Brain Structure and Function

, Volume 219, Issue 4, pp 1231–1237 | Cite as

GABAergic neurons in the medial septum-diagonal band of Broca (MSDB) are important for acquisition of the classically conditioned eyeblink response

  • J. J. Roland
  • K. L. Janke
  • R. J. Servatius
  • K. C. H. Pang
Original Article
First Online:
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Accepted:

Abstract

The medial septum and diagonal band of Broca (MSDB) influence hippocampal function through cholinergic, GABAergic, and glutamatergic septohippocampal neurons. Non-selective damage of the MSDB or intraseptal scopolamine impairs classical conditioning of the eyeblink response (CCER). Scopolamine preferentially inhibits GABAergic MSDB neurons suggesting that these neurons may be an important modulator of delay CCER, a form of CCER not dependent on the hippocampus. The current study directly examined the importance of GABAergic MSDB neurons in acquisition of delay CCER. Adult male Sprague–Dawley rats received either a sham (PBS) or GABAergic MSDB lesion using GAT1-saporin (SAP). Rats were given two consecutive days of delay eyeblink conditioning with 100 conditioned stimulus–unconditioned stimulus paired trials. Intraseptal GAT1-SAP impaired acquisition of CCER. The impairment was observed on the first day with sham and lesion groups reaching similar performance by the end of the second day. Our results provide evidence that GABAergic MSDB neurons are an important modulator of delay CCER. The pathways by which MSDB neurons influence the neural circuits necessary for delay CCER are discussed.

Keywords

Hippocampus Septohippocampal Delay eyeblink GAT1-saporin 
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Notes

Acknowledgements

The authors would like to thank Amanda Stewart for her help with histology and immunocytochemistry.  This work was supported by NIH grants T32-NS051157 and RO1-NS44373, Biomedical Laboratory Research & Development Service of the VA Office of Research and Development Award Number I01BX000132, Department of Defense and the Stress and Motivated Behavior Institute.

References

  1. Akase E, Alkon DL, Disterhoft JF (1989) Hippocampal lesions impair memory of short-delay conditioned eye blink in rabbits. Behav Neurosci 103(5):935–943PubMedCrossRefGoogle Scholar
  2. Allen MT, Padilla Y, Gluck MA (2002) Ibotenic acid lesions of the medial septum retard delay eyeblink conditioning in rabbits (Oryctolagus cuniculus). Behav Neurosci 116(4):733–738PubMedCrossRefGoogle Scholar
  3. Alreja M, Wu M, Liu W, Atkins JB, Leranth C, Shanabrough M (2000) Muscarinic tone sustains impulse flow in the septohippocampal GABA but not cholinergic pathway: implications for learning and memory. J Neurosci 20(21):8103–8110PubMedGoogle Scholar
  4. Amaral DG, Kurz J (1985) An analysis of the origins of the cholinergic and noncholinergic septal projections to the hippocampal formation of the rat. J Comp Neurol 240:37–59PubMedCrossRefGoogle Scholar
  5. Asaka Y, Griffin AL, Berry SD (2002) Reversible septal inactivation disrupts hippocampal slow-wave and unit activity and impairs trace conditioning in rabbits (Oryctolagus cuniculus). Behav Neurosci 116(3):434–442PubMedCrossRefGoogle Scholar
  6. Asaka Y, Mauldin KN, Griffin AL, Seager MA, Shurell E, Berry SD (2005) Nonpharmacological amelioration of age-related learning deficits: the impact of hippocampal theta-triggered training. Proc Natl Acad Sci USA 102(37):13284–13288PubMedCentralPubMedCrossRefGoogle Scholar
  7. Berger TW, Clark GA, Thompson RF (1980) Learning-dependent neuronal responses recorded from limbic system brain structures during classical-conditioning. Physiol Psychol 8(2):155–167CrossRefGoogle Scholar
  8. Berry SD, Hoffmann LC (2011) Hippocampal theta-dependent eyeblink classical conditioning: coordination of a distributed learning system. Neurobiol Learn Mem 95(2):185–189PubMedCrossRefGoogle Scholar
  9. Berry SD, Thompson RF (1978) Prediction of learning rate from the hippocampal electroencephalogram. Science 200:1298–1300PubMedCrossRefGoogle Scholar
  10. Berry SD, Thompson RF (1979) Medial septal lesions retard classical conditioning of the nictitating membrane response in rabbits. Science 205:209–211PubMedCrossRefGoogle Scholar
  11. Beylin AV, Gandhi CC, Wood GE, Talk AC, Matzel LD, Shors TJ (2001) The role of the hippocampus in trace conditioning: temporal discontinuity or task difficulty? Neurobiol Learn Mem 76:447–461PubMedCrossRefGoogle Scholar
  12. Blankenship MR, Huckfeldt R, Steinmetz JJ, Steinmetz JE (2005) The effects of amygdala lesions on hippocampal activity and classical eyeblink conditioning in rats. Brain Res 1035(2):120–130PubMedCrossRefGoogle Scholar
  13. Borhegyi Z, Varga V, Szilagyl N, Fabo D, Freund TF (2004) Phase segregation of medial septal GABAergic neurons during hippocampal theta activity. J Neurosci 24(39):8470–8479PubMedCrossRefGoogle Scholar
  14. Brazhnik ES, Fox SE (1999) Action potentials and relations to the theta rhythm of medial septal neurons in vivo. Exp Brain Res 127:244–258PubMedCrossRefGoogle Scholar
  15. Christian KM, Thompson RF (2003) Neural substrates of eyeblink conditioning: acquisition and retention. Learn Mem 10:427–455PubMedCrossRefGoogle Scholar
  16. Freund TF (1989) GABAergic septohippocampal neurons contain parvalbumin. Brain Res 478:375–381PubMedCrossRefGoogle Scholar
  17. Freund TF, Antal M (1988) GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus. Lett Nat 336:170–173CrossRefGoogle Scholar
  18. Frotscher M, Leranth C (1985) Cholinergic innervation of the rat hippocampus as revealed by choline acetyltransferase immunocytochemistry: a combined light and electron microscopic study. J Comp Neurol 239:237–246PubMedCrossRefGoogle Scholar
  19. Gaykema RPA, Luiten PGM, Nyakas C, Traber J (1990) Cortical projection patterns of the medial septum-diagonal band complex. J Comp Neurol 293:103–124PubMedCrossRefGoogle Scholar
  20. Givens BS, Olton DS (1990) Cholinergic and GABAergic modulation of medial septal area: effect on working memory. Behav Neurosci 104(6):849–855PubMedCrossRefGoogle Scholar
  21. Gray JA, McNaughton N (1983) Comparison between the behavioural effects of septal and hippocampal lesions: a review. Neurosci Biobehav Rev 7:119–188PubMedCrossRefGoogle Scholar
  22. Green JT, Arenos JD (2007) Hippocampal and cerebellar single-unit activity during delay and trace eyeblink conditioning in the rat. Neurobiol Learn Mem 87:269–284PubMedCentralPubMedCrossRefGoogle Scholar
  23. Gritti I, Henny P, Galloni F, Mainville L, Mariotti M, Jones BE (2006) Stereological estimates of the basal forebrain cell population in the rat, including neurons containing choline acetyltransferase, glutamic acid decarboxylase or phosphate-activated glutaminase and colocalizing vesicular glutamate transporters. Neuroscience 143:1051–1064PubMedCentralPubMedCrossRefGoogle Scholar
  24. Gulyas AI, Gorcs TJ, Freund TF (1990) Innervation of different peptide-containing neurons in the hippocampus by GABAergic septal afferents. Neuroscience 37(1):31–44PubMedCrossRefGoogle Scholar
  25. Harvey JA, Land T, McMaster E (1984) Anatomical study of the rabbit’s corneal-VIth nerve reflex: connections between cornea, trigemical sensory complex, and the abducens and accessory abducens nuclei. Brain Res 301:307–321PubMedCrossRefGoogle Scholar
  26. Hoffmann LC, Berry SD (2009) Cerebellar theta oscillations are synchronized during hippocampal theta-contingent trace conditioning. Proc Natl Acad Sci USA 106(50):21371–21376PubMedCentralPubMedCrossRefGoogle Scholar
  27. Hopkins DA, Holstege G (1978) Amygdaloid projections to the mesencephalon, pons and medulla oblongata in the cat. Exp Brain Res 32:529–547PubMedCrossRefGoogle Scholar
  28. Horikawa K, Armstrong WE (1988) A versatile means of intracellular labeling: injection of biocytin and its detection with avidin conjugates. J Neurosci Methods 25:1–11PubMedCrossRefGoogle Scholar
  29. Kesner RP, Crutcher KA, Measom MO (1986) Medial septal and nucleus basalis magnocellularis lesions produce order memory deficit in rats which mimic symptomology of Alzheimer’s disease. Neurobiol Aging 7:287–295PubMedCrossRefGoogle Scholar
  30. Koppen JR, Winter SS, Stuebing SL, Cheatwood JL, Wallace DG (2012) Infusion of GAT1-saporin into the medial septum/vertical limb of the diagonal band disrupts self-movement cue processing and spares mnemonic function. Brain Struct Funct (in press)Google Scholar
  31. Lavond DG, Kim JJ, Thompson RF (1993) Mammalian substrates of aversive classical conditioning. Annu Rev Psychol 44:317–342PubMedCrossRefGoogle Scholar
  32. Lee T, Kim JJ (2004) Differential effects of cerebellar, amygdalar, and hippocampal lesions on classical eyeblink conditioning in rats. J Neurosci 24(13):3242–3250PubMedCrossRefGoogle Scholar
  33. Lockhart M, Moore JW (1975) Classical differential and operant conditioning in rabbits (Oryctolagus cuniculus) with septal lesions. J Comp Physiol Psychol 88:147–154PubMedCrossRefGoogle Scholar
  34. Manseau F, Danik M, Williams S (2005) A functional glutamatergic neurone network in the medial septum and diagonal band area. J Physiol 566:865–884PubMedCentralPubMedCrossRefGoogle Scholar
  35. 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(4):1185–1201PubMedCrossRefGoogle Scholar
  36. Mizumori SJY, Perez GM, Alvarado MC, Barnes CA, McNaughton BL (1990) Reversible inactivation of the medial septum differentially affects two forms of learning in rats. Brain Res 528:12–20PubMedCrossRefGoogle Scholar
  37. Moore JW, Goodell N, Solomon PA (1976) Central cholinergic blockade by scopolamine and habituation, classical conditioning, and latent inhibition of the rabbit’s nictitating membrane response. Physiol Psychol 4:395–399CrossRefGoogle Scholar
  38. Nokia MS, Penttonen M, Korhonen T, Wikgren J (2008) Hippocampal theta (3–8 Hz) activity during classical eyeblink conditioning in rabbits. Neurobiol Learn Mem 90:62–70PubMedCrossRefGoogle Scholar
  39. Pang KCH, Jiao X, Sinha S, Beck KD, Servatius RJ (2011) Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance: effects on proactive interference. Hippocampus 21(8):835–846PubMedCentralPubMedGoogle Scholar
  40. Parent MB, Baxter MG (2004) Septohippocampal acetylcholine: involved in but not necessary for learning and memory? Learn Mem 11:9–20PubMedCentralPubMedCrossRefGoogle Scholar
  41. Powell DA, Churchwell J, Burriss L (2005) Medial prefrontal lesions and Pavlovian eyeblink and heart rate conditioning: effects of partial reinforcement on delay and trace conditioning in rabbits (Oryctolagus cuniculus). Behav Neurosci 119(1):180–189PubMedCrossRefGoogle Scholar
  42. Radley JJ, Gosselink KL, Sawchenko PE (2009) A discrete GABAergic relay mediates medial prefrontal cortical inhibition of the neuroendocrine stress response. J Neurosci 29(22):7330–7340PubMedCentralPubMedCrossRefGoogle Scholar
  43. Raymond JL, Lisberger SG, Mauk MD (1996) The cerebellum: a neuronal learning machine? Science 272:1126–1131PubMedCrossRefGoogle Scholar
  44. Russchen FT (1982) Amygdalopetal projections in the cat: II. subcortical afferent connections. A study with retrograde tracing techniques. J Comp Neurol 207:157–176PubMedCrossRefGoogle Scholar
  45. Sakamoto T, Endo S (2010) Amygdala, deep cerebellar nuclei and red nucleus contribute to delay eyeblink conditioning in C57BL/6 mice. Behav Neurosci 32:1537–1551Google Scholar
  46. Salafia WR, Romano AG, Tynan T, Host KC (1977) Disruption of rabbit (Oryctolagus cuniculus) nictitating membrane conditioning by posttrial electrical stimulation of hippocampus. Physiol Behav 18(2):207–212PubMedCrossRefGoogle Scholar
  47. Salvatierra A, Berry S (1989) Scopolamine disruption of septohippocampal activity and classical conditioning. Behav Neurosci 103:715–721PubMedCrossRefGoogle Scholar
  48. Schmaltz LW, Theios J (1972) Acquisition and extinction of a classically conditioned response in hippocampectomized rabbits (Oryctolagus cuniculus). J Comp Physiol Psychol 95:322–330Google Scholar
  49. Seager MA, Johnson LD, Chabot ES, Asaka Y, Berry SD (2002) Oscillatory brain states and learning: impact of hippocampal theta-contingent training. Proc Natl Acad Sci USA 99:1616–1620PubMedCentralPubMedCrossRefGoogle Scholar
  50. Servatius RJ (2000) Eyeblink conditioning in the freely moving rat: square-wave stimulation as the unconditioned stimulus. J Neurosci Methods 102:35–42PubMedCrossRefGoogle Scholar
  51. Shohamy D, Allen MT, Gluck MA (2000) Dissociating entorhinal and hippocampal involvement in latent inhibition. Behav Neurosci 114(5):867–874PubMedCrossRefGoogle Scholar
  52. Simon AP, Poindessous-Jazat F, Dutar P, Epelbaum J, Bassant MH (2006) Firing properties of anatomically identified neurons in the medial septum of anesthetized and unanesthetized restrained rats. J Neurosci 26:9038–9046PubMedCrossRefGoogle Scholar
  53. Solomon PR, Gottfried KE (1981) The septohippocampal cholinergic system and classical conditioning of the rabbit’s nictitating membrane response. J Comp Physiol Psychol 95(2):322–330PubMedCrossRefGoogle Scholar
  54. Solomon PR, Moore J (1975) Latent inhibition and stimulus generalization of the classically conditioned nictitating membrane response in rabbits (Oryctolagus cuniculus) following dorsal hippocampal ablation. J Comp Physiol Psychol 89:1192–1203PubMedCrossRefGoogle Scholar
  55. Solomon PR, Solomon SD, VanderSchaaf E, Perry HE (1983) Altered activity in the hippocampus is more detrimental to classical conditioning than removing the structure. Science 220(4594):329–331PubMedCrossRefGoogle Scholar
  56. Sotty F, Danik M, Manseau F, Laplante F, Quirion R, Williams S (2003) Distinct electrophysiological properties of glutamatergic, cholinergic and GABAergic rat septohippocampal neurons: novel implications for hippocampal rhythmicity. J Physiol 551:927–943PubMedCentralPubMedCrossRefGoogle Scholar
  57. Thompson RF (1986) The neurobiology of learning and memory. Science 233:941–947PubMedCrossRefGoogle Scholar
  58. Volz HP, Rehbein G, Triepel J, Knuepfer MM, Stumpf H, Stock G (1990) Afferent connections of the nucleus centralis amygdalae. Anat Embryol 181:177–194PubMedCrossRefGoogle Scholar
  59. Weisz DJ, Harden DG, Xiang Z (1992) Effects of amygdala lesions on reflex facilitation and conditioned response acquisition during nictitating membrane response conditioning in rabbit. Behav Neurosci 106:262–273PubMedCrossRefGoogle Scholar
  60. West MJ (1999) Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias. Trends Neurosci 22:51–61PubMedCrossRefGoogle Scholar
  61. Whalen PJ, Kapp BS (1991) Contributions of the amygdaloid central nucleus to the modulation of the nictitating membrane reflex in the rabbit. Behav Neurosci 105:141–153PubMedCrossRefGoogle Scholar
  62. Wikgren J, Nokia MS, Penttonen M (2010) Hippocampa-cerebellar theta band phase synchrony in rabbits. Neuroscience 165(4):1538–1545PubMedCrossRefGoogle Scholar
  63. Wu M, Shanabrough M, Leranth C, Alreja M (2000) Cholinergic excitation of septohippocampal GABA but not cholinergic neurons: implications for learning and memory. J Neurosci 20(10):3900–3908PubMedGoogle Scholar
  64. Wu G, Yao J, Zhang L, Li X, Fan Z, Yang Y, Sui J (2012) Reevaluating the role of the medial prefrontal cortex in delay eyeblink conditioning. Neurobiol Learn Mem 97:277–288PubMedCrossRefGoogle Scholar
  65. Yoder RM, Pang KCH (2005) Involvement of GABAergic and cholinergic medial septal neurons in hippocampal theta rhythm. Hippocampus 15(3):381–392PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • J. J. Roland
    • 1
  • K. L. Janke
    • 2
  • R. J. Servatius
    • 1
    • 2
    • 3
  • K. C. H. Pang
    • 1
    • 2
    • 3
  1. 1.Stress and Motivated Behavior InstituteEast OrangeUSA
  2. 2.Graduate School of Biomedical SciencesNJMS-UMDNJNewarkUSA
  3. 3.Neurobehavioral Research Laboratory (129), DVA Medical CenterNJHCSEast OrangeUSA

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