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Sex Differences in the Septo-Hippocampal Cholinergic System in Rats: Behavioral Consequences

  • Dai Mitsushima
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 8)

Abstract

The hippocampus is processing temporal and spatial information in particular contexts or episodes. Using freely moving rats, we monitored extracellular levels of acetylcholine (ACh), a critical neurotransmitter activating hippocampal circuits. We found that the ACh release in the dorsal hippocampus increases during the period of learning or exploration, exhibiting a sex-specific 24-h release profile. Moreover, neonatal increase in circulating androgen not only androgenizes behavioral and hormonal features, but also produces male-type ACh release profile after the development. The results suggest neonatal sexual differentiation of septo-hippocampal cholinergic system. Environmental conditions (such as stress, housing or food) of animals further affected the ACh release.

Although recent advances of neuroscience successfully revealed molecular/cellular mechanism of learning and memory, most research were performed using male animals at specific time period. Sex-specific or time-dependent hippocampal functions are still largely unknown.

Keywords

Acetylcholine Androgen Diurnal rhythm Estrogen Learning and memory Sex difference 

Notes

Acknowledgements

This work was supported by Grant-in-Aid 18590219 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to D.M.).

References

  1. Auerbach JM, Segal M (1996) Muscarinic receptors mediating depression and long-term potentiation in rat hippocampus. J Physiol 492:479–493PubMedPubMedCentralGoogle Scholar
  2. Beatty WW (1984) Hormonal organization of sex differences in play fighting and spatial behavior. Prog Brain Res 61:315–330PubMedCrossRefGoogle Scholar
  3. Brown RT (1968) Early experience and problem-solving ability. J Comp Physiol Psychol 65:433–440PubMedCrossRefGoogle Scholar
  4. Buzsáki 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
  5. Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, Peskind ER, Raskind MA, Craft S (2005) Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology 64:2063–2068PubMedCrossRefGoogle Scholar
  6. Cole AE, Nicoll RA (1983) Acetylcholine mediates a slow synaptic potential in hippocampal pyramidal cells. Science 221:1299–1301PubMedCrossRefGoogle Scholar
  7. Coyle JT, Price DL, DeLong MR (1983) Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 219:1184–1190PubMedCrossRefGoogle Scholar
  8. Cummings JL (2004) Alzheimer’s disease. N Engl J Med 351:56–67PubMedCrossRefGoogle Scholar
  9. Daniel JM, Fader AJ, Spencer AL, Dohanich GP (1997) Estrogen enhances performance of female rats during acquisition of a radial arm maze. Horm Behav 32:217–225PubMedCrossRefGoogle Scholar
  10. Day J, Damsma G, Fibiger HC (1991) Cholinergic activity in the rat hippocampus, cortex and striatum correlates with locomotor activity: an in vivo microdialysis study. Pharmacol Biochem Behav 38:723–729PubMedCrossRefGoogle Scholar
  11. Eckel-Mahan KL, Phan T, Han S, Wang H, Chan GC, Scheiner ZS, Storm DR (2008) Circadian oscillation of hippocampal MAPK activity and cAMP: implications for memory persistence. Nat Neurosci 11:1074–1082PubMedCrossRefPubMedCentralGoogle Scholar
  12. Einon D (1980) Spatial memory and response strategies in rats: age, sex and rearing differences in performance. Q J Exp Psychol 32:473–489PubMedCrossRefGoogle Scholar
  13. Endo Y, Mizuno T, Fujita K, Funabashi T, Kimura F (1994) Soft-diet feeding during development enhances later learning abilities in female rats. Physiol Behav 56:629–633PubMedCrossRefGoogle Scholar
  14. Falvo RE, Buhl A, Nalbandov AV (1974) Testosterone concentrations in the peripheral plasma of androgenized female rats and in the estrous cycle of normal female rats. Endocrinology 95:26–29PubMedCrossRefGoogle Scholar
  15. Fernández de Sevilla D, Núñez A, Borde M, Malinow R, Buño W (2008) Cholinergic-mediated IP3-receptor activation induces long-lasting synaptic enhancement in CA1 pyramidal neurons. J Neurosci 28:1469–1478PubMedCrossRefGoogle Scholar
  16. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366:2112–2117PubMedCrossRefPubMedCentralGoogle Scholar
  17. Gelbard-Sagiv H, Mukamel R, Harel M, Malach R, Fried I (2008) Internally generated reactivation of single neurons in human hippocampus during free recall. Science 322:96–101PubMedCrossRefPubMedCentralGoogle Scholar
  18. Gibbs RB, Pfaff DW (1992) Effects of estrogen and fimbria/fornix transaction on p75NGFR and ChAT expression in the medial septum and diagonal band of Broca. Exp Neurol 116:23–39PubMedCrossRefGoogle Scholar
  19. Gold PE (2003) Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol Learn Mem 80:194–210PubMedCrossRefGoogle Scholar
  20. Greenough WT, Madden TC, Fleischmann TB (1972) Effects of isolation, daily handling, and enriched rearing on maze learning. Psychon Sci 27:279–280CrossRefGoogle Scholar
  21. Herrera-Morales W, Mar I, Serrano B, Bermúdez-Rattoni F (2007) Activation of hippocampal postsynaptic muscarinic receptors is involved in long-term spatial memory formation. Eur J Neurosci 25:1581–1588PubMedCrossRefGoogle Scholar
  22. Hironaka N, Tanaka K, Izaki Y, Hori K, Nomura M (2001) Memory-related acetylcholine efflux from the rat prefrontal cortex and hippocampus: a microdialysis study. Brain Res 901:143–150PubMedCrossRefGoogle Scholar
  23. Hyman JM, Wyble BP, Goyal V, Rossi CA, Hasselmo ME (2003) Stimulation in hippocampal region CA1 in behaving rats yields long-term potentiation when delivered to the peak of theta and long-term depression when delivered to the trough. J Neurosci 23:11725–11731PubMedGoogle Scholar
  24. Hymovitch B (1952) The effects of experimental variations on problem solving in the rat. J Comp Physiol Psychol 45:313–321PubMedCrossRefGoogle Scholar
  25. Juraska JM, Henderson C, Muller J (1984) Differential rearing experience, gender, and radial maze performance. Dev Psychobiol 17:209–215PubMedCrossRefGoogle Scholar
  26. Komorowski RW, Manns JR, Eichenbaum H (2009) Robust conjunctive item-place coding by hippocampal neurons parallels learning what happens where. J Neurosci 29:9918–9929PubMedCrossRefPubMedCentralGoogle Scholar
  27. Kotani S, Yamauchi T, Teramoto T, Ogura H (2006) Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats. Neuroscience 142:505–514PubMedCrossRefGoogle Scholar
  28. Kritzer MF (1997) Selective colocalization of immunoreactivity for intracellular gonadal hormone receptors and tyrosine hydroxylase in the ventral tegmental area, substantia nigra, and retrorubral fields in the rat. J Comp Neurol 379:247–260PubMedCrossRefGoogle Scholar
  29. Kritzer MF, McLaughlin PJ, Smirlis T, Robinson JK (2001) Gonadectomy impairs T-maze acquisition in adult male rats. Horm Behav 39:167–174PubMedCrossRefGoogle Scholar
  30. Lee MG, Chrobak JJ, Sik A, Wiley RG, Buzsáki G (1994) Hippocampal theta activity following selective lesion of the septal cholinergic system. Neuroscience 62:1033–1047PubMedCrossRefGoogle Scholar
  31. Luine VN, Renner KJ, McEwen BS (1986) Sex-dependent differences in estrogen regulation of choline acetyltransferase are altered by neonatal treatments. Endocrinology 119:874–878PubMedCrossRefGoogle Scholar
  32. Luine V, Jacome LF, MacLusky NJ (2003) Rapid enhancement of visual and place memory by estrogens in rats. Endocrinology 144:2836–2844PubMedCrossRefGoogle Scholar
  33. Lund TD, Hinds LR, Handa RJ (2006) The androgen 5α-dihydrotestosterone and its metabolite 5α-androstan-3β, 17β-diol inhibit the hypothalamo-pituitary-adrenal response to stress by acting through estrogen receptor β-expressing neurons in the hypothalamus. J Neurosci 26:1448–1456PubMedCrossRefGoogle Scholar
  34. Markowska AJ, Savonenko AV (2002) Effectiveness of estrogen replacement in restoration of cognitive function after long-term estrogen withdrawal in aging rats. J Neurosci 22:10985–10995PubMedGoogle Scholar
  35. Markram H, Segal M (1990) Long-lasting facilitation of excitatory postsynaptic potentials in the rat hippocampus by acetylcholine. J Physiol 427:381–393PubMedPubMedCentralGoogle Scholar
  36. Masuda J, Mitsushima D, Funabashi T, Kimura F (2005) Sex and housing conditions affect the 24-h acetylcholine release profile in the hippocampus in rats. Neuroscience 132:537–542PubMedCrossRefGoogle Scholar
  37. McCurry SM, Logsdon RG, Vitiello MV, Teri L (2004) Treatment of sleep and nighttime disturbances in Alzheimer’s disease: a behavior management approach. Sleep Med 5:373–377PubMedCrossRefGoogle Scholar
  38. McEwen BS (1981) Neural gonadal steroid actions. Science 211:1303–1311PubMedCrossRefGoogle Scholar
  39. McEwen BS, Alves SE (1999) Estrogen actions in the central nervous system. Endocr Rev 20:279–307PubMedGoogle Scholar
  40. Mesulam MM, Mufson EJ, Wainer BH, Levey AI (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10:1185–1201PubMedCrossRefGoogle Scholar
  41. Miettinen RA, Kalesnykas G, Koivisto EH (2002) Estimation of the total number of cholinergic neurons containing estrogen receptor-a in the rat basal forebrain. J Histochem Cytochem 50:891–902PubMedCrossRefGoogle Scholar
  42. Mitsushima D, Mizuno T, Kimura F (1996) Age-related changes in diurnal acetylcholine release in the prefrontal cortex of male rats as measured by microdialysis. Neuroscience 72:429–434PubMedCrossRefGoogle Scholar
  43. Mitsushima D, Yamanoi C, Kimura F (1998) Restriction of environmental space attenuates locomotor activity and hippocampal acetylcholine release in male rats. Brain Res 805:207–212PubMedCrossRefGoogle Scholar
  44. Mitsushima D, Funabashi T, Shinohara K, Kimura F (2001) Impairment of maze learning in rats by restricting environmental space. Neurosci Lett 297:73–76PubMedCrossRefGoogle Scholar
  45. Mitsushima D, Masuda J, Kimura F (2003a) Sex differences in the stress-induced release of acetylcholine in the hippocampus and corticosterone from the adrenal cortex in rats. Neuroendocrinology 78:234–240PubMedCrossRefGoogle Scholar
  46. Mitsushima D, Tin-Tin-Win-Shwe, Kimura F (2003b) Sexual dimorphism in the GABAergic control of gonadotropin release in intact rats. Neurosci Res 46:399–405PubMedCrossRefGoogle Scholar
  47. Mitsushima D, Takase K, Funabashi T, Kimura F (2008) Gonadal steroid hormones maintain the stress-induced acetylcholine release in the hippocampus: simultaneous measurements of the extracellular acetylcholine and serum corticosterone levels in the same subjects. Endocrinology 149:802–811PubMedCrossRefGoogle Scholar
  48. Mitsushima D, Takase K, Funabashi T, Kimura F (2009) Gonadal steroids maintain 24-h acetylcholine release in the hippocampus: organizational and activational effects in behaving rats. J Neurosci 29:3808–3815PubMedCrossRefGoogle Scholar
  49. Mizuno T, Kimura F (1996) Medial septal injection of naloxone elevates acetylcholine release in the hippocampus and induces behavioral seizures in rats. Brain Res 713:1–7PubMedCrossRefGoogle Scholar
  50. Mizuno T, Endo Y, Arita J, Kimura F (1991) Acetylcholine release in the rat hippocampus as measured by the microdialysis method correlates with motor activity and exhibits a diurnal variation. Neuroscience 44:607–612PubMedCrossRefGoogle Scholar
  51. Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM (2004) Free testosterone and risk for Alzheimer disease in older men. Neurology 62:188–193PubMedCrossRefGoogle Scholar
  52. Mohapel P, Leanza G, Kokaia M, Lindvall O (2005) Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging 26:939–946PubMedCrossRefGoogle Scholar
  53. Moor E, DeBoer P, Westerink BHC (1998) GABA receptors and benzodiazepine binding sites modulate hippocampal acetylcholine release in vivo. Eur J Pharmacol 359:119–126PubMedCrossRefGoogle Scholar
  54. Mount C, Downtown D (2006) Alzheimer disease: progress or profit? Nat Med 12:780–784PubMedCrossRefGoogle Scholar
  55. Mufson EJ, Cai WJ, Jaffar S, Chen E, Stebbins G, Sendera T, Kordower JH (1999) Estrogen receptor immunoreactivity within subregions of the rat forebrain: neuronal distribution and association with perikarya containing choline acetyltransferase. Brain Res 849:253–274PubMedCrossRefGoogle Scholar
  56. Nakamura N, Fujita H, Kawata M (2002) Effects of gonadectomy on immunoreactivity for choline acetyltransferase in the cortex, hippocampus, and basal forebrain of adult male rats. Neuroscience 109:473–485PubMedCrossRefGoogle Scholar
  57. Nilsson OG, Leanza G, Bjorklund A (1992) Acetylcholine release in the hippocampus: regulation by monoaminergic afferents as assessed by in vivo microdialysis. Brain Res 584:132–140PubMedCrossRefGoogle Scholar
  58. Norbury R, Travis MJ, Erlandsson K, Waddington W, Ell PJ, Murphy DGM (2007) Estrogen therapy and brain muscarinic receptor density in healthy females: a SPET study. Horm Behav 51:249–257PubMedCrossRefGoogle Scholar
  59. Parducz A, Hajszan T, Maclusky NJ, Hoyk Z, Csakvari E, Kurunczi A, Prange-Kiel J, Leranth C (2006) Synaptic remodeling induced by gonadal hormones: neuronal plasticity as a mediator of neuroendocrine and behavioral responses to steroids. Neuroscience 138:977–985PubMedCrossRefGoogle Scholar
  60. Parent MB, Baxter MG (2004) Septohippocampal acetylcholine: involved in but not necessary for learning and memory? Learn Mem 11:9–20PubMedCrossRefPubMedCentralGoogle Scholar
  61. Perry E, Walker M, Grace J, Perry R (1999) Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trend Neurosci 22:273–280PubMedCrossRefGoogle Scholar
  62. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ (2005) Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 352:2379–2388PubMedCrossRefGoogle Scholar
  63. Pongrac JL, Gibbs RB, Defranco DB (2004) Estrogen-mediated regulation of cholinergic expression in basal forebrain neurons requires extracellular signal-regulated kinase activity. Neuroscience 124:809–816PubMedCrossRefGoogle Scholar
  64. Ragozzino ME, Unick KE, Gold PE (1996) Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose. Proc Natl Acad Sci USA 93:4693–4698PubMedCrossRefPubMedCentralGoogle Scholar
  65. Romeo RD, McCarthy JB, Wang A, Milner TA, McEwen BS (2005) Sex differences in hippocampal estradiol-induced N-methyl-D-aspartic acid binding and ultrastructural localization of estrogen receptor-α. Neuroendocrinology 81:391–399PubMedCrossRefGoogle Scholar
  66. Rosario ER, Chang L, Stanczyk FZ, Pike CJ (2004) Age-related testosterone deplation and the development of Alzheimer disease. JAMA 292:1431–1432PubMedCrossRefGoogle Scholar
  67. Rush ME, Blake CA (1982) Serum testosterone concentrations during the 4-day estrous cycle in normal and adrenalectomized rats. Proc Soc Exp Biol Med 169:216–221PubMedCrossRefGoogle Scholar
  68. Sarter M, Parikh V (2005) Choline transporters, cholinergic transmission and cognition. Nat Neurosci 6:48–56CrossRefGoogle Scholar
  69. Seeger T, Fedorova I, Zheng F, Miyakawa T, Koustova E, Gomeza J, Basile AS, Alzheimer C, Wess J (2004) M2 muscarinic acetylcholine receptor knock-out mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity. J Neurosci 24:10117–10127PubMedCrossRefGoogle Scholar
  70. Seymoure P, Dou H, Juraska JM (1996) Sex differences in radial maze performance: influence of rearing environment and room cues. Psychobiology 24:33–37Google Scholar
  71. Shinoe T, Matsui M, Taketo MM, Manabe T (2005) Modulation of synaptic plasticity by physiological activation of M1 muscarinic acetylcholine receptors in the mouse hippocampus. J Neurosci 25:11194–11200PubMedCrossRefGoogle Scholar
  72. Shors TJ, Chua C, Falduto J (2001) Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus. J Neurosci 21:6292–6297PubMedGoogle Scholar
  73. Smith HV (1972) Effects of environmental enrichment on open-field activity and Hebb–Williams problem solving in rats. J Comp Physiol Psychol 80:163–168CrossRefGoogle Scholar
  74. Stancampiano R, Cocco S, Cugusi C, Sarais L, Fadda F (1999) Serotonin and acetylcholine release response in the rat hippocampus during a spatial memory task. Neuroscience 89:1135–1143PubMedCrossRefGoogle Scholar
  75. Starkstein SE, Jorge R, Mizrahi R, Robinson RG (2005) The construct of minor and major depression in Alzheimer’s disease. Am J Psychiatry 162:2086–2093PubMedCrossRefGoogle Scholar
  76. Swaab DF, Hofman MA (1995) Sexual differentiation of the human hypothalamus in relation to gender and sexual orientation. Trend Neurosci 18:264–270PubMedCrossRefGoogle Scholar
  77. Swanson LW (1982) The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 9:321–353PubMedCrossRefGoogle Scholar
  78. Takase K, Funabashi T, Mogi K, Mitsushima D, Kimura F (2005a) Feeding with powdered diet after weaning increases visuospatial ability in association with increases in the expression of N-methyl-D-aspartate receptors in the hippocampus of female rats. Neurosci Res 53:169–175PubMedCrossRefGoogle Scholar
  79. Takase K, Mitsushima D, Masuda J, Mogi K, Funabashi T, Endo Y, Kimura F (2005b) Feeding with powdered diet after weaning affects sex difference in acetylcholine release in the hippocampus in rats. Neuroscience 136:593–599PubMedCrossRefGoogle Scholar
  80. Takase K, Kimura F, Yagami T, Mitsushima D (2009) Sex-specific 24-h acetylcholine release profile in the medial prefrontal cortex: simultaneous measurement of spontaneous locomotor activity in behaving rats. Neuroscience 159:7–15PubMedCrossRefGoogle Scholar
  81. van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running enhances neurogenesis, learning and long-term potentiation in mice. Proc Natl Acad Sci USA 96:13427–13431PubMedCrossRefPubMedCentralGoogle Scholar
  82. Weiner DM, Levey AI, Sunahara RK, Niznik HB, O’Dowd BF, Seeman P, Brann MR (1991) D1 and D2 dopamine receptor mRNA in rat brain. Proc Natl Acad Sci USA 88:1859–1863PubMedCrossRefPubMedCentralGoogle Scholar
  83. Widmer H, Ferrigan L, Davies CH, Cobb SR (2006) Evoked slow muscarinic acetylcholinergic synaptic potentials in rat hippocampal interneurons. Hippocampus 16:617–628PubMedCrossRefGoogle Scholar
  84. Williams CL, Meck WH (1991) The organizational effects of gonadal steroids on sexually dimorphic spatial ability. Psychoneuroendocrinology 16:155–176PubMedCrossRefGoogle Scholar
  85. Winblad B, Kilander L, Eriksson S, Minthon L, Båtsman S, Wetterholm AL, Jansson-Blixt C, Haglund A (2006) Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study. Lancet 367:1057–1065PubMedCrossRefGoogle Scholar
  86. Yanai J, Rogel-Fuchs Y, Pick CG, Slotkin T, Seidler FJ, Zahalka EA, Newman ME (1993) Septohippocampal cholinergic changes after destruction of the A10-septal dopaminergic pathways. Neuropharmacology 32:113–117PubMedCrossRefGoogle Scholar
  87. Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JCS (2002) Hormone replacement therapy and incidence of Alzheimer disease in older women. JAMA 288:2123–2129PubMedCrossRefGoogle Scholar

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© Springer Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Dai Mitsushima
    • 1
  1. 1.Department of PhysiologyYokohama City University Graduate School of MedicineYokohamaJapan

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