditions.


The specific modulation of basal forebrain and brainstem cholinergic systems by neurosteroids may account for the effects of these compounds on sleep and memory processes. To improve our understanding of the role of neurosteroids in cholinergic systems during normal and pathological aging, we need to determine whether there is specific regionalization of neurosteroids, and we need to investigate the relationship between neurosteroid concentrations in cholinergic nuclei and age-related sleep and memory impairments.


Acetylcholine In vivo microdialysis Learning and memory Neurotransmitter release Prefrontal REM sleep Steroid 



Supported by INSERM, Université de Bordeaux II, and the European Community (QLK6-CT-2000-00179).


  1. Arendt T, Bruckner MK, Bigl V, Marcova L (1995a) Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer’s disease. II. Ageing, Korsakoff’s disease, Parkinson’s disease, and Alzheimer’s disease. J Comp Neurol 351:189–222PubMedCrossRefGoogle Scholar
  2. Arendt T, Bruckner MK, Bigl V, Marcova L (1995b) Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer’s disease. III. The basal forebrain compared with other subcortical areas. J Comp Neurol 351:223–246CrossRefPubMedGoogle Scholar
  3. Arendt T, Schindler C, Bruckner MK, Eschrich K, Bigl V, Zedlick D, Marcova L (1997) Plastic neuronal remodeling is impaired in patients with Alzheimer’s disease carrying apolipoprotein epsilon 4 allele. J Neurosci 17:516–529PubMedGoogle Scholar
  4. Armstrong DM, Saper CB, Levey AI, Wainer BH, Terry RD (1983) Distribution of cholinergic neurons in rat brain: demonstrated by the immunocytochemical localization of choline acetyltransferase. J Comp Neurol 216:53–68CrossRefPubMedGoogle Scholar
  5. Barbaccia ML, Concas A, Serra M, Biggio G (1998) Stress and neurosteroids in adult and aged rats. Exp Gerontol 33:697–712CrossRefPubMedGoogle Scholar
  6. Bartus RT, Dean RL III, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414PubMedCrossRefGoogle Scholar
  7. Baxter MG, Bucci DJ, Gorman LK, Wiley RG, Gallagher M (1995) Selective immunotoxic lesions of basal forebrain cholinergic cells: effects on learning and memory in rats. Behav Neurosci 109:714–722CrossRefPubMedGoogle Scholar
  8. Berger-Sweeney J, Heckers S, Mesulam MM, Wiley RG, Lappi DA, Sharma M (1994) Differential effects on spatial navigation of immunotoxin-induced cholinergic lesions of the medial septal area and nucleus basalis magnocellularis. J Neurosci 14:4507–4519PubMedGoogle Scholar
  9. Bernardi F, Salvestroni C, Casarosa E, Nappi RE, Lanzone A, Luisi S, Purdy RH, Petraglia F, Genazzani AR (1998) Aging is associated with changes in allopregnanolone concentrations in brain, endocrine glands and serum in male rats. Eur J Endocrinol 138:316–321CrossRefPubMedGoogle Scholar
  10. Bevan MD, Bolam JP (1995) Cholinergic, GABAergic, and glutamate-enriched inputs from the mesopontine tegmentum to the subthalamic nucleus in the rat. J Neurosci 15:7105–7120PubMedGoogle Scholar
  11. Brashear HR, Zaborszky L, Heimer L (1986) Distribution of GABAergic and cholinergic neurons in the rat diagonal band. Neuroscience 17:439–451PubMedCrossRefGoogle Scholar
  12. Brown RC, Han Z, Cascio C, Papadopoulos V (2003) Oxidative stress-mediated DHEA formation in Alzheimer’s disease pathology. Neurobiol Aging 24:57–65CrossRefPubMedGoogle Scholar
  13. Butcher LL, Oh JD, Woolf NJ, Edwards RH, Roghani A (1992) Organization of central cholinergic neurons revealed by combined in situ hybridization histochemistry and choline-O-acetyltransferase immunocytochemistry. Neurochem Int 21:429–445CrossRefPubMedGoogle Scholar
  14. Buzsaki G, Bickford RG, Ponomareff G, Thal LJ, Mandel R, Gage FH (1988) Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J Neurosci 8:4007–4026PubMedGoogle Scholar
  15. Carlsen J, Zaborszky L, Heimer L (1985) Cholinergic projections from the basal forebrain to the basolateral amygdaloid complex: a combined retrograde fluorescent and immunohistochemical study. J Comp Neurol 234:155–167CrossRefPubMedGoogle Scholar
  16. Charara A, Smith Y, Parent A (1996) Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: Phaseolus vulgaris-leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry. J Comp Neurol 364:254–266CrossRefPubMedGoogle Scholar
  17. Clements JR, Grant S (1990) Glutamate-like immunoreactivity in neurons of the laterodorsal tegmental and pedunculopontine nuclei in the rat. Neurosci Lett 120:70–73CrossRefPubMedGoogle Scholar
  18. Dagan Y (2002) Circadian rhythm sleep disorders (CRSD). Sleep Med Rev 6:45–54CrossRefPubMedGoogle Scholar
  19. Damianisch K, Rupprecht R, Lancel M (2001) The influence of subchronic administration of the neurosteroid allopregnanolone on sleep in the rat. Neuropsychopharmacology 25:576–584CrossRefPubMedGoogle Scholar
  20. Darbra S, George O, Bouyer JJ, Piazza PV, Le Moal M, Mayo W (2004) Sleep–wake states and cortical synchronization control by pregnenolone sulfate into the pedunculopontine nucleus. J Neurosci Res 76:742–747CrossRefPubMedGoogle Scholar
  21. Darnaudery M, Koehl M, Pallares M, Le Moal M, Mayo W (1998) The neurosteroid pregnenolone sulfate increases cortical acetylcholine release: a microdialysis study in freely moving rats. J Neurochem 71:2018–2022PubMedCrossRefGoogle Scholar
  22. Darnaudery M, Bouyer JJ, Pallares M, Le Moal M, Mayo W (1999a) The promnesic neurosteroid pregnenolone sulfate increases paradoxical sleep in rats. Brain Res 818:492–498CrossRefPubMedGoogle Scholar
  23. Darnaudery M, Pallares M, Bouyer JJ, Le Moal M, Mayo W (1999b) Infusion of neurosteroids into the rat nucleus basalis affects paradoxical sleep in accordance with their memory modulating properties. Neuroscience 92:583–588CrossRefPubMedGoogle Scholar
  24. Darnaudery M, Koehl M, Piazza PV, Le Moal M, Mayo W (2000) Pregnenolone sulfate increases hippocampal acetylcholine release and spatial recognition. Brain Res 852:173–179CrossRefPubMedGoogle Scholar
  25. Darnaudery M, Pallares M, Piazza PV, Le Moal M, Mayo W (2002) The neurosteroid pregnenolone sulfate infused into the medial septum nucleus increases hippocampal acetylcholine and spatial memory in rats. Brain Res 951:237–242CrossRefPubMedGoogle Scholar
  26. Datta S (1997) Cellular basis of pontine ponto-geniculo-occipital wave generation and modulation. Cell Mol Neurobiol 17:341–365CrossRefPubMedGoogle Scholar
  27. Datta S, Siwek DF (1997) Excitation of the brain stem pedunculopontine tegmentum cholinergic cells induces wakefulness and REM sleep. J Neurophysiol 77:2975–2988PubMedGoogle Scholar
  28. Datta S, Siwek DF (2002) Single cell activity patterns of pedunculopontine tegmentum neurons across the sleep–wake cycle in the freely moving rats. J Neurosci Res 70:611–621CrossRefPubMedGoogle Scholar
  29. Datta S, Patterson EH, Siwek DF (1997) Endogenous and exogenous nitric oxide in the pedunculopontine tegmentum induces sleep. Synapse 27:69–78CrossRefPubMedGoogle Scholar
  30. Datta S, Mavanji V, Ulloor J, Patterson EH (2004) Activation of phasic pontine-wave generator prevents rapid eye movement sleep deprivation-induced learning impairment in the rat: a mechanism for sleep-dependent plasticity. J Neurosci 24:1416–1427CrossRefPubMedGoogle Scholar
  31. Davies SW, McBean GJ, Roberts PJ (1984) A glutamatergic innervation of the nucleus basalis/substantia innominata. Neurosci Lett 45:105–110CrossRefPubMedGoogle Scholar
  32. Dazzi L, Sanna A, Cagetti E, Concas A, Biggio G (1996) Inhibition by the neurosteroid allopregnanolone of basal and stress-induced acetylcholine release in the brain of freely moving rats. Brain Res 710:275–280CrossRefPubMedGoogle Scholar
  33. Dellu F, Mayo W, Cherkaoui J, Le Moal M, Simon H (1991) Learning disturbances following excitotoxic lesion of cholinergic pedunculo-pontine nucleus in the rat. Brain Res 544:126–132CrossRefPubMedGoogle Scholar
  34. Detari L, Juhasz G, Kukorelli T (1984) Firing properties of cat basal forebrain neurones during sleep–wakefulness cycle. Electroencephalogr Clin Neurophysiol 58:362–368CrossRefPubMedGoogle Scholar
  35. Dingledine R, Kelly JS (1977) Brain stem stimulation and the acetylcholine-evoked inhibition of neurones in the feline nucleus reticularis thalami. J Physiol 271:135–154PubMedGoogle Scholar
  36. Dutar P, Lamour Y, Jobert A (1985) Septohippocampal neurons in the rat: an in vivo intracellular study. Brain Res 340:135–142CrossRefPubMedGoogle Scholar
  37. el Mansari M, Sakai K, Jouvet M (1989) Unitary characteristics of presumptive cholinergic tegmental neurons during the sleep–waking cycle in freely moving cats. Exp Brain Res 76:519–529PubMedCrossRefGoogle Scholar
  38. Everitt BJ, Robbins TW (1997) Central cholinergic systems and cognition. Annu Rev Psychol 48:649–684CrossRefPubMedGoogle Scholar
  39. Fisher RS, Buchwald NA, Hull CD, Levine MS (1988) GABAergic basal forebrain neurons project to the neocortex: the localization of glutamic acid decarboxylase and choline acetyltransferase in feline corticopetal neurons. J Comp Neurol 272:489–502CrossRefPubMedGoogle Scholar
  40. Fischer W, Chen KS, Gage FH, Bjorklund A (1992) Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging. Neurobiol Aging 13:9–23CrossRefPubMedGoogle Scholar
  41. Flood JF, Morley JE, Roberts E (1992) Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci U S A 89:1567–1571PubMedCrossRefGoogle Scholar
  42. Foley D, Ancoli-Israel S, Britz P, Walsh J (2004) Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America survey. J Psychosom Res 56:497–502CrossRefPubMedGoogle Scholar
  43. Ford B, Holmes CJ, Mainville L, Jones BE (1995) GABAergic neurons in the rat pontomesencephalic tegmentum: codistribution with cholinergic and other tegmental neurons projecting to the posterior lateral hypothalamus. J Comp Neurol 363:177–196CrossRefPubMedGoogle Scholar
  44. Frye CA (1995) The neurosteroid 3 alpha, 5 apha-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy. Brain Res 696:113–120CrossRefPubMedGoogle Scholar
  45. Frye CA, Lacey EH (1999) The neurosteroids DHEA and DHEAS may influence cognitive performance by altering affective state. Physiol Behav 66:85–92CrossRefPubMedGoogle Scholar
  46. Fujimoto K, Yoshida M, Ikeguchi K, Niijima K (1989) Impairment of active avoidance produced after destruction of pedunculopontine nucleus areas in the rat. Neurosci Res 6:321–328CrossRefPubMedGoogle Scholar
  47. Fujimoto K, Ikeguchi K, Yoshida M (1992) Impaired acquisition, preserved retention and retrieval of avoidance behavior after destruction of pedunculopontine nucleus areas in the rat. Neurosci Res 13:43–51CrossRefPubMedGoogle Scholar
  48. Fuller TA, Russchen FT, Price JL (1987) Sources of presumptive glutamergic/aspartergic afferents to the rat ventral striatopallidal region. J Comp Neurol 258:317–338CrossRefPubMedGoogle Scholar
  49. Grady CL, Craik FI (2000) Changes in memory processing with age. Curr Opin Neurobiol 10:224–231CrossRefPubMedGoogle Scholar
  50. Gritti I, Mainville L, Jones BE (1993) Codistribution of GABA- with acetylcholine-synthesizing neurons in the basal forebrain of the rat. J Comp Neurol 329:438–457CrossRefPubMedGoogle Scholar
  51. Haber S, Elde R (1981) Correlation between met-enkephalin and substance P immunoreactivity in the primate globus pallidus. Neuroscience 6:1291–1297CrossRefPubMedGoogle Scholar
  52. Hagan JJ, Salamone JD, Simpson J, Iversen SD, Morris RG (1988) Place navigation in rats is impaired by lesions of medial septum and diagonal band but not nucleus basalis magnocellularis. Behav Brain Res 27:9–20CrossRefPubMedGoogle Scholar
  53. Herholz K, Weisenbach S, Zundorf G, Lenz O, Schroder H, Bauer B, Kalbe E, Heiss WD (2004) In vivo study of acetylcholine esterase in basal forebrain, amygdala, and cortex in mild to moderate Alzheimer disease. Neuroimage 21:136–143CrossRefPubMedGoogle Scholar
  54. Hobson JA, Pace-Schott EF (2002) The cognitive neuroscience of sleep: neuronal systems, consciousness and learning. Nat Rev Neurosci 3:679–693CrossRefPubMedGoogle Scholar
  55. Houser CR, Crawford GD, Barber RP, Salvaterra PM, Vaughn JE (1983) Organization and morphological characteristics of cholinergic neurons: an immunocytochemical study with a monoclonal antibody to choline acetyltransferase. Brain Res 266:97–119CrossRefPubMedGoogle Scholar
  56. Ingham CA, Bolam JP, Smith AD (1988) GABA-immunoreactive synaptic boutons in the rat basal forebrain: comparison of neurons that project to the neocortex with pallidosubthalamic neurons. J Comp Neurol 273:263–282CrossRefPubMedGoogle Scholar
  57. Ingram DK, London ED, Reynolds MA (1982) Circadian rhythmicity and sleep: effects of aging in laboratory animals. Neurobiol Aging 3:287–297CrossRefPubMedGoogle Scholar
  58. Isaacson RL, Varner JA, Baars JM, De Wied D (1995) The effects of pregnenolone sulfate and ethylestrenol on retention of a passive avoidance task. Brain Res 689:79–84CrossRefPubMedGoogle Scholar
  59. Jakab RL, Leranth C (2005) Septum. In: Paxinos G (ed) The rat nervous system. Academic, London, pp 405–442Google Scholar
  60. Jasper HH, Tessier J (1971) Acetylcholine liberation from cerebral cortex during paradoxical (REM) sleep. Science 172:601–602PubMedCrossRefGoogle Scholar
  61. Johansson IM, Birzniece V, Lindblad C, Olsson T, Backstrom T (2002) Allopregnanolone inhibits learning in the Morris water maze. Brain Res 934:125–131CrossRefPubMedGoogle Scholar
  62. Jones BE (1990) Immunohistochemical study of choline acetyltransferase-immunoreactive processes and cells innervating the pontomedullary reticular formation in the rat. J Comp Neurol 295:485–514CrossRefPubMedGoogle Scholar
  63. Kayama Y, Ohta M, Jodo E (1992) Firing of ‘possibly’ cholinergic neurons in the rat laterodorsal tegmental nucleus during sleep and wakefulness. Brain Res 569:210–220CrossRefPubMedGoogle Scholar
  64. Keating GL, Walker SC, Winn P (2002) An examination of the effects of bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus on responding to sucrose reward. Behav Brain Res 134:217–228CrossRefPubMedGoogle Scholar
  65. Kelsey JE, Vargas H (1993) Medial septal lesions disrupt spatial, but not nonspatial, working memory in rats. Behav Neurosci 107:565–574CrossRefPubMedGoogle Scholar
  66. Kim SB, Hill M, Kwak YT, Hampl R, Jo DH, Morfin R (2003) Neurosteroids: cerebrospinal fluid levels for Alzheimer’s disease and vascular dementia diagnostics. J Clin Endocrinol Metab 88:5199–5206CrossRefPubMedGoogle Scholar
  67. King SR, Manna PR, Ishii T, Syapin PJ, Ginsberg SD, Wilson K, Walsh LP, Parker KL, Stocco DM, Smith RG, Lamb DJ (2002) An essential component in steroid synthesis, the steroidogenic acute regulatory protein, is expressed in discrete regions of the brain. J Neurosci 22:10613–10620PubMedGoogle Scholar
  68. Kobayashi K, Miyazu K, Seki M, Fukutani Y, Hayashi M, Aoki T, Muramori F, Yamaguchi N (1994) Age-related changes in nerve growth factor receptor immunoreactive neurons in the magnocellular basal forebrain system in rat brain—an immunocytochemical and morphometric study. Dementia 5:57–61PubMedCrossRefGoogle Scholar
  69. Krnjevic K, Silver A (1965) A histochemical study of cholinergic fibres in the cerebral cortex. J Anat 99:711–759PubMedGoogle Scholar
  70. Ladurelle N, Eychenne B, Denton D, Blair-West J, Schumacher M, Robel P, Baulieu E (2000) Prolonged intracerebroventricular infusion of neurosteroids affects cognitive performances in the mouse. Brain Res 858:371–379CrossRefPubMedGoogle Scholar
  71. Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA (2003) Neurosteroid modulation of GABAA receptors. Prog Neurobiol 71:67–80CrossRefPubMedGoogle Scholar
  72. Lancel M, Faulhaber J, Schiffelholz T, Romeo E, Di Michele F, Holsboer F, Rupprecht R (1997) Allopregnanolone affects sleep in a benzodiazepine-like fashion. J Pharmacol Exp Ther 282:1213–1218PubMedGoogle Scholar
  73. Leonard TO, Lydic R (1997) Pontine nitric oxide modulates acetylcholine release, rapid eye movement sleep generation, and respiratory rate. J Neurosci 17:774–785PubMedGoogle Scholar
  74. Lolova IS, Lolov SR, Itzev DE (1996) Changes in NADPH-diaphorase neurons of the rat laterodorsal and pedunculopontine tegmental nuclei in aging. Mech Ageing Dev 90:111–128CrossRefPubMedGoogle Scholar
  75. Lolova IS, Lolov SR, Itzev DE (1997) Aging and the dendritic morphology of the rat laterodorsal and pedunculopontine tegmental nuclei. Mech Ageing Dev 97:193–205CrossRefPubMedGoogle Scholar
  76. Maquet P (2000) Functional neuroimaging of normal human sleep by positron emission tomography. J Sleep Res 9:207–231CrossRefPubMedGoogle Scholar
  77. Marston HM, Everitt BJ, Robbins TW (1993) Comparative effects of excitotoxic lesions of the hippocampus and septum/diagonal band on conditional visual discrimination and spatial learning. Neuropsychologia 31:1099–1118CrossRefPubMedGoogle Scholar
  78. Martinez-Serrano A, Bjorklund A (1998) Ex vivo nerve growth factor gene transfer to the basal forebrain in presymptomatic middle-aged rats prevents the development of cholinergic neuron atrophy and cognitive impairment during aging. Proc Natl Acad Sci U S A 95:1858–1863CrossRefPubMedGoogle Scholar
  79. Mathis C, Paul SM, Crawley JN (1994) The neurosteroid pregnenolone sulfate blocks NMDA antagonist-induced deficits in a passive avoidance memory task. Psychopharmacology (Berl) 116:201–206CrossRefGoogle Scholar
  80. Mathis C, Vogel E, Cagniard B, Criscuolo F, Ungerer A (1996) The neurosteroid pregnenolone sulfate blocks deficits induced by a competitive NMDA antagonist in active avoidance and lever-press learning tasks in mice. Neuropharmacology 35:1057–1064CrossRefPubMedGoogle Scholar
  81. Matthews DB, Morrow AL, Tokunaga S, McDaniel JR (2002) Acute ethanol administration and acute allopregnanolone administration impair spatial memory in the Morris water task. Alcohol Clin Exp Res 26:1747–1751CrossRefPubMedGoogle Scholar
  82. Maurice T (2001) Beneficial effect of the [sigma]1 receptor agonist PRE-084 against the spatial learning deficits in aged rats. Eur J Pharmacol 431:223–227CrossRefPubMedGoogle Scholar
  83. Mavanji V, Datta S (2003) Activation of the phasic pontine-wave generator enhances improvement of learning performance: a mechanism for sleep-dependent plasticity. Eur J Neurosci 17:359–370CrossRefPubMedGoogle Scholar
  84. Mayo W, Dellu F, Robel P, Cherkaoui J, Le Moal M, Baulieu EE, Simon H (1993) Infusion of neurosteroids into the nucleus basalis magnocellularis affects cognitive processess in the rat. Brain Res 607:324–308CrossRefPubMedGoogle Scholar
  85. Mayo W, George O, Darbra S, Bouyer JJ, Vallee M, Darnaudery M, Pallares M, Lemaire-Mayo V, Le Moal M, Piazza PV, Abrous N (2003) Individual differences in cognitive aging: implication of pregnenolone sulfate. Prog Neurobiol 71:43–48CrossRefPubMedGoogle Scholar
  86. McAlonan GM, Wilkinson LS, Robbins TW, Everitt BJ (1995) The effects of AMPA-induced lesions of the septo-hippocampal cholinergic projection on aversive conditioning to explicit and contextual cues and spatial learning in the water maze. Eur J Neurosci 7:281–292CrossRefPubMedGoogle Scholar
  87. Mellon SH, Griffin LD, Compagnone NA (2001) Biosynthesis and action of neurosteroids. Int Meet Rep Steroids Nerv Syst 78:7–8Google Scholar
  88. Mendelson WB, Martin JV, Perlis M, Wagner R, Majewska MD, Paul SM (1987) Sleep induction by an adrenal steroid in the rat. Psychopharmacology (Berl) 93:226–229CrossRefGoogle Scholar
  89. Mesulam MM (1995) The cholinergic contribution to neuromodulation in the cerebral cortex. Semin Neurosci 7:297–307CrossRefGoogle Scholar
  90. Mesulam MM (1998) Some cholinergic themes related to Alzheimer’s disease: synaptology of the nucleus basalis, location of m2 receptors, interactions with amyloid metabolism, and perturbations of cortical plasticity. J Physiol (Paris) 92:293–298CrossRefGoogle Scholar
  91. Mesulam MM, Mufson EJ, Wainer BH, Levey AI (1983a) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1–Ch6). Neuroscience 10:1185–1201CrossRefPubMedGoogle Scholar
  92. Mesulam MM, Mufson EJ, Levey AI, Wainer BH (1983b) Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol 214:170–197CrossRefPubMedGoogle Scholar
  93. Meziane H, Mathis C, Paul SM, Ungerer A (1996) The neurosteroid pregnenolone sulfate reduces learning deficits induced by scopolamine and has promnestic effects in mice performing an appetitive learning task. Psychopharmacology (Berl) 126:323–330CrossRefGoogle Scholar
  94. Mignot E, Taheri S, Nishino S (2002) Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders. Nat Neurosci 5(Suppl):1071–1075CrossRefPubMedGoogle Scholar
  95. Mitchell AS, Dalrymple-Alford JC, Christie MA (2002) Spatial working memory and the brainstem cholinergic innervation to the anterior thalamus. J Neurosci 22:1922–1928PubMedGoogle Scholar
  96. Moragues N, Ciofi P, Lafon P, Odessa MF, Tramu G, Garret M (2000) cDNA cloning and expression of a gamma-aminobutyric acid A receptor epsilon-subunit in rat brain. Eur J Neurosci 12:4318–4330CrossRefPubMedGoogle Scholar
  97. Moragues N, Ciofi P, Tramu G, Garret M (2002) Localisation of GABA(A) receptor epsilon-subunit in cholinergic and aminergic neurones and evidence for co-distribution with the theta-subunit in rat brain. Neuroscience 111:657–669CrossRefPubMedGoogle Scholar
  98. Moruzzi G, Magoun HW (1995) Brain stem reticular formation and activation of the EEG. 1949. J Neuropsychiatry Clin Neurosci 7:251–267PubMedGoogle Scholar
  99. Muir JL (1997) Acetylcholine, aging, and Alzheimer’s disease. Pharmacol Biochem Behav 56:687–696CrossRefPubMedGoogle Scholar
  100. Muir JL, Dunnett SB, Robbins TW, Everitt BJ (1992) Attentional functions of the forebrain cholinergic systems: effects of intraventricular hemicholinium, physostigmine, basal forebrain lesions and intracortical grafts on a multiple-choice serial reaction time task. Exp Brain Res 89:611–622CrossRefPubMedGoogle Scholar
  101. Muir JL, Everitt BJ, Robbins TW (1995) Reversal of visual attentional dysfunction following lesions of the cholinergic basal forebrain by physostigmine and nicotine but not by the 5-HT3 receptor antagonist, ondansetron. Psychopharmacology (Berl) 118:82–92CrossRefGoogle Scholar
  102. Muir JL, Bussey TJ, Everitt BJ, Robbins TW (1996) Dissociable effects of AMPA-induced lesions of the vertical limb diagonal band of Broca on performance of the 5-choice serial reaction time task and on acquisition of a conditional visual discrimination. Behav Brain Res 82:31–44CrossRefPubMedGoogle Scholar
  103. Myers BL, Badia P (1995) Changes in circadian rhythms and sleep quality with aging: mechanisms and interventions. Neurosci Biobehav Rev 19:553–571CrossRefPubMedGoogle Scholar
  104. Nyberg L, Persson J, Nilsson LG (2002) Individual differences in memory enhancement by encoding enactment: relationships to adult age and biological factors. Neurosci Biobehav Rev 26:835–839CrossRefPubMedGoogle Scholar
  105. Oh JD, Woolf NJ, Roghani A, Edwards RH, Butcher LL (1992) Cholinergic neurons in the rat central nervous system demonstrated by in situ hybridization of choline acetyltransferase mRNA. Neuroscience 47:807–822CrossRefPubMedGoogle Scholar
  106. Pace-Schott EF, Hobson JA (2002) The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 3:591–605PubMedGoogle Scholar
  107. Pallares M, Darnaudery M, Day J, Le Moal M, Mayo W (1998) The neurosteroid pregnenolone sulfate infused into the nucleus basalis increases both acetylcholine release in the frontal cortex or amygdala and spatial memory. Neuroscience 87:551–558CrossRefPubMedGoogle Scholar
  108. Perez DLM, Possani LD, Tapia R, Teran L, Palacios R, Fuxe K, Hokfelt T, Ljungdahl A (1981) Demonstration of central gamma-aminobutyrate-containing nerve terminals by means of antibodies against glutamate decarboxylase. Neuroscience 6:875–895CrossRefPubMedGoogle Scholar
  109. Perry EK, Morris CM, Court JA, Cheng A, Fairbairn AF, McKeith IG, Irving D, Brown A, Perry RH (1995) Alteration in nicotine binding sites in Parkinson’s disease, Lewy body dementia and Alzheimer’s disease: possible index of early neuropathology. Neuroscience 64:385–395CrossRefPubMedGoogle Scholar
  110. Perry E, Walker M, Grace J, Perry R (1999) Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci 22:273–280CrossRefPubMedGoogle Scholar
  111. Phillis JW (1968) Acetylcholine release from the cerebral cortex: its role in cortical arousal. Brain Res 7:378–389CrossRefPubMedGoogle Scholar
  112. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G (2000) GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101:815–850CrossRefPubMedGoogle Scholar
  113. Racchi M, Govoni S, Solerte SB, Galli CL, Corsini E (2001) Dehydroepiandrosterone and the relationship with aging and memory: a possible link with protein kinase C functional machinery. Brain Res Brain Res Rev 37:287–293CrossRefPubMedGoogle Scholar
  114. Rajkowski KM, Robel P, Baulieu EE (1997) Hydroxysteroid sulfotransferase activity in the rat brain and liver as a function of age and sex. Steroids 62:427–436CrossRefPubMedGoogle Scholar
  115. Ransmayr G, Faucheux B, Nowakowski C, Kubis N, Federspiel S, Kaufmann W, Henin D, Hauw JJ, Agid Y, Hirsch EC (2000) Age-related changes of neuronal counts in the human pedunculopontine nucleus. Neurosci Lett 288:195–198CrossRefPubMedGoogle Scholar
  116. Rhodes ME, Li PK, Flood JF, Johnson DA (1996) Enhancement of hippocampal acetylcholine release by the neurosteroid dehydroepiandrosterone sulfate: an in vivo microdialysis study. Brain Res 733:284–286CrossRefPubMedGoogle Scholar
  117. Rhodes ME, Li PK, Burke AM, Johnson DA (1997) Enhanced plasma DHEAS, brain acetylcholine and memory mediated by steroid sulfatase inhibition. Brain Res 773:28–32CrossRefPubMedGoogle Scholar
  118. Riekkinen P Jr, Aaltonen M, Riekkinen P (1991) Tetrahydroaminoacridine inhibits high voltage spindle activity in aged rats after acute and chronic treatment. Psychopharmacology (Berl) 103:265–267CrossRefGoogle Scholar
  119. Rosenberg RS, Zepelin H, Rechtschaffen A (1979) Sleep in young and old rats. J Gerontol 34:525–532PubMedGoogle Scholar
  120. Rye DB (1997) Contributions of the pedunculopontine region to normal and altered REM sleep. Sleep 20:757–788PubMedGoogle Scholar
  121. Rye DB, Wainer BH, Mesulam MM, Mufson EJ, Saper CB (1984) Cortical projections arising from the basal forebrain: a study of cholinergic and noncholinergic components employing combined retrograde tracing and immunohistochemical localization of choline acetyltransferase. Neuroscience 13:627–643CrossRefPubMedGoogle Scholar
  122. Rye DB, Saper CB, Lee HJ, Wainer BH (1987) Pedunculopontine tegmental nucleus of the rat: cytoarchitecture, cytochemistry, and some extrapyramidal connections of the mesopontine tegmentum. J Comp Neurol 259:483–528CrossRefPubMedGoogle Scholar
  123. Saito H, Sakai K, Jouvet M (1977) Discharge patterns of the nucleus parabrachialis lateralis neurons of the cat during sleep and waking. Brain Res 134:59–72CrossRefPubMedGoogle Scholar
  124. Saper CB (1984) Organization of cerebral cortical afferent systems in the rat. II. Magnocellular basal nucleus. J Comp Neurol 222:313–342CrossRefPubMedGoogle Scholar
  125. Saper CB, Chelimsky TC (1984) A cytoarchitectonic and histochemical study of nucleus basalis and associated cell groups in the normal human brain. Neuroscience 13:1023–1037CrossRefPubMedGoogle Scholar
  126. Sarter M, Bruno JP (1997) Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev 23:28–46CrossRefPubMedGoogle Scholar
  127. Sarter M, Bruno JP (2004) Developmental origins of the age-related decline in cortical cholinergic function and associated cognitive abilities. Neurobiol Aging 25:1127–1139CrossRefPubMedGoogle Scholar
  128. Satoh K, Armstrong DM, Fibiger HC (1983) A comparison of the distribution of central cholinergic neurons as demonstrated by acetylcholinesterase pharmacohistochemistry and choline acetyltransferase immunohistochemistry. Brain Res Bull 11:693–720CrossRefPubMedGoogle Scholar
  129. Satorra-Marin N, Coll-Andreu M, Portell-Cortes I, Aldavert-Vera L, Morgado-Bernal I (2001) Impairment of two-way active avoidance after pedunculopontine tegmental nucleus lesions: effects of conditioned stimulus duration. Behav Brain Res 118:1–9CrossRefPubMedGoogle Scholar
  130. Schiffelholz T, Holsboer F, Lancel M (2000) High doses of systemic DHEA-sulfate do not affect sleep structure and elicit moderate changes in non-REM sleep EEG in rats. Physiol Behav 69:399–404CrossRefPubMedGoogle Scholar
  131. Schumacher M, Weill-Engerer S, Liere P, Robert F, Franklin RJ, Garcia-Segura LM, Lambert JJ, Mayo W, Melcangi RC, Parducz A, Suter U, Carelli C, Baulieu EE, Akwa Y (2003) Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog Neurobiol 71:3–29CrossRefPubMedGoogle Scholar
  132. Shute CC, Lewis PR (1963) Cholinesterase-containing systems of the brain of the rat. Nature 199:1160–1164PubMedCrossRefGoogle Scholar
  133. Sierra A, Lavaque E, Perez-Martin M, Azcoitia I, Hales DB, Garcia-Segura LM (2003) Steroidogenic acute regulatory protein in the rat brain: cellular distribution, developmental regulation and overexpression after injury. Eur J Neurosci 18:1458–1467CrossRefPubMedGoogle Scholar
  134. Steckler T, Inglis W, Winn P, Sahgal A (1994) The pedunculopontine tegmental nucleus: a role in cognitive processes? Brain Res Brain Res Rev 19:298–318PubMedGoogle Scholar
  135. Steinbusch HW, Nieuwenhuys R (1981) Localization of serotonin-like immunoreactivity in the central nervous system and pituitary of the rat, with special references to the innervation of the hypothalamus. Adv Exp Med Biol 133:7–35PubMedGoogle Scholar
  136. Steininger TL, Wainer BH, Blakely RD, Rye DB (1997) Serotonergic dorsal raphe nucleus projections to the cholinergic and noncholinergic neurons of the pedunculopontine tegmental region: a light and electron microscopic anterograde tracing and immunohistochemical study. J Comp Neurol 382:302–322CrossRefPubMedGoogle Scholar
  137. Steriade M, Datta S, Pare D, Oakson G, Curro Dossi RC (1990) Neuronal activities in brain-stem cholinergic nuclei related to tonic activation processes in thalamocortical systems. J Neurosci 10:2541–2559PubMedGoogle Scholar
  138. Stone WS (1989) Sleep and aging in animals. Relationships with circadian rhythms and memory. Clin Geriatr Med 5:363–379PubMedGoogle Scholar
  139. Szymusiak R, McGinty D (1986) Sleep-related neuronal discharge in the basal forebrain of cats. Brain Res 370:82–92CrossRefPubMedGoogle Scholar
  140. Szymusiak R, Alam N, McGinty D (2000) Discharge patterns of neurons in cholinergic regions of the basal forebrain during waking and sleep. Behav Brain Res 115:171–182CrossRefPubMedGoogle Scholar
  141. Taylor CL, Kozak R, Latimer MP, Winn P (2004) Effects of changing reward on performance of the delayed spatial win-shift radial maze task in pedunculopontine tegmental nucleus lesioned rats. Behav Brain Res 153:431–438CrossRefPubMedGoogle Scholar
  142. Torres EM, Perry TA, Blockland A, Wilkinson LS, Wiley RG, Lappi DA, Dunnet SB (1994) Behavioural, histochemical and biochemical consequences of selective immunolesions in discrete regions of the basal forebrain cholinergic system. Neuroscience 63:95–122CrossRefPubMedGoogle Scholar
  143. Torterolo P, Yamuy J, Sampogna S, Morales FR, Chase MH (2001) GABAergic neurons of the laterodorsal and pedunculopontine tegmental nuclei of the cat express c-fos during carbachol-induced active sleep. Brain Res 892:309–319CrossRefPubMedGoogle Scholar
  144. Turkmen S, Lundgren P, Birzniece V, Zingmark E, Backstrom T, Johansson IM (2004) 3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) antagonism of the GABA potentiation and the learning impairment induced in rats by allopregnanolone. Eur J Neurosci 20:1604–1612CrossRefPubMedGoogle Scholar
  145. Urani A, Privat A, Maurice T (1998) The modulation by neurosteroids of the scopolamine-induced learning impairment in mice involves an interaction with sigma1 (sigma1) receptors. Brain Res 799:64–77CrossRefPubMedGoogle Scholar
  146. Vallée M, Mayo W, Darnaudery M, Corpechot C, Young J, Koehl M, Le Moal M, Baulieu EE, Robel P, Simon H (1997) Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus. Proc Natl Acad Sci U S A 94:14865–14870CrossRefPubMedGoogle Scholar
  147. Vallée M, Mayo W, Le Moal M (2001) Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging. Brain Res Brain Res Rev 37:301–312CrossRefPubMedGoogle Scholar
  148. Vallée M, George O, Vitiello S, Le Moal M, Mayo W (2004) New insights into the role of neuroactive steroids in cognitive aging. Exp Gerontol 39:1695–1704CrossRefPubMedGoogle Scholar
  149. Van Someren EJ (2000) Circadian rhythms and sleep in human aging. Chronobiol Int 17:233–243CrossRefPubMedGoogle Scholar
  150. Weill-Engerer S, David JP, Sazdovitch V, Liere P, Eychenne B, Pianos A, Schumacher M, Delacourte A, Baulieu EE, Akwa Y (2002a) Neurosteroid quantification in human brain regions: comparison between Alzheimer’s and nondemented patients. J Clin Endocrinol Metab 87:5138–5143CrossRefPubMedGoogle Scholar
  151. Weill-Engerer S, David JP, Sazdovitch V, Liere P, Eychenne B, Pianos A, Schumacher M, Delacourte A, Baulieu EE, Akwa Y (2002b) Neurosteroid quantification in human brain regions: comparison between Alzheimer’s and nondemented patients. J Clin Endocrinol Metab 87:5138–5143CrossRefPubMedGoogle Scholar
  152. Wenk GL (1997) The nucleus basalis magnocellularis cholinergic system: one hundred years of progress. Neurobiol Learn Mem 67:85–95CrossRefPubMedGoogle Scholar
  153. Woolf NJ (1991) Cholinergic systems in mammalian brain and spinal cord. Prog Neurobiol 37:475–524CrossRefPubMedGoogle Scholar
  154. Woolf NJ, Butcher LL (1981) Cholinergic neurons in the caudate–putamen complex proper are intrinsically organized: a combined Evans blue and acetylcholinesterase analysis. Brain Res Bull 7:487–507CrossRefPubMedGoogle Scholar
  155. Woolf NJ, Eckenstein F, Butcher LL (1984) Cholinergic systems in the rat brain: I. Projections to the limbic telencephalon. Brain Res Bull 13:751–784CrossRefPubMedGoogle Scholar
  156. Young TB (2004) Epidemiology of daytime sleepiness: definitions, symptomatology, and prevalence. J Clin Psychiatry 65(Suppl 16):12–16PubMedGoogle Scholar
  157. Zaborszky L, Carlsen J, Brashear HR, Heimer L (1986) Cholinergic and GABAergic afferents to the olfactory bulb in the rat with special emphasis on the projection neurons in the nucleus of the horizontal limb of the diagonal band. J Comp Neurol 243:488–509CrossRefPubMedGoogle Scholar
  158. Zou LB, Yamada K, Sasa M, Nakata Y, Nabeshima T (2000) Effects of sigma(1) receptor agonist SA4503 and neuroactive steroids on performance in a radial arm maze task in rats. Neuropharmacology 39:1617–1627CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Olivier George
    • 1
  • Monique Vallée
    • 1
  • Michel Le Moal
    • 1
  • Willy Mayo
    • 1
  1. 1.INSERM, U588, Institut François MagendieUniversité de Bordeaux IIBordeauxFrance

Personalised recommendations