The Glutamatergic Postrhinal Cortex–Ventrolateral Orbitofrontal Cortex Pathway Regulates Spatial Memory Retrieval

  • Xinyang Qi
  • Zhanhong Jeff Du
  • Lin Zhu
  • Xuemei Liu
  • Hua Xu
  • Zheng Zhou
  • Cheng Zhong
  • Shijiang Li
  • Liping WangEmail author
  • Zhijun ZhangEmail author
Original Article


A deficit in spatial memory has been taken as an early predictor of Alzheimer’s disease (AD) or mild cognitive impairment (MCI). The uncinate fasciculus (UF) is a long-range white-matter tract that connects the anterior temporal lobe with the orbitofrontal cortex (OFC) in primates. Previous studies have shown that the UF impairment associated with spatial memory deficits may be an important pathological change in aging and AD, but its exact role in spatial memory is not well understood. The pathway arising from the postrhinal cortex (POR) and projecting to the ventrolateral orbitofrontal cortex (vlOFC) performs most of the functions of the UF in rodents. Although the literature suggests an association between spatial memory and the regions connected by the POR–vlOFC pathway, the function of the pathway in spatial memory is relatively unknown. To further illuminate the function of the UF in spatial memory, we dissected the POR–vlOFC pathway in mice. We determined that the POR–vlOFC pathway is a glutamatergic structure, and that glutamatergic neurons in the POR regulate spatial memory retrieval. We also demonstrated that the POR–vlOFC pathway specifically transmits spatial information to participate in memory retrieval. These findings provide a deeper understanding of UF function and dysfunction related to disorders of memory, as in MCI and AD.


Spatial memory Postrhinal cortex Ventrolateral orbitofrontal cortex Mild cognitive impairment Alzheimer’s disease 



This work was supported by the National Major Science and Technology Program of China (2016YFC1306700), the National Natural Science Foundation of China (81420108012, 81671046, 81425010 and 31630031), the Jiangsu Provincial Medical Program for Distinguished Scholars (2016006), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18_0167), China.

Conflict of interest

All authors declare that no competing interests exist.


  1. 1.
    Madl T, Chen K, Montaldi D, Trappl R. Computational cognitive models of spatial memory in navigation space: A review. Neural Netw 2015, 65: 18–43.CrossRefGoogle Scholar
  2. 2.
    Siedlecki KL, Salthouse TA. Using contextual analysis to investigate the nature of spatial memory. Psychon Bull Rev 2014, 21: 721–727.CrossRefGoogle Scholar
  3. 3.
    Iachini I, Iavarone A, Senese VP, Ruotolo F, Ruggiero G. Visuospatial memory in healthy elderly, AD and MCI: a review. Curr Aging Sci 2009, 2: 43–59.CrossRefGoogle Scholar
  4. 4.
    Kunz L, Schröder TN, Lee H, Montag C, Lachmann B, Sariyska R, et al. Reduced grid-cell-like representations in adults at genetic risk for Alzheimer’s disease. Science 2015, 350: 430–433.CrossRefGoogle Scholar
  5. 5.
    Wei EX, Oh ES, Harun A, Ehrenburg M, Agrawal Y. Vestibular loss predicts poorer spatial cognition in patients with Alzheimer’s disease. J Alzheimers Dis 2018, 61: 995–1003.CrossRefGoogle Scholar
  6. 6.
    Ranganath C. Working memory for visual objects: complementary roles of inferior temporal, medial temporal, and prefrontal cortex. Neuroscience 2006, 139: 277–289.CrossRefGoogle Scholar
  7. 7.
    Mohr HM, Goebel R, Linden DE. Content- and task-specific dissociations of frontal activity during maintenance and manipulation in visual working memory. J Neurosci 2006, 26: 4465–4471.CrossRefGoogle Scholar
  8. 8.
    Von Der Heide RJ, Skipper LM, Klobusicky E, Olson IR. Dissecting the uncinate fasciculus: disorders, controversies and a hypothesis. Brain 2013, 136: 1692–1707.CrossRefGoogle Scholar
  9. 9.
    Thiebaut de Schotten M, Dell’Acqua F, Valabregue R, Catani M. Monkey to human comparative anatomy of the frontal lobe association tracts. Cortex 2012, 48: 82–96.CrossRefGoogle Scholar
  10. 10.
    Lebel C, Beaulieu C. Longitudinal development of human brain wiring continues from childhood into adulthood. J Neurosci 2011, 31: 10937–10947.CrossRefGoogle Scholar
  11. 11.
    Phan KL, Orlichenko A, Boyd E, Angstadt M, Coccaro EF, Liberzon I, et al. Preliminary evidence of white matter abnormality in the uncinate fasciculus in generalized social anxiety disorder. Biol Psychiatry 2009, 66: 691–694.CrossRefGoogle Scholar
  12. 12.
    Riva-Posse P, Choi KS, Holtzheimer PE, McIntyre CC, Gross RE, Chaturvedi A, et al. Defining critical white matter pathways mediating successful subcallosal cingulate deep brain stimulation for treatment-resistant depression. Biol Psychiatry 2014, 76: 963–969.CrossRefGoogle Scholar
  13. 13.
    Ćurčić-Blake B, Nanetti L, van der Meer L, Cerliani L, Renken R, Pijnenborg GH, et al. Not on speaking terms: hallucinations and structural network disconnectivity in schizophrenia. Brain Struct Funct 2015, 220: 407–418.CrossRefGoogle Scholar
  14. 14.
    Craig MC, Catani M, Deeley Q, Latham R, Daly E, Kanaan R, et al. Altered connections on the road to psychopathy. Mol Psychiatry 2009, 14: 946–953, 907.CrossRefGoogle Scholar
  15. 15.
    Mahoney CJ, Simpson IJ, Nicholas JM, Fletcher PD, Downey LE, Golden HL, et al. Longitudinal diffusion tensor imaging in frontotemporal dementia. Ann Neurol 2015, 77: 33–46.CrossRefGoogle Scholar
  16. 16.
    Douaud G, Jbabdi S, Behrens TE, Menke RA, Gass A, Monsch AU, et al. DTI measures in crossing-fibre areas: increased diffusion anisotropy reveals early white matter alteration in MCI and mild Alzheimer’s disease. Neuroimage 2011, 55: 880–890.CrossRefGoogle Scholar
  17. 17.
    Villain N, Fouquet M, Baron JC, Mézenge F, Landeau B, de La Sayette V, et al. Sequential relationships between grey matter and white matter atrophy and brain metabolic abnormalities in early Alzheimer’s disease. Brain 2010, 133: 3301–3314.CrossRefGoogle Scholar
  18. 18.
    Korthauer LE, Nowak NT, Moffat SD, An Y, Rowland LM, Barker PB, et al. Correlates of virtual navigation performance in older adults. Neurobiol Aging 2016, 39: 118–127.CrossRefGoogle Scholar
  19. 19.
    Wu YF, Wu WB, Liu QP, He WW, Ding H, Nedelska Z, et al. Presence of lacunar infarctions is associated with the spatial navigation impairment in patients with mild cognitive impairment: a DTI study. Oncotarget 2016, 7: 78310–78319.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Delatour B, Witter MP. Projections from the parahippocampal region to the prefrontal cortex in the rat: evidence of multiple pathways. Eur J Neurosci 2002, 15: 1400–1407.CrossRefGoogle Scholar
  21. 21.
    Beaudin SA, Singh T, Agster KL, Burwell RD. Borders and comparative cytoarchitecture of the perirhinal and postrhinal cortices in an F1 hybrid mouse. Cereb Cortex 2013, 23: 460–476.CrossRefGoogle Scholar
  22. 22.
    Delatour B, Witter MP. Projections from the parahippocampal region to the prefrontal cortex in the rat: evidence of multiple pathways. Eur J Neurosci 2002, 15: 1400–1407.CrossRefGoogle Scholar
  23. 23.
    Agster KL, Burwell RD. Cortical efferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. Hippocampus 2009, 19: 1159–1186.CrossRefGoogle Scholar
  24. 24.
    Allen-Brain-Atlas. Mouse Connectivity. Available from
  25. 25.
    Liu P, Bilkey DK. The effects of NMDA lesions centered on the postrhinal cortex on spatial memory tasks in the rat. Behav Neurosci 2002, 116: 860–873.CrossRefGoogle Scholar
  26. 26.
    Vafaei AA, Rashidy-Pour A. Reversible lesion of the rat’s orbitofrontal cortex interferes with hippocampus-dependent spatial memory. Behav Brain Res 2004, 149: 61-68.CrossRefGoogle Scholar
  27. 27.
    Abdel-Aal RA, Assi AA, Kostandy BB. Memantine prevents aluminum-induced cognitive deficit in rats. Behav Brain Res 2011, 225: 31–38.CrossRefGoogle Scholar
  28. 28.
    Sills JB, Connors BW, Burwell RD. Electrophysiological and morphological properties of neurons in layer 5 of the rat postrhinal cortex. Hippocampus 2012, 22: 1912–1922.CrossRefGoogle Scholar
  29. 29.
    Beer Z, Chwiesko C, Kitsukawa T, Sauvage MM. Spatial and stimulus-type tuning in the LEC, MEC, POR, PrC, CA1, and CA3 during spontaneous item recognition memory. Hippocampus 2013, 23: 1425–1438.CrossRefGoogle Scholar
  30. 30.
    Boyce R, Glasgow SD, Williams S, Adamantidis A. Causal evidence for the role of REM sleep theta rhythm in contextual memory consolidation. Science 2016, 352: 812–816.CrossRefGoogle Scholar
  31. 31.
    Taylor IM, Du Z, Bigelow ET, Eles JR, Horner AR, Catt KA, et al. Aptamer-functionalized neural recording electrodes for the direct measurement of cocaine in vivo. J Mater Chem B Mater Biol Med 2017, 5: 2445–2458.CrossRefGoogle Scholar
  32. 32.
    Du ZJ, Luo X, Weaver C, Cui XT. Poly (3, 4-ethylenedioxythiophene)-ionic liquid coating improves neural recording and stimulation functionality of MEAs. J Mater Chem C Mater Opt Electron Devices 2015, 3: 6515–6524.CrossRefGoogle Scholar
  33. 33.
    Wagenaar DA, Potter SM. Real-time multi-channel stimulus artifact suppression by local curve fitting. J Neurosci Methods 2002, 120: 113–120.CrossRefGoogle Scholar
  34. 34.
    Ludwig KA, Uram JD, Yang J, Martin DC, Kipke DR. Chronic neural recordings using silicon microelectrode arrays electrochemically deposited with a poly(3,4-ethylenedioxythiophene) (PEDOT) film. J Neural Eng 2006, 3: 59–70.CrossRefGoogle Scholar
  35. 35.
    Shoham S, Fellows MR, Normann RA. Robust, automatic spike sorting using mixtures of multivariate t-distributions. J Neurosci Methods 2003, 127: 111–122.CrossRefGoogle Scholar
  36. 36.
    Yang Y, Wang Z, Jin S, Gao D, Liu N, Chen S, et al. Opposite monosynaptic scaling of BLP-vCA1 inputs governs hopefulness- and helplessness-modulated spatial learning and memory. Nat Commun 2016, 7: 11935.CrossRefGoogle Scholar
  37. 37.
    Liu P, Bilkey DK. The effects of NMDA lesions centered on the postrhinal cortex on spatial memory tasks in the rat. Behav Neurosci 2002, 116: 860–873.CrossRefGoogle Scholar
  38. 38.
    Ramos JM. Differential contribution of hippocampus, perirhinal cortex and postrhinal cortex to allocentric spatial memory in the radial maze. Behav Brain Res 2013, 247: 59–64.CrossRefGoogle Scholar
  39. 39.
    Zhang GR, Cao H, Kong L, O’Brien J, Baughns A, Jan M, et al. Identified circuit in rat postrhinal cortex encodes essential information for performing specific visual shape discriminations. Proc Natl Acad Sci U S A 2010, 107: 14478–14483.CrossRefGoogle Scholar
  40. 40.
    Boldogkoi Z, Balint K, Awatramani GB, Balya D, Busskamp V, Viney TJ, et al. Genetically timed, activity-sensor and rainbow transsynaptic viral tools. Nat Methods 2009, 6: 127–130.CrossRefGoogle Scholar
  41. 41.
    McCarty DM. Self-complementary AAV vectors; advances and applications. Mol Ther 2008, 16: 1648–1656.CrossRefGoogle Scholar
  42. 42.
    Betley JN, Sternson SM. Adeno-associated viral vectors for mapping, monitoring, and manipulating neural circuits. Hum Gene Ther 2011, 22: 669–677.CrossRefGoogle Scholar
  43. 43.
    Vafaei AA, Rashidy-Pour A. Reversible lesion of the rat’s orbitofrontal cortex interferes with hippocampus-dependent spatial memory. Behav Brain Res 2004, 149: 61–68.CrossRefGoogle Scholar
  44. 44.
    Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res 1988, 31: 47–59.CrossRefGoogle Scholar
  45. 45.
    Clarke JR, Cammarota M, Gruart A, Izquierdo I, Delgado-Garcia JM. Plastic modifications induced by object recognition memory processing. Proc Natl Acad Sci U S A 2010, 107: 2652–2657.CrossRefGoogle Scholar
  46. 46.
    Burgess N, Maguire EA, Spiers HJ, O’Keefe J. A temporoparietal and prefrontal network for retrieving the spatial context of lifelike events. Neuroimage 2001, 14: 439–453.CrossRefGoogle Scholar
  47. 47.
    Furtak SC, Ahmed OJ, Burwell RD. Single neuron activity and theta modulation in postrhinal cortex during visual object discrimination. Neuron 2012, 76: 976–988.CrossRefGoogle Scholar
  48. 48.
    Suter EE, Weiss C, Disterhoft JF. Perirhinal and postrhinal, but not lateral entorhinal, cortices are essential for acquisition of trace eyeblink conditioning. Learn Mem 2013, 20: 80–84.CrossRefGoogle Scholar
  49. 49.
    Bucci DJ, Burwell RD. Deficits in attentional orienting following damage to the perirhinal or postrhinal cortices. Behav Neurosci 2004, 118: 1117–1122.CrossRefGoogle Scholar
  50. 50.
    Vidyasagar TR, Salzmann E, Creutzfeldt OD. Unit activity in the hippocampus and the parahippocampal temporobasal association cortex related to memory and complex behaviour in the awake monkey. Brain Res 1991, 544: 269–278.CrossRefGoogle Scholar
  51. 51.
    Mayo CD, Mazerolle EL, Ritchie L, Fisk JD, Gawryluk JR. Longitudinal changes in microstructural white matter metrics in Alzheimer’s disease. Neuroimage Clin 2017, 13: 330–338.CrossRefGoogle Scholar
  52. 52.
    O’Dwyer L, Lamberton F, Bokde AL, Ewers M, Faluyi YO, Tanner C, et al. Multiple indices of diffusion identifies white matter damage in mild cognitive impairment and Alzheimer’s disease. PLoS One 2011, 6: e21745.CrossRefGoogle Scholar
  53. 53.
    Li W, Muftuler LT, Chen G, Ward BD, Budde MD, Jones JL, et al. Effects of the coexistence of late-life depression and mild cognitive impairment on white matter microstructure. J Neurol Sci 2014, 338: 46–56.CrossRefGoogle Scholar
  54. 54.
    Zald DH, Kim SW. Anatomy and function of the orbital frontal cortex, I: anatomy, neurocircuitry; and obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci 1996, 8: 125–138.CrossRefGoogle Scholar
  55. 55.
    Petrides M. The orbitofrontal cortex: novelty, deviation from expectation, and memory. Ann N Y Acad Sci 2007, 1121: 33–53.CrossRefGoogle Scholar
  56. 56.
    Swanson A, Allen A, Shapiro L, Gourley S. GABAAα1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection. Neuropsychopharmacology 2015, 40: 1027–1036.CrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2019

Authors and Affiliations

  • Xinyang Qi
    • 1
  • Zhanhong Jeff Du
    • 2
  • Lin Zhu
    • 1
  • Xuemei Liu
    • 2
  • Hua Xu
    • 1
  • Zheng Zhou
    • 2
  • Cheng Zhong
    • 2
  • Shijiang Li
    • 3
  • Liping Wang
    • 2
    Email author
  • Zhijun Zhang
    • 1
    • 2
    Email author
  1. 1.Department of Neurology, Affiliated ZhongDa Hospital, Institute of Neuropsychiatry, School of MedicineSoutheast UniversityNanjingChina
  2. 2.Shenzhen Key Lab of Neuropsychiatric Modulation and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences (CAS) Center for Excellence in Brain Science and Intelligence Technology, the Brain Cognition and Brain Disease Institute for Collaboration Research of the Shenzhen Institutes of Advanced Technology at the CAS and the McGovern Institute at Massachusetts Institute of TechnologyShenzhenChina
  3. 3.Department of BiophysicsMedical College of WisconsinMilwaukeeUSA

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