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Separate elements of episodic memory subserved by distinct hippocampal–prefrontal connections

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Abstract

Episodic memory formation depends on information about a stimulus being integrated within a precise spatial and temporal context, a process dependent on the hippocampus and prefrontal cortex. Investigations of putative functional interactions between these regions are complicated by multiple direct and indirect hippocampal–prefrontal connections. Here application of a pharmacogenetic deactivation technique enabled us to investigate the mnemonic contributions of two direct hippocampal–medial prefrontal cortex (mPFC) pathways, one arising in the dorsal CA1 (dCA1) and the other in the intermediate CA1 (iCA1). While deactivation of either pathway impaired episodic memory, the resulting pattern of mnemonic deficits was different: deactivation of the dCA1→mPFC pathway selectively disrupted temporal order judgments while iCA1→mPFC pathway deactivation disrupted spatial memory. These findings reveal a previously unsuspected division of function among CA1 neurons that project directly to the mPFC. Such subnetworks may enable the distinctiveness of contextual information to be maintained in an episodic memory circuit.

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Figure 1: Episodic memory depends on a functional interaction between the hippocampus and mPFC.
Figure 2: Daun02 attenuates activity of CA1 pyramidal neurons.
Figure 3: Selective deactivation of the dCA1→mPFC projection disrupts the temporal component of episodic memory while selective deactivation of the iCA1→mPFC projection disrupts the spatial component of episodic-like memory.
Figure 4: Deactivation of the dCA1→mPFC projection selectively impaired object temporal order memory whereas selective deactivation of the iCA1→mPFC projection impaired object-in-place memory.
Figure 5: Deactivation of either the dCA1→mPFC or iCA1→mPFC projection did not alter either object recognition or object location memory.

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  • 25 May 2017

    A ReadMe file and a more complete analysis suite have been added to the Supplementary Software.

References

  1. Tulving, E. Organisation of Memory (Academic, New York, 1972).

  2. Diana, R.A., Yonelinas, A.P. & Ranganath, C. Imaging recollection and familiarity in the medial temporal lobe: a three-component model. Trends Cogn. Sci. 11, 379–386 (2007).

    PubMed  Google Scholar 

  3. Eichenbaum, H., Yonelinas, A.P. & Ranganath, C. The medial temporal lobe and recognition memory. Annu. Rev. Neurosci. 30, 123–152 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Eichenbaum, H.T. Memory Systems (MIT Press, Cambridge, Massachusetts, USA, 1994).

  5. Dickerson, B.C. & Eichenbaum, H. The episodic memory system: neurocircuitry and disorders. Neuropsychopharmacology 35, 86–104 (2010).

    PubMed  Google Scholar 

  6. King, D.R., de Chastelaine, M., Elward, R.L., Wang, T.H. & Rugg, M.D. Recollection-related increases in functional connectivity predict individual differences in memory accuracy. J. Neurosci. 35, 1763–1772 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Watrous, A.J., Tandon, N., Conner, C.R., Pieters, T. & Ekstrom, A.D. Frequency-specific network connectivity increases underlie accurate spatiotemporal memory retrieval. Nat. Neurosci. 16, 349–356 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Preston, A.R. & Eichenbaum, H. Interplay of hippocampus and prefrontal cortex in memory. Curr. Biol. 23, R764–R773 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Wheeler, M.A., Stuss, D.T. & Tulving, E. Frontal lobe damage produces episodic memory impairment. J. Int. Neuropsychol. Soc. 1, 525–536 (1995).

    CAS  PubMed  Google Scholar 

  10. Duarte, A., Ranganath, C. & Knight, R.T. Effects of unilateral prefrontal lesions on familiarity, recollection, and source memory. J. Neurosci. 25, 8333–8337 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Nolde, S.F., Johnson, M.K. & Raye, C.L. The role of prefrontal cortex during tests of episodic memory. Trends Cogn. Sci. 2, 399–406 (1998).

    CAS  PubMed  Google Scholar 

  12. Petrides, M. Deficits on conditional associative-learning tasks after frontal- and temporal-lobe lesions in man. Neuropsychologia 23, 601–614 (1985).

    CAS  PubMed  Google Scholar 

  13. Ekstrom, A.D., Copara, M.S., Isham, E.A., Wang, W.C. & Yonelinas, A.P. Dissociable networks involved in spatial and temporal order source retrieval. Neuroimage 56, 1803–1813 (2011).

    PubMed  Google Scholar 

  14. Buckner, R.L., Kelley, W.M. & Petersen, S.E. Frontal cortex contributes to human memory formation. Nat. Neurosci. 2, 311–314 (1999).

    CAS  PubMed  Google Scholar 

  15. Barredo, J., Öztekin, I. & Badre, D. Ventral fronto-temporal pathway supporting cognitive control of episodic memory retrieval. Cereb. Cortex 25, 1004–1019 (2015).

    PubMed  Google Scholar 

  16. Benchenane, K. et al. Coherent theta oscillations and reorganization of spike timing in the hippocampal- prefrontal network upon learning. Neuron 66, 921–936 (2010).

    CAS  PubMed  Google Scholar 

  17. Dere, E., Huston, J.P. & De Souza Silva, M.A. Integrated memory for objects, places, and temporal order: evidence for episodic-like memory in mice. Neurobiol. Learn. Mem. 84, 214–221 (2005).

    PubMed  Google Scholar 

  18. Good, M.A., Barnes, P., Staal, V., McGregor, A. & Honey, R.C. Context- but not familiarity-dependent forms of object recognition are impaired following excitotoxic hippocampal lesions in rats. Behav. Neurosci. 121, 218–223 (2007).

    CAS  PubMed  Google Scholar 

  19. DeVito, L.M. & Eichenbaum, H. Distinct contributions of the hippocampus and medial prefrontal cortex to the “what-where-when” components of episodic-like memory in mice. Behav. Brain Res. 215, 318–325 (2010).

    PubMed  Google Scholar 

  20. Condé, F., Maire-Lepoivre, E., Audinat, E. & Crépel, F. Afferent connections of the medial frontal cortex of the rat. II. Cortical and subcortical afferents. J. Comp. Neurol. 352, 567–593 (1995).

    PubMed  Google Scholar 

  21. Hoover, W.B. & Vertes, R.P. Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct. Funct. 212, 149–179 (2007).

    PubMed  Google Scholar 

  22. Varela, C., Kumar, S., Yang, J.Y. & Wilson, M.A. Anatomical substrates for direct interactions between hippocampus, medial prefrontal cortex, and the thalamic nucleus reuniens. Brain Struct. Funct. 219, 911–929 (2014).

    CAS  PubMed  Google Scholar 

  23. Ennaceur, A. One-trial object recognition in rats and mice: methodological and theoretical issues. Behav. Brain Res. 215, 244–254 (2010).

    CAS  PubMed  Google Scholar 

  24. Jay, T.M. & Witter, M.P. Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin. J. Comp. Neurol. 313, 574–586 (1991).

    CAS  PubMed  Google Scholar 

  25. Koya, E. et al. Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization. Nat. Neurosci. 12, 1069–1073 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Cruz, F.C. et al. New technologies for examining the role of neuronal ensembles in drug addiction and fear. Nat. Rev. Neurosci. 14, 743–754 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Farquhar, D. et al. Suicide gene therapy using E. coli beta-galactosidase. Cancer Chemother. Pharmacol. 50, 65–70 (2002).

    CAS  PubMed  Google Scholar 

  28. Dong, H.-W., Swanson, L.W., Chen, L., Fanselow, M.S. & Toga, A.W. Genomic-anatomic evidence for distinct functional domains in hippocampal field CA1. Proc. Natl. Acad. Sci. USA 106, 11794–11799 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Barker, G.R.I. & Warburton, E.C. When is the hippocampus involved in recognition memory? J. Neurosci. 31, 10721–10731 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Navawongse, R. & Eichenbaum, H. Distinct pathways for rule-based retrieval and spatial mapping of memory representations in hippocampal neurons. J. Neurosci. 33, 1002–1013 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. MacDonald, C.J., Carrow, S., Place, R. & Eichenbaum, H. Distinct hippocampal time cell sequences represent odor memories in immobilized rats. J. Neurosci. 33, 14607–14616 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kraus, B.J., Robinson, R.J. II, White, J.A., Eichenbaum, H. & Hasselmo, M.E. Hippocampal “time cells”: time versus path integration. Neuron 78, 1090–1101 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Eichenbaum, H. Time cells in the hippocampus: a new dimension for mapping memories. Nat. Rev. Neurosci. 15, 732–744 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Witter, M.P., Wouterlood, F.G., Naber, P.A. & Van Haeften, T. Anatomical organization of the parahippocampal-hippocampal network. Ann. NY Acad. Sci. 911, 1–24 (2000).

    CAS  PubMed  Google Scholar 

  35. Naber, P.A., Lopes da Silva, F.H. & Witter, M.P. Reciprocal connections between the entorhinal cortex and hippocampal fields CA1 and the subiculum are in register with the projections from CA1 to the subiculum. Hippocampus 11, 99–104 (2001).

    CAS  PubMed  Google Scholar 

  36. Knierim, J.J., Neunuebel, J.P. & Deshmukh, S.S. Functional correlates of the lateral and medial entorhinal cortex: objects, path integration and local-global reference frames. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369, 20130369 (2013).

    PubMed  Google Scholar 

  37. Ito, H.T. & Schuman, E.M. Functional division of hippocampal area CA1 via modulatory gating of entorhinal cortical inputs. Hippocampus 22, 372–387 (2012).

    CAS  PubMed  Google Scholar 

  38. Kinnavane, L., Amin, E., Horne, M. & Aggleton, J.P. Mapping parahippocampal systems for recognition and recency memory in the absence of the rat hippocampus. Eur. J. Neurosci. 40, 3720–3734 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Henriksen, E.J. et al. Spatial representation along the proximodistal axis of CA1. Neuron 68, 127–137 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bast, T., Wilson, I.A., Witter, M.P. & Morris, R.G.M. From rapid place learning to behavioral performance: a key role for the intermediate hippocampus. PLoS Biol. 7, 0730–0746 (2009).

    CAS  Google Scholar 

  41. Apergis-Schoute, J., Pinto, A. & Paré, D. Ultrastructural organization of medial prefrontal inputs to the rhinal cortices. Eur. J. Neurosci. 24, 135–144 (2006).

    PubMed  Google Scholar 

  42. Xu, W. & Südhof, T.C. A neural circuit for memory specificity and generalization. Science 339, 1290–1295 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    CAS  PubMed  Google Scholar 

  44. Neunuebel, J.P., Yoganarasimha, D., Rao, G. & Knierim, J.J. Conflicts between local and global spatial frameworks dissociate neural representations of the lateral and medial entorhinal cortex. J. Neurosci. 33, 9246–9258 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Knierim, J.J. & Neunuebel, J.P. Tracking the flow of hippocampal computation: Pattern separation, pattern completion, and attractor dynamics. Neurobiol. Learn. Mem. 129, 38–49 (2016).

    CAS  PubMed  Google Scholar 

  46. Poppenk, J., Evensmoen, H.R., Moscovitch, M. & Nadel, L. Long-axis specialization of the human hippocampus. Trends Cogn. Sci. 17, 230–240 (2013).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Strange, B.A., Witter, M.P., Lein, E.S. & Moser, E.I. Functional organization of the hippocampal longitudinal axis. Nat. Rev. Neurosci. 15, 655–669 (2014).

    CAS  PubMed  Google Scholar 

  50. Igarashi, K.M., Ito, H.T., Moser, E.I. & Moser, M.-B. Functional diversity along the transverse axis of hippocampal area CA1. FEBS Lett. 588, 2470–2476 (2014).

    CAS  PubMed  Google Scholar 

  51. Swanson, L.W. Brain Maps: Structure of the Rat Brain (Elsevier, 1992).

  52. Barker, G.R.I. et al. The different effects on recognition memory of perirhinal kainate and NMDA glutamate receptor antagonism: implications for underlying plasticity mechanisms. J. Neurosci. 26, 3561–3566 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Barker, G.R.I. & Warburton, E.C. NMDA receptor plasticity in the perirhinal and prefrontal cortices is crucial for the acquisition of long-term object-in-place associative memory. J. Neurosci. 28, 2837–2844 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kerrigan, T.L., Brown, J.T. & Randall, A.D. Characterization of altered intrinsic excitability in hippocampal CA1 pyramidal cells of the Aβ-overproducing PDAPP mouse. Neuropharmacology 79, 515–524 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Booth, C.A., Brown, J.T. & Randall, A.D. Neurophysiological modification of CA1 pyramidal neurons in a transgenic mouse expressing a truncated form of disrupted-in-schizophrenia 1. Eur. J. Neurosci. 39, 1074–1090 (2014).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank J. Robbins for help with the experiments, L. Barnes (Oxford BioMedica) for help with the vector plasmids, J.T. Brown (Exeter University) and C.A. Booth (Bristol University) for providing MATLAB scripts, M.W. Brown for comments and discussions on the manuscript and A. Doherty for assistance with preparation of the figures. The work was supported by the Biotechnology and Biology Sciences Research Council grants BB100310X/1 to E.C.W., J.B.U. and L.-F.W. and BB/L001896/1 to Z.I.B. and E.C.W.

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Contributions

E.C.W., G.R.I.B., Z.I.B., P.J.B. and J.B.U. contributed to the study design; G.R.I.B., E.C.W., and H.S. contributed to the behavioral experiments and data collection; J.B.U., L.-F.W., G.S.R., and K.A.M. designed, optimized and provided the viral constructs; G.R.I.B. conducted the surgery; P.J.B. performed and analyzed the electrophysiology experiments. E.C.W. and G.R.I.B. wrote the manuscript. All authors discussed and commented on the manuscript.

Corresponding author

Correspondence to E Clea Warburton.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Diffusion of fluorescent conjugated muscimol within the HPC following infusion into the dHPC and iHPC

Representative sections of one rat brain with intracerebral cannulae implanted into the dorsal hippocampus (dHPC) and intermediate hippocampus (iHPC) in opposite hemispheres, at -4.5mm. -4.8mm, -5.2mm, -5.6mm, -6.0mm, -6.3mm, -6.7mm and – 7.0mm from bregma. Sections were visualized under fluorescent microscopy for fluoro-conjugated muscimol (0.5mg/ml/ 0.5μl). Animals were sacrificed 20min after the end of the infusion. Scale bars are 1mm in length.

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Supplementary Figure 1 and Supplementary Tables 1–3 (PDF 666 kb)

Supplementary Methods Checklist (PDF 435 kb)

Supplementary Software

Supplementary software for electrophysiological analysis (ZIP 37 kb)

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Barker, G., Banks, P., Scott, H. et al. Separate elements of episodic memory subserved by distinct hippocampal–prefrontal connections. Nat Neurosci 20, 242–250 (2017). https://doi.org/10.1038/nn.4472

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