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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Change history
25 May 2017
A ReadMe file and a more complete analysis suite have been added to the Supplementary Software.
References
Tulving, E. Organisation of Memory (Academic, New York, 1972).
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).
Eichenbaum, H., Yonelinas, A.P. & Ranganath, C. The medial temporal lobe and recognition memory. Annu. Rev. Neurosci. 30, 123–152 (2007).
Eichenbaum, H.T. Memory Systems (MIT Press, Cambridge, Massachusetts, USA, 1994).
Dickerson, B.C. & Eichenbaum, H. The episodic memory system: neurocircuitry and disorders. Neuropsychopharmacology 35, 86–104 (2010).
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).
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).
Preston, A.R. & Eichenbaum, H. Interplay of hippocampus and prefrontal cortex in memory. Curr. Biol. 23, R764–R773 (2013).
Wheeler, M.A., Stuss, D.T. & Tulving, E. Frontal lobe damage produces episodic memory impairment. J. Int. Neuropsychol. Soc. 1, 525–536 (1995).
Duarte, A., Ranganath, C. & Knight, R.T. Effects of unilateral prefrontal lesions on familiarity, recollection, and source memory. J. Neurosci. 25, 8333–8337 (2005).
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).
Petrides, M. Deficits on conditional associative-learning tasks after frontal- and temporal-lobe lesions in man. Neuropsychologia 23, 601–614 (1985).
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).
Buckner, R.L., Kelley, W.M. & Petersen, S.E. Frontal cortex contributes to human memory formation. Nat. Neurosci. 2, 311–314 (1999).
Barredo, J., Öztekin, I. & Badre, D. Ventral fronto-temporal pathway supporting cognitive control of episodic memory retrieval. Cereb. Cortex 25, 1004–1019 (2015).
Benchenane, K. et al. Coherent theta oscillations and reorganization of spike timing in the hippocampal- prefrontal network upon learning. Neuron 66, 921–936 (2010).
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).
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).
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).
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).
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).
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).
Ennaceur, A. One-trial object recognition in rats and mice: methodological and theoretical issues. Behav. Brain Res. 215, 244–254 (2010).
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).
Koya, E. et al. Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization. Nat. Neurosci. 12, 1069–1073 (2009).
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).
Farquhar, D. et al. Suicide gene therapy using E. coli beta-galactosidase. Cancer Chemother. Pharmacol. 50, 65–70 (2002).
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).
Barker, G.R.I. & Warburton, E.C. When is the hippocampus involved in recognition memory? J. Neurosci. 31, 10721–10731 (2011).
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).
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).
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).
Eichenbaum, H. Time cells in the hippocampus: a new dimension for mapping memories. Nat. Rev. Neurosci. 15, 732–744 (2014).
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).
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).
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).
Ito, H.T. & Schuman, E.M. Functional division of hippocampal area CA1 via modulatory gating of entorhinal cortical inputs. Hippocampus 22, 372–387 (2012).
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).
Henriksen, E.J. et al. Spatial representation along the proximodistal axis of CA1. Neuron 68, 127–137 (2010).
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).
Apergis-Schoute, J., Pinto, A. & Paré, D. Ultrastructural organization of medial prefrontal inputs to the rhinal cortices. Eur. J. Neurosci. 24, 135–144 (2006).
Xu, W. & Südhof, T.C. A neural circuit for memory specificity and generalization. Science 339, 1290–1295 (2013).
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).
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).
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).
Poppenk, J., Evensmoen, H.R., Moscovitch, M. & Nadel, L. Long-axis specialization of the human hippocampus. Trends Cogn. Sci. 17, 230–240 (2013).
Moser, M.-B. & Moser, E.I. Functional differentiation in the hippocampus. Hippocampus 8, 608–619 (1998).
Fanselow, M.S. & Dong, H.-W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010).
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).
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).
Swanson, L.W. Brain Maps: Structure of the Rat Brain (Elsevier, 1992).
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).
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).
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).
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).
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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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.
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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 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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DOI: https://doi.org/10.1038/nn.4472
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