Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A pathophysiological framework of hippocampal dysfunction in ageing and disease

Nature Reviews Neuroscience volume 12, pages 585–601 (2011)Cite this article

Subjects

This article has been updated

Key Points

  • Expression profiling has established a 'molecular map' of the hippocampal formation, organized over its transverse and long axes. This molecular map provides a possible substrate for regional vulnerability and can in part account for why ageing and a range of diseases target different hippocampal subregions.

  • Electrophysiological, functional MRI and behavioural studies have suggested a 'functional map' of the hippocampal formation, organized over its transverse and long axes. This map can explain why ageing and a range of diseases manifest with phenotypic diversity, despite targeting the same brain structure.

  • Perhaps surprisingly, hippocampal dysfunction can be characterized by either an abnormal hypometabolic or hypermetabolic state.

  • Establishing differential patterns of hippocampal vulnerability could provide information on the underlying mechanisms. For example, the fact that the entorhinal cortex is vulnerable to Alzheimer's disease but is relatively spared in cognitive ageing suggests that these conditions are mediated by separate pathogenic mechanisms.

  • Establishing abnormalities in metabolic state can also suggest mechanistic clues. For example, the hippocampal hypermetabolism that is observed in schizophrenia is proposed to be linked to elevations in synaptic glutamate.

  • Results from MRI tools that have been developed to image the hippocampal circuit have given rise to a pathophysiological framework. Newer imaging tools and large-scale longitudinal studies are expected to address outstanding issues, including mapping how ageing and disease spread over time, and providing additional insights into pathogenesis.

Abstract

The hippocampal formation has been implicated in a growing number of disorders, from Alzheimer's disease and cognitive ageing to schizophrenia and depression. How can the hippocampal formation, a complex circuit that spans the temporal lobes, be involved in a range of such phenotypically diverse and mechanistically distinct disorders? Recent neuroimaging findings indicate that these disorders differentially target distinct subregions of the hippocampal circuit. In addition, some disorders are associated with hippocampal hypometabolism, whereas others show evidence of hypermetabolism. Interpreted in the context of the functional and molecular organization of the hippocampal circuit, these observations give rise to a unified pathophysiological framework of hippocampal dysfunction.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The organization of the hippocampal formation.
Figure 2: Regional vulnerability and metabolic state differentiate disorders that affect the hippocampal formation.
Figure 3: A proposed 'functional map' of the hippocampal circuit.
Figure 4: Proposed hippocampus-based networks in schizophrenia and depression.

Change history

  • 08 September 2011

    The addresses of the first 2 authors (Scott A. Small and Scott A. Schobel) were not displayed correctly. This has now been corrected.

References

  1. Zola-Morgan, S., Squire, L. R. & Amaral, D. G. Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J. Neurosci. 6, 2950–2967 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wu, W. et al. The brain in the age of old: the hippocampal formation is targeted differentially by diseases of late life. Ann. Neurol. 64, 698–706 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sloviter, R. S., Sollas, A. L., Dean, E. & Neubort, S. Adrenalectomy-induced granule cell degeneration in the rat hippocampal dentate gyrus: characterization of an in vivo model of controlled neuronal death. J. Comp. Neurol. 330, 324–336 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Fanselow, M. S. & Dong, H. W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhao, X. et al. Transcriptional profiling reveals strict boundaries between hippocampal subregions. J. Comp. Neurol. 441, 187–196 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Thompson, C. L. et al. Genomic anatomy of the hippocampus. Neuron 60, 1010–1021 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Coultrap, S. J., Nixon, K. M., Alvestad, R. M., Valenzuela, C. F. & Browning, M. D. Differential expression of NMDA receptor subunits and splice variants among the CA1, CA3 and dentate gyrus of the adult rat. Brain Res. Mol. Brain Res. 135, 104–111 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Sloviter, R. S. et al. Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy. Science 243, 535–538 (1989).

    Article  CAS  PubMed  Google Scholar 

  9. Amaral, D. G. & Witter, M. P. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571–591 (1989).

    Article  CAS  PubMed  Google Scholar 

  10. Lorente de Nó, R. Studies on the structure of the cerebral cortex II. Continuation of the study of the ammonic system. J. Psychol. Neurol. 46, 113–117 (1934).

    Google Scholar 

  11. van Strien, N. M., Cappaert, N. L. & Witter, M. P. The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network. Nature Rev. Neurosci. 10, 272–282 (2009).

    Article  CAS  Google Scholar 

  12. Lavenex, P. & Amaral, D. G. Hippocampal–neocortical interaction: a hierarchy of associativity. Hippocampus 10, 420–430 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Squire, L. R., Stark, C. E. & Clark, R. E. The medial temporal lobe. Annu. Rev. Neurosci. 27, 279–306 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Rosene, D. L. & Van Hoesen, G. W. Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey. Science 198, 315–317 (1977).

    Article  CAS  PubMed  Google Scholar 

  15. Kobayashi, Y. & Amaral, D. G. Macaque monkey retrosplenial cortex: II. Cortical afferents. J. Comp. Neurol. 466, 48–79 (2003).

    Article  PubMed  Google Scholar 

  16. Friedman, D. P., Aggleton, J. P. & Saunders, R. C. Comparison of hippocampal, amygdala, and perirhinal projections to the nucleus accumbens: combined anterograde and retrograde tracing study in the Macaque brain. J. Comp. Neurol. 450, 345–365 (2002).

    Article  PubMed  Google Scholar 

  17. Small, S., Nava, A., DeLaPaz, R., Mayeux, R. & Stern, Y. Circuit mechanisms underlying memory encoding and retrieval in the long axis of the hippocampal formation. Nature Neurosci. 4, 442–449 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Papatheodoropoulos, C. & Kostopoulos, G. Dorsal-ventral differentiation of short-term synaptic plasticity in rat CA1 hippocampal region. Neurosci. Lett. 286, 57–60 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Papatheodoropoulos, C. & Kostopoulos, G. Decreased ability of rat temporal hippocampal CA1 region to produce long-term potentiation. Neurosci. Lett. 279, 177–180 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Izaki, Y., Takita, M. & Nomura, M. Comparative induction of long-term depression between dorsal and ventral hippocampal CA1 in the anesthetized rat. Neurosci. Lett. 294, 171–174 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Kjelstrup, K. B. et al. Finite scale of spatial representation in the hippocampus. Science 321, 140–143 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Jung, M. W., Wiener, S. I. & McNaughton, B. L. Comparison of spatial firing characteristics of units in dorsal and ventral hippocampus of the rat. J. Neurosci. 14, 7347–7356 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bast, T., Wilson, I. A., Witter, M. P. & Morris, R. G. From rapid place learning to behavioral performance: a key role for the intermediate hippocampus. PLoS Biol. 7, e1000089 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bast, T. & Feldon, J. Hippocampal modulation of sensorimotor processes. Prog. Neurobiol. 70, 319–345 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Moser, M. B. & Moser, E. I. Functional differentiation in the hippocampus. Hippocampus 8, 608–619 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Lau, J. Y. et al. BDNF gene polymorphism (Val66Met) predicts amygdala and anterior hippocampus responses to emotional faces in anxious and depressed adolescents. Neuroimage 53, 952–961 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Rempel-Clower, N. L., Zola, S. M., Squire, L. R. & Amaral, D. G. Three cases of enduring memory impairment after bilateral damage limited to the hippocampal formation. J. Neurosci. 16, 5233–5255 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zola, S. M. et al. Impaired recognition memory in monkeys after damage limited to the hippocampal region. J. Neurosci. 20, 451–463 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H. & Del Tredici, K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 112, 389–404 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Thal, D. R., Rub, U., Orantes, M. & Braak, H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800 (2002).

    Article  PubMed  Google Scholar 

  31. Gomez-Isla, T. et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci. 16, 4491–4500 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. West, M. J., Coleman, P. D., Flood, D. G. & Troncoso, J. C. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet 344, 769–772 (1994). Using careful measures of neuronal loss, this is one of the first studies to show that the dentate gyrus is relatively resistant to Alzheimer's disease.

    Article  CAS  PubMed  Google Scholar 

  33. Schwarcz, R. & Witter, M. P. Memory impairment in temporal lobe epilepsy: the role of entorhinal lesions. Epilepsy Res. 50, 161–177 (2002).

    Article  PubMed  Google Scholar 

  34. Du, F. et al. Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy. Epilepsy Res. 16, 223–233 (1993).

    Article  CAS  PubMed  Google Scholar 

  35. Moreno, H. et al. Imaging the Aβ-related neurotoxicity of Alzheimer disease. Arch. Neurol. 64, 1467–1477 (2007).

    Article  PubMed  Google Scholar 

  36. Mueller, S. G. et al. Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer's disease. Hum. Brain Mapp. 31, 1339–1347 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Mueller, S. G. & Weiner, M. W. Selective effect of age, Apo e4, and Alzheimer's disease on hippocampal subfields. Hippocampus 19, 558–564 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mueller, S. G. et al. Subfield atrophy pattern in temporal lobe epilepsy with and without mesial sclerosis detected by high-resolution MRI at 4 Tesla: preliminary results. Epilepsia 50, 1474–1483 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Erickson, C. A. & Barnes, C. A. The neurobiology of memory changes in normal aging. Exp. Gerontol. 38, 61–69 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Small, S. A. Measuring correlates of brain metabolism with high-resolution MRI: a promising approach for diagnosing Alzheimer disease and mapping its course. Alzheimer Dis. Assoc. Disord. 17, 154–161 (2003).

    Article  PubMed  Google Scholar 

  41. Small, S. A., Chawla, M. K., Buonocore, M., Rapp, P. R. & Barnes, C. A. Imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging. Proc. Natl Acad. Sci. USA 101, 7181–7186 (2004). This study applied a high-resolution variant of fMRI in ageing rhesus monkeys to show that the dentate gyrus is differentially affected by normal ageing, and that the entorhinal cortex is relatively preserved.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Moreno, H., Hua, F., Brown, T. & Small, S. Longitudinal mapping of mouse cerebral blood volume with MRI. NMR Biomed. 19, 535–543 (2006).

    Article  PubMed  Google Scholar 

  43. Small, S. A., Tsai, W. Y., DeLaPaz, R., Mayeux, R. & Stern, Y. Imaging hippocampal function across the human life span: is memory decline normal or not? Ann. Neurol. 51, 290–295 (2002).

    Article  PubMed  Google Scholar 

  44. Marr, D. Simple Memory: a theory for archicortex. Phil. Trans. R. Soc. Lond. B 262, 23–81 (1971).

    Article  CAS  Google Scholar 

  45. Gilbert, P. E., Kesner, R. P. & Lee, I. Dissociating hippocampal subregions: double dissociation between dentate gyrus and CA1. Hippocampus 11, 626–636 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Leutgeb, J. K., Leutgeb, S., Moser, M. B. & Moser, E. I. Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science 315, 961–966 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. McHugh, T. J. et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317, 94–99 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Clelland, C. D. et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bakker, A., Kirwan, C. B., Miller, M. & Stark, C. E. Pattern separation in the human hippocampal CA3 and dentate gyrus. Science 319, 1640–1642 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Toner, C. K., Pirogovsky, E., Kirwan, C. B. & Gilbert, P. E. Visual object pattern separation deficits in nondemented older adults. Learn. Mem. 16, 338–342 (2009).

    Article  PubMed  Google Scholar 

  51. Yassa, M. A. et al. Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults. Hippocampus 20 May 2010 (doi:10.1002/hipo.20808).

  52. Yassa, M. A. et al. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage 51, 1242–1252 (2010).

    Article  PubMed  Google Scholar 

  53. Raz, N., Ghisletta, P., Rodrigue, K. M., Kennedy, K. M. & Lindenberger, U. Trajectories of brain aging in middle-aged and older adults: regional and individual differences. Neuroimage 51, 501–511 (2010).

    Article  PubMed  Google Scholar 

  54. Raz, N. et al. Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb. Cortex 15, 1676–1689 (2005).

    Article  PubMed  Google Scholar 

  55. Shing, Y. L. et al. Hippocampal subfield volumes: age, vascular risk, and correlation with associative memory. Front. Aging Neurosci. 3, 2 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Yassa, M. A., Muftuler, L. T. & Stark, C. E. Ultrahigh-resolution microstructural diffusion tensor imaging reveals perforant path degradation in aged humans in vivo. Proc. Natl Acad. Sci. USA 107, 12687–12691 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jespersen, S. N., Kroenke, C. D., Ostergaard, L., Ackerman, J. J. & Yablonskiy, D. A. Modeling dendrite density from magnetic resonance diffusion measurements. Neuroimage 34, 1473–1486 (2007).

    Google Scholar 

  58. Yassa, M. A., Mattfeld, A. T., Stark, S. M. & Stark, C. E. Age-related memory deficits linked to circuit-specific disruptions in the hippocampus. Proc. Natl Acad. Sci. USA 108, 8873–8878 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ashton, D., Van Reempts, J., Haseldonckx, M. & Willems, R. Dorsal-ventral gradient in vulnerability of CA1 hippocampus to ischemia: a combined histological and electrophysiological study. Brain Res. 487, 368–372 (1989).

    Article  CAS  PubMed  Google Scholar 

  60. Casanova, M. F. & Rothberg, B. Shape distortion of the hippocampus: a possible explanation of the pyramidal cell disarray reported in schizophrenia. Schizophr. Res. 55, 19–24 (2002).

    Article  PubMed  Google Scholar 

  61. Narr, K. L. et al. Regional specificity of hippocampal volume reductions in first-episode schizophrenia. Neuroimage 21, 1563–1575 (2004). This study used a structural MRI variant to show selective volume reductions in CA1 in first-episode schizophrenia.

    Article  PubMed  Google Scholar 

  62. Schobel, S. A. et al. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch. Gen. Psychiatry 66, 938–946 (2009). This study used an fMRI variant to show that CA1 is affected even in prodromal stages of schizophrenia, and that the abnormality is suggestive of abnormal hypermetabolism.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Posener, J. A. et al. High-dimensional mapping of the hippocampus in depression. Am. J. Psychiatry 160, 83–89 (2003). This study used a structural MRI variant to show selective volume reductions in the subiculum in depression.

    Article  PubMed  Google Scholar 

  64. Ballmaier, M. et al. Hippocampal morphology and distinguishing late-onset from early-onset elderly depression. Am. J. Psychiatry 165, 229–237 (2008).

    Article  PubMed  Google Scholar 

  65. Oler, J. A. et al. Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature 466, 864–868 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ressler, K. J. & Mayberg, H. S. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nature Neurosci. 10, 1116–1124 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Bremner, J. D. et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am. J. Psychiatry 152, 973–981 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang, Z. et al. Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder. Arch. Gen. Psychiatry 67, 296–303 (2010). This study used a structural MRI variant to show selective volume reductions in the dentate gyrus (or CA3) in PTSD.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Fox, P. T. & Raichle, M. E. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc. Natl Acad. Sci. USA 83, 1140–1144 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Donahue, M. J. et al. Hemodynamic changes after visual stimulation and breath holding provide evidence for an uncoupling of cerebral blood flow and volume from oxygen metabolism. J. Cereb. Blood Flow Metab. 29, 176–185 (2009).

    Article  PubMed  Google Scholar 

  71. Buxton, R. B. Interpreting oxygenation-based neuroimaging signals: the importance and the challenge of understanding brain oxygen metabolism. Front. Neuroenergetics 2, 8 (2010).

    PubMed  PubMed Central  Google Scholar 

  72. Ances, B. M. et al. Regional differences in the coupling of cerebral blood flow and oxygen metabolism changes in response to activation: implications for BOLD-fMRI. Neuroimage 39, 1510–1521 (2008).

    Article  PubMed  Google Scholar 

  73. Chiarelli, P. A. et al. Flow-metabolism coupling in human visual, motor, and supplementary motor areas assessed by magnetic resonance imaging. Magn. Reson. Med. 57, 538–547 (2007).

    Article  PubMed  Google Scholar 

  74. Davis, T. L., Kwong, K. K., Weisskoff, R. M. & Rosen, B. R. Calibrated functional MRI: mapping the dynamics of oxidative metabolism. Proc. Natl Acad. Sci. USA 95, 1834–1839 (1998). This is a landmark study that established that, if uncalibrated, BOLD cannot reliably map brain metabolism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Brown, G. G. et al. BOLD and perfusion response to finger-thumb apposition after acetazolamide administration: differential relationship to global perfusion. J. Cereb. Blood Flow Metab. 23, 829–837 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Chiarelli, P. A., Bulte, D. P., Piechnik, S. & Jezzard, P. Sources of systematic bias in hypercapnia-calibrated functional MRI estimation of oxygen metabolism. Neuroimage 34, 35–43 (2007).

    Article  PubMed  Google Scholar 

  77. Ances, B. M. et al. Effects of aging on cerebral blood flow, oxygen metabolism, and blood oxygenation level dependent responses to visual stimulation. Hum. Brain Mapp. 30, 1120–1132 (2009).

    Article  PubMed  Google Scholar 

  78. Fleisher, A. S. et al. Cerebral perfusion and oxygenation differences in Alzheimer's disease risk. Neurobiol. Aging 30, 1737–1748 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. de Leon, M. J. et al. Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc. Natl Acad. Sci. USA 98, 10966–10971 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Shin, L. M. et al. Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch. Gen. Psychiatry 66, 1099–1107 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Molina, M. E., Isoardi, R., Prado, M. N. & Bentolila, S. Basal cerebral glucose distribution in long-term post-traumatic stress disorder. World J. Biol. Psychiatry 1–9 (2007).

  82. Yehuda, R. et al. Changes in relative glucose metabolic rate following cortisol administration in aging veterans with posttraumatic stress disorder: an FDG-PET neuroimaging study. J. Neuropsychiatry Clin. Neurosci. 21, 132–143 (2009).

    Article  PubMed  Google Scholar 

  83. Malaspina, D. et al. Resting neural activity distinguishes subgroups of schizophrenia patients. Biol. Psychiatry 56, 931–937 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Kawasaki, Y. et al. Regional cerebral blood flow in patients with schizophrenia. A preliminary report. Eur. Arch. Psychiatry Clin. Neurosci. 241, 195–200 (1992). This is the first in a series of studies that established that the hippocampal formation in schizophrenia is characterized by a hypermetabolic state.

    Article  CAS  PubMed  Google Scholar 

  85. Friston, K. J., Liddle, P. F., Frith, C. D., Hirsch, S. R. & Frackowiak, R. S. The left medial temporal region and schizophrenia. A PET study. Brain 115, 367–382 (1992).

    Article  PubMed  Google Scholar 

  86. Heckers, S. et al. Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nature Neurosci. 1, 318–323 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Medoff, D. R., Holcomb, H. H., Lahti, A. C. & Tamminga, C. A. Probing the human hippocampus using rCBF: contrasts in schizophrenia. Hippocampus 11, 543–550 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Videbech, P. et al. The Danish PET/depression project: PET findings in patients with major depression. Psychol. Med. 31, 1147–1158 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Videbech, P. et al. The Danish PET/depression project: clinical symptoms and cerebral blood flow. A regions-of-interest analysis. Acta Psychiatr. Scand. 106, 35–44 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Lui, S. et al. Depressive disorders: focally altered cerebral perfusion measured with arterial spin-labeling MR imaging. Radiology 251, 476–484 (2009).

    Article  PubMed  Google Scholar 

  91. Fitzgerald, P. B., Laird, A. R., Maller, J. & Daskalakis, Z. J. A meta-analytic study of changes in brain activation in depression. Hum. Brain Mapp. 29, 683–695 (2008). This meta-analysis shows that when antidepressants are effective they typically cause a reduction in hippocampal metabolism.

    Article  PubMed  Google Scholar 

  92. Wolf, R. L. et al. Detection of mesial temporal lobe hypoperfusion in patients with temporal lobe epilepsy by use of arterial spin labeled perfusion MR imaging. AJNR Am. J. Neuroradiol. 22, 1334–1341 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Wu, R. H. et al. MR measurement of regional relative cerebral blood volume in epilepsy. J. Magn. Reson. Imaging 9, 435–440 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Elliott, B., Joyce, E. & Shorvon, S. Delusions, illusions and hallucinations in epilepsy: 2. Complex phenomena and psychosis. Epilepsy Res. 85, 172–186 (2009).

    Article  PubMed  Google Scholar 

  95. Elliott, B., Joyce, E. & Shorvon, S. Delusions, illusions and hallucinations in epilepsy: 1. Elementary phenomena. Epilepsy Res. 85, 162–171 (2009).

    Article  PubMed  Google Scholar 

  96. Squire, L. R. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231 (1992).

    Article  CAS  PubMed  Google Scholar 

  97. Moser, E. I., Kropff, E. & Moser, M. B. Place cells, grid cells, and the brain's spatial representation system. Annu. Rev. Neurosci. 31, 69–89 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Doeller, C. F., Barry, C. & Burgess, N. Evidence for grid cells in a human memory network. Nature 463, 657–661 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Young, B. J., Otto, T., Fox, G. D. & Eichenbaum, H. Memory representation within the parahippocampal region. J. Neurosci. 17, 5183–5195 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Suzuki, W. A., Miller, E. K. & Desimone, R. Object and place memory in the macaque entorhinal cortex. J. Neurophysiol. 78, 1062–1081 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Tahvildari, B., Fransen, E., Alonso, A. A. & Hasselmo, M. E. Switching between “On” and “Off” states of persistent activity in lateral entorhinal layer III neurons. Hippocampus 17, 257–263 (2007).

    Article  PubMed  Google Scholar 

  102. Jensen, O. & Lisman, J. E. Hippocampal sequence-encoding driven by a cortical multi-item working memory buffer. Trends Neurosci. 28, 67–72 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Hasselmo, M. E. Grid cell mechanisms and function: contributions of entorhinal persistent spiking and phase resetting. Hippocampus 18, 1213–1229 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Schon, K. et al. Scopolamine reduces persistent activity related to long-term encoding in the parahippocampal gyrus during delayed matching in humans. J. Neurosci. 25, 9112–9123 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Schon, K., Hasselmo, M. E., Lopresti, M. L., Tricarico, M. D. & Stern, C. E. Persistence of parahippocampal representation in the absence of stimulus input enhances long-term encoding: a functional magnetic resonance imaging study of subsequent memory after a delayed match-to-sample task. J. Neurosci. 24, 11088–11097 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Olsen, R. K. et al. Performance-related sustained and anticipatory activity in human medial temporal lobe during delayed match-to-sample. J. Neurosci. 29, 11880–11890 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fernandez, G., Brewer, J. B., Zhao, Z., Glover, G. H. & Gabrieli, J. D. Level of sustained entorhinal activity at study correlates with subsequent cued-recall performance: a functional magnetic resonance imaging study with high acquisition rate. Hippocampus 9, 35–44 (1999).

    Article  CAS  PubMed  Google Scholar 

  108. Brickman, A. M., Stern, Y. & Small, S. A. Hippocampal subregions differentially associate with standardized memory tests. Hippocampus 7 Sep 2010 (doi:10.1002/hipo.20840).

  109. Albert, M. S. Cognitive and neurobiologic markers of early Alzheimer disease. Proc. Natl Acad. Sci. USA 93, 13547–13551 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Elias, M. F. et al. The preclinical phase of alzheimer disease: a 22-year prospective study of the Framingham Cohort. Arch. Neurol. 57, 808–813 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Albert, M. S. The ageing brain: normal and abnormal memory. Phil. Trans. R. Soc. Lond. B 352, 1703–1709 (1997).

    Article  CAS  Google Scholar 

  112. Petersen, R. C., Smith, G., Kokmen, E., Ivnik, R. J. & Tangalos, E. G. Memory function in normal aging. Neurology 42, 396–401 (1992). This is one in a series of papers that shows that performance on delayed retention is relatively unaffected in normal ageing.

    Article  CAS  PubMed  Google Scholar 

  113. Foster, T. C. Involvement of hippocampal synaptic plasticity in age-related memory decline. Brain Res. Brain Res. Rev. 30, 236–249 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Kent, K., Hess, K., Tonegawa, S. & Small, S. A. CA3 NMDA receptors are required for experience-dependent shifts in hippocampal activity. Hippocampus 17, 1003–1011 (2007).

    Article  PubMed  Google Scholar 

  115. Lee, I., Yoganarasimha, D., Rao, G. & Knierim, J. J. Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3. Nature 430, 456–459 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Leutgeb, S., Leutgeb, J. K., Treves, A., Moser, M. B. & Moser, E. I. Distinct ensemble codes in hippocampal areas CA3 and CA1. Science 305, 1295–1298 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Dolcos, F., LaBar, K. S. & Cabeza, R. Interaction between the amygdala and the medial temporal lobe memory system predicts better memory for emotional events. Neuron 42, 855–863 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Brewin, C. R. The nature and significance of memory disturbance in posttraumatic stress disorder. Annu. Rev. Clin. Psychol. 7, 203–227 (2011).

    Article  PubMed  Google Scholar 

  119. Blum, K. I. & Abbott, L. F. A model of spatial map formation in the hippocampus of the rat. Neural Comput. 8, 85–93 (1996).

    Article  CAS  PubMed  Google Scholar 

  120. Lisman, J. E. Relating hippocampal circuitry to function: recall of memory sequences by reciprocal dentate-CA3 interactions. Neuron 22, 233–242 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. Magee, J. C. Dendritic integration of excitatory synaptic input. Nature Rev. Neurosci. 1, 181–190 (2000).

    Article  CAS  Google Scholar 

  122. Nolan, M. F. et al. A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons. Cell 119, 719–732 (2004).

    CAS  PubMed  Google Scholar 

  123. Vinogradova, O. S. Hippocampus as comparator: role of the two input and two output systems of the hippocampus in selection and registration of information. Hippocampus 11, 578–598 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Suthana, N. A., Ekstrom, A. D., Moshirvaziri, S., Knowlton, B. & Bookheimer, S. Y. Human hippocampal CA1 involvement during allocentric encoding of spatial information. J. Neurosci. 29, 10512–10519 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bartsch, T. et al. Focal lesions of human hippocampal CA1 neurons in transient global amnesia impair place memory. Science 328, 1412–1415 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Zeineh, M. M., Engel, S. A., Thompson, P. M. & Bookheimer, S. Y. Dynamics of the hippocampus during encoding and retrieval of face-name pairs. Science 299, 577–580 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. Gabrieli, J. D. E., Brewer, J. B., Desmond, J. E. & Glover, G. H. Separate neural bases of two fundamental memory processes in the human medial temporal lobe. Science 276, 264–266 (1997).

    Article  CAS  PubMed  Google Scholar 

  128. Eldridge, L. L., Engel, S. A., Zeineh, M. M., Bookheimer, S. Y. & Knowlton, B. J. A dissociation of encoding and retrieval processes in the human hippocampus. J. Neurosci. 25, 3280–3286 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Viskontas, I. V., Carr, V. A., Engel, S. A. & Knowlton, B. J. The neural correlates of recollection: hippocampal activation declines as episodic memory fades. Hippocampus 19, 265–272 (2009).

    Article  PubMed  Google Scholar 

  130. O'Mara, S. Controlling hippocampal output: the central role of subiculum in hippocampal information processing. Behav. Brain Res. 174, 304–312 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Carr, V. A., Rissman, J. & Wagner, A. D. Imaging the human medial temporal lobe with high-resolution fMRI. Neuron 65, 298–308 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Scoville, W. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21 (1957).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mikell, C. B. et al. The hippocampus and nucleus accumbens as potential therapeutic targets for neurosurgical intervention in schizophrenia. Stereotact. Funct. Neurosurg. 87, 256–265 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Zobel, A. et al. Changes in regional cerebral blood flow by therapeutic vagus nerve stimulation in depression: an exploratory approach. Psychiatry Res. 139, 165–179 (2005).

    Article  PubMed  Google Scholar 

  135. Lodge, D. J. & Grace, A. A. Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J. Neurosci. 27, 11424–11430 (2007). This paper shows that hyperactivity in the anterior or ventral hippocampus can lead to increased striatal dopamine release.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Laruelle, M. et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc. Natl Acad. Sci. USA 93, 9235–9240 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Abi-Dargham, A. et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am. J. Psychiatry 155, 761–767 (1998).

    Article  CAS  PubMed  Google Scholar 

  138. Seminowicz, D. A. et al. Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 22, 409–418 (2004).

    Article  CAS  PubMed  Google Scholar 

  139. Fonteijn, H. M., Norris, D. G. & Verstraten, F. A. Exploring the anatomical basis of effective connectivity models with DTI-based fiber tractography. Int. J. Biomed. Imaging 2008, 423192 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Small, S. A. et al. Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann. Neurol. 58, 909–919 (2005). This paper relied on the pattern of hippocampal dysfunction observed in Alzheimer's disease to identify a novel defect in intracellular sorting and trafficking, illustrating the utility of the pathophysiological framework.

    Article  CAS  PubMed  Google Scholar 

  141. Small, S. A. Retromer sorting: a pathogenic pathway in late-onset Alzheimer disease. Arch. Neurol. 65, 323–328 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Small, S. A. & Gandy, S. Sorting through the cell biology of Alzheimer's disease: intracellular pathways to pathogenesis. Neuron 52, 15–31 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. McEwen, B. S. Corticosteroids and hippocampal plasticity. Ann. N. Y Acad. Sci. 746, 134–142 (1994).

    Article  CAS  PubMed  Google Scholar 

  144. McEwen, B. S. The brain is the central organ of stress and adaptation. Neuroimage 47, 911–913 (2009).

    Article  PubMed  Google Scholar 

  145. Conrad, C. D., LeDoux, J. E., Magarinos, A. M. & McEwen, B. S. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav. Neurosci. 113, 902–913 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. McKittrick, C. R. et al. Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites. Synapse 36, 85–94 (2000).

    Article  CAS  PubMed  Google Scholar 

  147. Stewart, M. G. et al. Stress suppresses and learning induces plasticity in CA3 of rat hippocampus: a three-dimensional ultrastructural study of thorny excrescences and their postsynaptic densities. Neuroscience 131, 43–54 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. Sunanda, Rao, M. S. & Raju, T. R. Effect of chronic restraint stress on dendritic spines and excrescences of hippocampal CA3 pyramidal neurons-a quantitative study. Brain Res. 694, 312–317 (1995).

    Article  CAS  PubMed  Google Scholar 

  149. Sandi, C. et al. Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training. Eur. J. Neurosci. 17, 2447–2456 (2003).

    Article  PubMed  Google Scholar 

  150. Christian, K. M., Miracle, A. D., Wellman, C. L. & Nakazawa, K. Chronic stress-induced hippocampal dendritic retraction requires CA3 NMDA receptors. Neuroscience 174, 26–36 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Gage, F. H. Neurogenesis in the adult brain. J. Neurosci. 22, 612–613 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nature Med. 4, 1313–1317 (1998).

    Article  CAS  PubMed  Google Scholar 

  153. Kuhn, H. G., Dickinson-Anson, H. & Gage, F. H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027–2033 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Sahay, A. et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Zapala, M. A. et al. Adult mouse brain gene expression patterns bear an embryologic imprint. Proc. Natl Acad. Sci. USA 102, 10357–10362 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Shimokata, H. et al. Age as independent determinant of glucose tolerance. Diabetes 40, 44–51 (1991).

    Article  CAS  PubMed  Google Scholar 

  157. Gresl, T. A. et al. Dietary restriction and glucose regulation in aging rhesus monkeys: a follow-up report at 8.5 yr. Am. J. Physiol. Endocrinol. Metab. 281, E757–765 (2001).

    Article  CAS  PubMed  Google Scholar 

  158. Goodyear, L. J. & Kahn, B. B. Exercise, glucose transport, and insulin sensitivity. Annu. Rev. Med. 49, 235–261 (1998).

    Article  CAS  PubMed  Google Scholar 

  159. Pereira, A. C. et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc. Natl Acad. Sci. USA 104, 5638–5643 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Vaynman, S., Ying, Z. & Gomez-Pinilla, F. Exercise induces BDNF and synapsin I to specific hippocampal subfields. J. Neurosci. Res. 76, 356–362 (2004).

    Article  CAS  PubMed  Google Scholar 

  161. Erickson, K. I. et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl Acad. Sci. USA 108, 3017–3022 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Tibbo, P., Hanstock, C., Valiakalayil, A. & Allen, P. 3-T proton MRS investigation of glutamate and glutamine in adolescents at high genetic risk for schizophrenia. Am. J. Psychiatry 161, 1116–1118 (2004).

    Article  PubMed  Google Scholar 

  163. Theberge, J. et al. Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am. J. Psychiatry 159, 1944–1946 (2002).

    Article  PubMed  Google Scholar 

  164. Benes, F. M. Evidence for altered trisynaptic circuitry in schizophrenic hippocampus. Biol. Psychiatry 46, 589–599 (1999). This landmark paper identified a loss in hippocampal interneurons that is predicted to cause selective hippocampal hyperactivity.

    Article  CAS  PubMed  Google Scholar 

  165. Moghaddam, B. Bringing order to the glutamate chaos in schizophrenia. Neuron 40, 881–884 (2003).

    Article  CAS  PubMed  Google Scholar 

  166. Jia, P., Wang, L., Meltzer, H. Y. & Zhao, Z. Common variants conferring risk of schizophrenia: a pathway analysis of GWAS data. Schizophr. Res. 122, 38–42 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Gaisler-Salomon, I. et al. Glutaminase-deficient mice display hippocampal hypoactivity, insensitivity to pro-psychotic drugs and potentiated latent inhibition: relevance to schizophrenia. Neuropsychopharmacology 34, 2305–2322 (2009).

    Article  CAS  PubMed  Google Scholar 

  168. Boeijinga, P. H. & Boddeke, H. W. Serotonergic modulation of neurotransmission in the rat subicular cortex in vitro: a role for 5-HT1B receptors. Naunyn Schmiedebergs Arch. Pharmacol. 348, 553–557 (1993).

    Article  CAS  PubMed  Google Scholar 

  169. Mueggler, T. et al. Mapping of CBV changes in 5-HT(1A) terminal fields by functional MRI in the mouse brain. Eur. Neuropsychopharmacol. 21, 344–353 (2011).

    Article  CAS  PubMed  Google Scholar 

  170. Drevets, W. C. et al. Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl. Med. Biol. 34, 865–877 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Lacefield, C. O., Itskov, V., Reardon, T., Hen, R. & Gordon, J. A. Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus. Hippocampus 29 Sep 2010 (doi:10.1002/hipo.20860).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  PubMed  Google Scholar 

  173. Autry, A. E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Augustinack, J. C. et al. Detection of entorhinal layer II using 7Tesla [corrected] magnetic resonance imaging. Ann. Neurol. 57, 489–494 (2005).

    Article  PubMed  Google Scholar 

  175. van Elst, L. T. et al. Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study. Biol. Psychiatry 58, 724–730 (2005).

    Article  CAS  PubMed  Google Scholar 

  176. Manganas, L. N. et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 318, 980–985 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Van Dijk, K. R. et al. Intrinsic functional connectivity as a tool for human connectomics: theory, properties, and optimization. J. Neurophysiol. 103, 297–321 (2010).

    Article  PubMed  Google Scholar 

  178. Pautler, R. G. In vivo, trans-synaptic tract-tracing utilizing manganese-enhanced magnetic resonance imaging (MEMRI). NMR Biomed. 17, 595–601 (2004).

    Article  CAS  PubMed  Google Scholar 

  179. Belliveau, J. W. et al. Functional mapping of the human visual cortex by magnetic resonance imaging. Science 254, 716–719 (1991).

    Article  CAS  PubMed  Google Scholar 

  180. Williams, D. S., Detre, J. A., Leigh, J. S. & Koretsky, A. P. Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc. Natl Acad. Sci. USA 89, 212–216 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Kwong, K. K. et al. Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc. Natl Acad. Sci. USA 89, 5675–5679 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Lin, W., Celik, A. & Paczynski, R. P. Regional cerebral blood volume: a comparison of the dynamic imaging and the steady state methods. J. Magn. Reson. Imaging 9, 44–52 (1999).

    Article  CAS  PubMed  Google Scholar 

  183. Ogawa, S., Lee, T. M., Nayak, A. S. & Glynn, P. Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magn. Reson. Med. 14, 68–78 (1990).

    Article  CAS  PubMed  Google Scholar 

  184. Griffeth, V. E. & Buxton, R. B. A theoretical framework for estimating cerebral oxygen metabolism changes using the calibrated-BOLD method: modeling the effects of blood volume distribution, hematocrit, oxygen extraction fraction, and tissue signal properties on the BOLD signal. Neuroimage 58, 198–212 (2011).

    Article  PubMed  Google Scholar 

  185. Leontiev, O., Dubowitz, D. J. & Buxton, R. B. CBF/CMRO2 coupling measured with calibrated BOLD fMRI: sources of bias. Neuroimage 36, 1110–1122 (2007).

    Article  PubMed  Google Scholar 

  186. Griffeth, V. E. M., Perthen, J. E. & Buxton, R. B. Prospects for quantitative fMRI: investigating the effects of caffeine on baseline oxygen metabolism and the response to a visual stimulus in humans. Neuroimage 57, 809–816 (2011).

    Article  PubMed  Google Scholar 

  187. Leenders, K. L. et al. Cerebral blood flow, blood volume and oxygen utilization. Normal values and effect of age. Brain 113, 27–47 (1990).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

S.A.Sm. is supported by US National Institute on Aging (NIA) grants AG025161, AG034618, AG034618 and AG035015, the US National Institute of Mental Health (NIMH) grant MH093398, and the James S. McDonnell Foundation. M.P.W. is supported by the Kavli Foundation and center of excellence grant from the Norwegian Research Council (Nr 145,993). C.A.B. is supported by the McKnight Brain Research Foundation and NIA grant AG003376. S.A.Sc. is supported by NIMH grant K23MH09056. We thank C. Stark, H. Eichenbaum, and I. Asllani for comments on earlier versions of this manuscript.

Author information

Authors and Affiliations

  1. Department of Neurology, and The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 West 168th St, P&S 16. New York, New York 10032, USA.,

    Scott A. Small

  2. Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, New York 10032, USA.,

    Scott A. Schobel

  3. Department of Radiology, University of California, San Diego CA 92093, USA.,

    Richard B. Buxton

  4. Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam, The Netherlands, and The Kavli Institute for Systems Neuroscience, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.,

    Menno P. Witter

  5. Evelyn F. McKnight Brain Institute, University of Arizona, Tuscon, Arizona 85724-5115, USA.,

    Carol A. Barnes

Authors
  1. Scott A. Small
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Scott A. Schobel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard B. Buxton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Menno P. Witter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carol A. Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott A. Small.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Small, S., Schobel, S., Buxton, R. et al. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci 12, 585–601 (2011). https://doi.org/10.1038/nrn3085

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3085

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing