Experimental Brain Research

, Volume 167, Issue 1, pp 1–16 | Cite as

Projections from the entorhinal cortex, perirhinal cortex, presubiculum, and parasubiculum to the medial thalamus in macaque monkeys: identifying different pathways using disconnection techniques

  • Richard C. Saunders
  • Mortimer Mishkin
  • John P. AggletonEmail author
Research Article


The projections from the perirhinal cortex, entorhinal cortex, parasubiculum, and presubiculum to the thalamus were examined using both anterograde and retrograde tracers. Attention focused on the routes taken by these projections, which were delineated by combining surgical tract section with the placement of a tracer. Projections to the anterior thalamic nuclei almost exclusively used the fornix. These relatively light projections, which arose from all areas of the entorhinal cortex, from the presubiculum, parasubiculum, and area 35 of the perirhinal cortex, terminated mainly in the anterior ventral nucleus. In contrast, the projections to the lateral dorsal nucleus from the entorhinal cortex, presubiculum and parasubiculum were denser than those to the anterior thalamic nuclei. The projections to the lateral dorsal nucleus used two routes. While nearly all of the projections from the subicular complex used the fornix, many of the entorhinal cortex projections passed caudally in the temporopulvinar bundle to reach the lateral dorsal nucleus. The perirhinal cortex, as well as the entorhinal cortex, also projects to nucleus medialis dorsalis. These projections exclusively used the external capsule and thence the inferior thalamic peduncle. Other temporal-thalamic projections included those to the medial pulvinar, via the temporopulvinar bundle, from the perirhinal and entorhinal cortices, and those to the paraventricular nucleus from the entorhinal cortex. By identifying these routes, it is possible to appreciate how different lesions might disconnect temporal–diencephalic pathways and so contribute to memory disorders.


Anterior thalamic nuclei Lateral dorsal thalamic nucleus Fornix Hippocampus Subiculum Thalamus 



The authors wish to thank Lorraine Woods for helping to prepare the figures.


  1. Aggleton JP, Brown MW (1999) Episodic memory, amnesia, and the hippocampal–anterior thalamic axis. Behav Brain Sci 22:425–489CrossRefPubMedGoogle Scholar
  2. Aggleton JP, Mishkin M (1984) Projections of the amygdala to the thalamus in the cynomolgus monkey. J Comp Neurol 222:56–68CrossRefPubMedGoogle Scholar
  3. Aggleton JP, Mishkin M (1993a) Visual recognition impairment following medial thalamic lesions in monkeys. Neuropsychologia 21:189–197CrossRefGoogle Scholar
  4. Aggleton JP, Mishkin M (1993b) Memory impairments following restricted medial thalamic lesions in monkeys. Exp Brain Res 52:199–209Google Scholar
  5. Aggleton JP, Sahgal A (1993) The contribution of the anterior thalamic nuclei to anterograde amnesia. Neuropsychologia 31:1001–1019CrossRefPubMedGoogle Scholar
  6. Aggleton JP, Desimone R, Mishkin M (1986) The origin, course, and termination of the hippocampo-thalamic projections in the macaque. J Comp Neurol 243:409–421CrossRefPubMedGoogle Scholar
  7. Aggleton JP, McMackin D, Carpenter K, Hornak J, Kapur N, Halpin S, Wiles CM, Kamel H, Brennan P, Gaffan D (2000) Differential effects of colloid cysts in the third ventricle that spare or compromise the fornix. Brain 123:800–815CrossRefPubMedGoogle Scholar
  8. Amaral DG, Cowan WM (1980) Subcortical afferents to the hippocampal formation in the monkey. J Comp Neurol 189:573–591PubMedCrossRefGoogle Scholar
  9. Bachevalier J, Parkinson JK, Mishkin M (1985) Visual recognition in monkeys: effects of separate vs. combined transection of fornix and amygdalofugal pathways. Exp Brain Res 57:554–561PubMedGoogle Scholar
  10. Bentivoglio M, Kultas-Ilinsky K, ilinsky I (1993) Limbic thalamus: structure, intrinsic organisation, and connections. In: Vogt BA, Gabriel M (eds) Neurobiology of the cingulate cortex and limbic thalamus. Birkhauser, Boston, pp 71–122Google Scholar
  11. Beracochea DJ, Jaffard R, Leonard LE (1989) Effects of anterior or dorsomedial thalamic lesions on learning and memory in rats. Behav Neural Biol 51:364–376CrossRefPubMedGoogle Scholar
  12. Braak H, Griffing K, Braak E (1997) Neuroanatomy of Alzheimer’s disease. Alzh Res 3:235–247Google Scholar
  13. Brodman K (1909) Vergleichende Lakalisationslehre der Grosshirnrinde: in ihren Prinzipien dargestellt anf Grund des Zellenbaues. Verlag von Johann Ambrosisus Barth, LeipzigGoogle Scholar
  14. Brown MW, Wilson FAW, Riches P (1987) Neuronal evidence that inferomedial temporal cortex is more important than hippocampus in certain processes underlying recognition memory. Brain Res 409:158–162CrossRefPubMedGoogle Scholar
  15. Byatt G, Dalrymple-Alford JC (1996) Both anteromedial and anteroventral thalamic lesions impair radial-maze learning in rats. Behav Neurosci 110:1335–1348CrossRefPubMedGoogle Scholar
  16. Cramon DY, von Hebel N, Schuri U (1985) A contribution to the anatomical basis of thalamic amnesia. Brain 108:993–1008PubMedCrossRefGoogle Scholar
  17. Daitz HM, Powell TPS (1954) Studies of the connexions of the fornix system. J Neurol Neurosurg Psychiatry 17:75–82PubMedCrossRefGoogle Scholar
  18. Delay J, Brion S (1969) Le syndrome de Korsakoff. Masson, ParisGoogle Scholar
  19. Gaffan D (1992) The role of the hippocampus-fornix-mammillary system in episodic memory. In: Squire LR, Butters N (eds) Neuropsychology of memory, 2nd edn. Guilford Press, New York, pp 336–346Google Scholar
  20. Gaffan D, Gaffan EA (1991) Amnesia in man following transection of the fornix. Brain 114:2611–2618PubMedCrossRefGoogle Scholar
  21. Gaffan D, Parker A (1996) Interaction of perirhinal cortex with the fornix-fimbria: memory for objects and “object-in-place” memory. J Neurosci 16:5864–5869PubMedGoogle Scholar
  22. Goulet S, Dore FY, Murray EA (1998) Aspiration lesions of the amygdala disrupt the rhinal corticothalamic projection system in rhesus monkeys. Exp Brain Res 119:131–140CrossRefPubMedGoogle Scholar
  23. Gower EC (1989) Efferent projections from limbic cortex of the temporal pole to the magnocellular medial dorsal nucleus in the rhesus monkey. J Comp Neurol 280:343–358CrossRefPubMedGoogle Scholar
  24. Graf-Radford N R, Tranel D, van Hoesen GW, Brandt JP (1990) Diencephalic amnesia. Brain 113:1–25PubMedCrossRefGoogle Scholar
  25. Harding A, Halliday G, Caime D, Kril J (2000) Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia. Brain 123:141–154CrossRefPubMedGoogle Scholar
  26. Hardy H, Heimer L (1977) A safer and more sensitive substitute for diaminobenzidene in the light microscopic demonstration of retrograde and anterograde transport of HRP. Neurosci Lett 5:235–240CrossRefPubMedGoogle Scholar
  27. Hodges JR, Carpenter K (1991) Anterograde amnesia with fornix damage following removal of IIIrd ventricle colloid cyst. J Neurol Neurosurg Psychiatry 54:633–638PubMedGoogle Scholar
  28. Hunt PR, Aggleton JP (1998a) An examination of the spatial working memory deficit following neurotoxic medial dorsal thalamic lesions in rats. Behav Brain Res 97:129–141CrossRefPubMedGoogle Scholar
  29. Hunt PR, Aggleton JP (1998b) Neurotoxic lesions of the dorsomedial thalamus impair the acquisition but not the performance of delayed matching to place by rats: a deficit in shifting response rules. J Neurosci 18:10045–10052PubMedGoogle Scholar
  30. Insausti R, Amaral DG, Cowan WM (1987) The entorhinal cortex of the monkey: III Subcortical afferents. J Comp Neurol 264:396–408CrossRefPubMedGoogle Scholar
  31. Keizer K, Kuypers HGJM, Huisman AM, Dann O (1983) Diamidino yellow dihydrochloride (DY.2HCL); a new fluorescent retrograde neuronal tracer which migrates only very slowly out of the cell. Exp Brain Res 51:179–191CrossRefPubMedGoogle Scholar
  32. Klingler J, Gloor P (1960) The connections of the amygdala and the anterior temporal cortex in the human brain. J Comp Neurol 115:333–369CrossRefPubMedGoogle Scholar
  33. Krayniak PF, Siegel A, Meibach RC, Fruchtman D, Scrimenti M (1979) Origin of the fornix system in the squirrel monkey. Brain Res 160:401–411CrossRefPubMedGoogle Scholar
  34. Kuypers HGJM, Bentivoglio M, Catsman-Berrevoets CE, Bharos AT (1980) Double retrograde neuronal labeling through divergent axon collaterals using two fluorescent tracers with the same excitation wavelength which label different features of the cell. Exp Brain Res 40:383–392CrossRefPubMedGoogle Scholar
  35. Leonard BW, Amaral DG, Squire LR, Zola-Morgan S (1995) Transient memory impairment in monkeys with bilateral lesions of the entorhinal cortex. J Neurosci 15:5637–5659PubMedGoogle Scholar
  36. Lorente de No R (1934) Studies on the structure of the cerebral cortex. II continuations of the study of the ammonic system. J Psychol Neurol (Leipzig) 46:113–177Google Scholar
  37. Malkova L, Bachevalier J, Mishkin M, Saunders RC (2001) Neurotoxic lesions of perirhinal cortex impair visual recognition memory in rhesus monkeys. NeuroReport 12:1913–1917PubMedCrossRefGoogle Scholar
  38. Meibach RC, Siegel A (1977) Thalamic projections of the hippocampal formation: evidence for an alternative pathway involving the internal capsule. Brain Res 134:1–12CrossRefPubMedGoogle Scholar
  39. Mesulam M-M (1978) Tetramethyl benzidene for horseradish peroxidase neurohistochemistry: A noncarcinogenic blue reaction-product with superior sensitivity for visualizing neural afferents and efferents. J Histochem Cytochem 26:106–117PubMedGoogle Scholar
  40. Meunier M, Bachevalier J, Mishkin M, Murray EA (1993) Effects on visual recognition of combined and separate ablations of the entorhinal and perirhinal cortex in rhesus monkeys. J Neurosci 12:5418–5432Google Scholar
  41. Mishkin M (1978) Memory in monkeys severely impaired by combined but not by separate removal of amygdala and hippocampus. Nature 273:297–298CrossRefPubMedGoogle Scholar
  42. Mizumori SJY, Williams JD (1993) Directionally selective mnemonic properties of neurons in the lateral dorsal nucleus of the thalamus of rats. J Neurosci 13:4015–4028PubMedGoogle Scholar
  43. Mizumori SJY, Miya DY, Ward KE (1994) Reversible inactivation of the lateral dorsal thalamus disrupts hippocampal place representation and impairs spatial learning. Brain Res 644:168–174CrossRefPubMedGoogle Scholar
  44. Murray EA (1992) Medial temporal lobe structures contributing to recognition memory: the amygdaloid complex versus the rhinal cortex. In: Aggleton JP (ed) The amygdala: neurobiological aspects of emotion, memory, and mental dysfunction. Wiley–Liss, New York, pp 453–470Google Scholar
  45. Murray EA, Mishkin M (1998) Object recognition and location memory in monkeys with excitotoxic lesions of the amygdala and hippocampus. J Neurosci 18:6568–6582PubMedGoogle Scholar
  46. Nauta WJH (1961) Fibre degeneration following lesions of the amygdaloid complex in the monkey. J Anatomy 95:515–532Google Scholar
  47. Olszewski I (1952) The thalamus of the Macaca mulatta. S Karger, BaselGoogle Scholar
  48. Parker A, Gaffan D (1997) The effects of anterior thalamic and cingulate cortex lesions on ″object-in-place″ memory in monkeys. Neuropsychologia 35:1093–1102CrossRefPubMedGoogle Scholar
  49. Poletti CE, Cresswell G (1977) Fornix system efferent projections in the squirrel monkey: an experimental degeneration study. J Comp Neurol 175:101–128CrossRefPubMedGoogle Scholar
  50. Powell EW (1973) Limbic projections to the thalamus of the monkey. J Neurophysiol 4:514–531Google Scholar
  51. Rosene D, Roy NJ, Davis BJ (1986) A cryoprotection method that facilitates cutting frozen sections of whole monkey brains for histological and histochemical processing without freezing artifact. J Histochem Cytochem 34:1301–1315PubMedGoogle Scholar
  52. Russchen FT, Amaral DG, Price JL (1987) The afferent input to the magnocellular division of the mediodorsal thalamic nucleus in the monkey Macaca fascicularis. J Comp Neurol 256:175–210CrossRefPubMedGoogle Scholar
  53. Saleem KS, Tanaka K (1996) Divergent projections from the anterior inferotemporal area TE to the perirhinal and entorhinal cortices in macaque monkey. J Neurosci 16:4757–4775PubMedGoogle Scholar
  54. Saunders RC, Rosene DL (1988) A comparison of the efferents of the amygdala and the hippocampal formation in the rhesus monkey: I Convergence in the entorhinal, prorhinal, and perirhinal cortices. J Comp Neurol 271:153–184CrossRefPubMedGoogle Scholar
  55. Shibata H (1996) Direct projections from the entorhinal area to the anteroventral and laterodorsal thalamic nuclei in the rat. Neurosci Res 26:83–87PubMedGoogle Scholar
  56. Suzuki WA (1996) Neuroanatomy of the monkey entorhinal, perirhinal and parahippocampal cortices: organization of cortical inputs and interconnections with amygdala and striatum. Sem Neurosci 8:3–12CrossRefGoogle Scholar
  57. Suzuki WA, Amaral DG (1994) Topographic organization of the reciprocal connections between the monkey entorhinal cortex and the perirhinal and parahippocampal cortices. J Neurosci 14:1856–1877PubMedGoogle Scholar
  58. Suzuki WA, Amaral DG (2003) Where are the perirhinal and parahippocampal cortices? A historical overview of the nomenclature and boundaries applied to the primate medial temporal lobe. Neuroscience 120:893–906CrossRefPubMedGoogle Scholar
  59. Suzuki WA, Zola-Morgan S, Squire LR, Amaral DG (1993) Lesions of the perirhinal and parahippocampal cortices in the monkey produce long-lasting memory impairment in the visual and tactual modalities. J Neurosci 13:2430–2451PubMedGoogle Scholar
  60. Van Groen T, Wyss JM (1990) The connections of the presubiculum and parasubiculum in the rat. Brain Res 518:227–243CrossRefPubMedGoogle Scholar
  61. Van Groen T, Kadish I, Wyss JM (2002) The role of the laterodorsal nucleus of the thalamus in spatial learning and memory in the rat. Behav Brain Res 136:329–337CrossRefPubMedGoogle Scholar
  62. Van der Werf YD, Witter MP, Uylings HBM, Jolles J (2000) Neuropsychology of infarctions in the thalamus: a review. Neuropsychologia 38:613–627CrossRefPubMedGoogle Scholar
  63. Van der Werf YD, Scheltens P, Lindeboom J, Witter MP, Uylings HBM, Jolles J (2003) Deficits of memory executive functioning and attention following infarctions in the thalamus; a study of 22 cases with localised lesions. Neuropsychologia 41:1330–1344CrossRefPubMedGoogle Scholar
  64. Van der Werf YD, Jolles J, Witter MP, Uylings HBM (2003) Contributions of thalamic nuclei to declarative memory functioning. Cortex 39:1047–1062PubMedGoogle Scholar
  65. Vann SD, Aggleton JP (2004) The mammillary bodies—two memory systems in one? Nat Rev Neurosci 5:35–44CrossRefPubMedGoogle Scholar
  66. Warburton EC, Morgan A, Baird A, Muir JL, Aggleton JP (2001) The conjoint importance of the hippocampus and anterior thalamic thalamic nuclei for allocentric spatial learning: evidence from a disconnection study in the rat. J Neurosci 21:7323–7330PubMedGoogle Scholar
  67. Whitlock DG, Nauta WJH (1956) Subcortical projections from the temporal neocortex in Macaca mulatta. J Comp Neurol 106:183–212CrossRefPubMedGoogle Scholar
  68. Witter MP (2002) The parahippocampal region: past, present, and future. In Witter M, Wouterlood F (eds) The parahippocampal region. Oxford University Press, Oxford, pp 3–19Google Scholar
  69. Witter M, Wouterlood F (2002) The parahippocampal region. Oxford University Press, OxfordGoogle Scholar
  70. Yeterian EH, Pandya DN (1988) Corticothalamic connections of paralimbic regions in the rhesus monkey. J Comp Neurol 269:130–146CrossRefPubMedGoogle Scholar
  71. Zola-Morgan S, Squire LR (1985) Amnesia in monkeys after lesions of the mediodorsal nucleus of the thalamus. Ann Neurol 17:558–564CrossRefPubMedGoogle Scholar
  72. Zola-Morgan S, Squire LR, Amaral DG (1989a) Lesions of the hippocampal formation but not lesions of the fornix or the mammillary nuclei produce long-lasting memory impairment in monkeys. J Neurosci 9:898–913PubMedGoogle Scholar
  73. Zola-Morgan S, Squire LR, Amaral DG, Suzuki WA (1989b) Lesions of perirhinal and parahippocampal cortex that spare the amygdala and hippocampal formation produce severe memory impairment. J Neurosci 9:4355–4370PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Richard C. Saunders
    • 1
  • Mortimer Mishkin
    • 1
  • John P. Aggleton
    • 2
    Email author
  1. 1.Laboratory of NeuropsychologyNational Institute of Mental HealthBethesdaUSA
  2. 2.School of PsychologyCardiff UniversityCardiff, WalesUK

Personalised recommendations