The prefrontal cortex (PFC) and hippocampus support complementary functions in episodic memory.
Connections between the PFC and the hippocampus are particularly important for episodic memory.
In addition, these areas interact bidirectionally through oscillatory synchrony.
Distinct types of interactions between the PFC and hippocampus are supported by a direct hippocampus–PFC connection and by bidirectional pathways via intermediaries in the thalamus and perirhinal and lateral entorhinal cortices.
This Review outlines a model of how the PFC and hippocampus interact during episodic memory tasks.
The roles of the hippocampus and prefrontal cortex (PFC) in memory processing — individually or in concert — are a major topic of interest in memory research. These brain areas have distinct and complementary roles in episodic memory, and their interactions are crucial for learning and remembering events. Considerable evidence indicates that the PFC and hippocampus become coupled via oscillatory synchrony that reflects bidirectional flow of information. Furthermore, newer studies have revealed specific mechanisms whereby neural representations in the PFC and hippocampus are mediated through direct connections or through intermediary regions. These findings suggest a model of how the hippocampus and PFC, along with their intermediaries, operate as a system that uses the current context of experience to retrieve relevant memories.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21 (1957).
Cohen, N. J. & Eichenbaum, H. Memory, Amnesia, and the Hippocampal System (MIT Press, 1993).
Eichenbaum, H. Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 44, 109–120 (2004).
Eichenbaum, H. Memory: organization and control. Annu. Rev. Psychol. 68, 19–45 (2017).
Eacott, M. J. & Norman, G. Integrated memory for object, place, and context in rats: a possible model of episodic-like memory? J. Neurosci. 24, 1948–1953 (2004).
Langston, R. F. & Wood, E. R. Associative recognition and the hippocampus: differential effects of hippocampal lesions on object–place, object–context and object–place–context memory. Hippocampus 20, 1139–1153 (2010).
Butterly, D. A., Petroccione, M. A. & Smith, D. M. Hippocampal context processing is critical for interference free recall of odor memories in rats. Hippocampus 22, 906–913 (2012).
Corcoran, K. A. & Maren, S. Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction. J. Neurosci. 21, 1720–1726 (2001).
Holland, P. C. & Bouton, M. E. Hippocampus and context in classical conditioning. Curr. Opin. Neurobiol. 9, 195–202 (1999).
Moita, M. A. P., Rosis, S., Zhou, Y., LeDoux, J. E. & Blair, H. T. Hippocampal place cells acquire location-specific responses to the conditioned stimulus during auditory fear conditioning. Neuron 37, 485–497 (2003).
Manns, J. R. & Eichenbaum, H. A cognitive map for object memory in the hippocampus. Learn. Mem. 16, 616–624 (2009).
Komorowski, R. W., Manns, J. R. & Eichenbaum, H. Robust conjunctive item–place coding by hippocampal neurons parallels learning what happens where. J. Neurosci. 29, 9918–9929 (2009).
Itskov, P. M., Vinnik, E. & Diamond, M. E. Hippocampal representation of touch-guided behavior in rats: persistent and independent traces of stimulus and reward location. PLoS ONE 6, e16462 (2011).
Itskov, P. M., Vinnik, E., Honey, C., Schnupp, J. & Diamond, M. E. Sound sensitivity of neurons in rat hippocampus during performance of a sound-guided task. J. Neurophysiol. 107, 1822–1834 (2012).
Vinnik, E., Antopolskiy, S., Itskov, P. M. & Diamond, M. E. Auditory stimuli elicit hippocampal neuronal responses during sleep. Front. Syst. Neurosci. 6, 49 (2012).
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).
Bulkin, D. A., Law, L. M. & Smith, D. M. Placing memories in context: hippocampal representations promote retrieval of appropriate memories. Hippocampus 26, 958–971 (2016).
Kjelstrup, K. B. et al. Finite scale of spatial representation in the hippocampus. Science 321, 140–143 (2008).
Royer, S., Sirota, A., Patel, J. & Buzsáki, G. Distinct representations and theta dynamics in dorsal and ventral hippocampus. J. Neurosci. 30, 1777–1787 (2010).
Komorowski, R. W. et al. Ventral hippocampal neurons are shaped by experience to represent behaviorally relevant contexts. J. Neurosci. 33, 8079–8087 (2013).
Poppenk, J., Evensmoen, H. R., Moscovitch, M. & Nadel, L. Long-axis specialization of the human hippocampus. Trends Cogn. Sci. 17, 230–240 (2013).
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).
Milner, B., Corkin, S. & Teuber, H.-L. Further analysis of the hippocampal amnesic syndrome: 14-year follow-up study of H.M. Neuropsychol. 6, 215–234 (1968).
Moscovitch, M. Memory and working-with-memory: a component process model based on modules and central systems. J. Cogn. Neurosci. 4, 257–267 (1992).
Dobbins, I. G., Foley, H., Schacter, D. L. & Wagner, A. D. Executive control during episodic retrieval: multiple prefrontal processes subserve source memory. Neuron 35, 989–996 (2002).
Postle, B. R. Working memory as an emergent property of the mind and brain. Neuroscience 139, 23–38 (2006).
Ranganath, C. & Blumenfield, R. in Learning and Memory: A Comprehensive Reference (ed. Byrne, J. H.) 261–279 (Oxford Univ. Press, 2008).
Kuhl, B. A. & Wagner, A. D. in Encyclopedia of Neuroscience 437–444 (Elsevier, 2009).
Preston, A. R. & Eichenbaum, H. Interplay of hippocampus and prefrontal cortex in memory. Curr. Biol. 23, R764–R773 (2013).
Szczepanski, S. M. & Knight, R. T. Insights into human behavior from lesions to the prefrontal cortex. Neuron 83, 1002–1018 (2014).
Shimamura, A. P., Jurica, P. J., Mangels, J. A., Gershberg, F. B. & Knight, R. T. Susceptibility to memory interference effects following frontal lobe damage: findings from tests of paired-associate learning. J. Cogn. Neurosci. 7, 144–152 (1995).
Eichenbaum, H., Fortin, N., Sauvage, M., Robitsek, R. J. & Farovik, A. An animal model of amnesia that uses Receiver Operating Characteristics (ROC) analysis to distinguish recollection from familiarity deficits in recognition memory. Neuropsychologia 48, 2281–2289 (2010).
Fortin, N. J., Wright, S. P. & Eichenbaum, H. Recollection-like memory retrieval in rats is dependent on the hippocampus. Nature 431, 188–191 (2004).
Farovik, A., Dupont, L. M., Arce, M. & Eichenbaum, H. Medial prefrontal cortex supports recollection, but not familiarity, in the rat. J. Neurosci. 28, 13428–13434 (2008).
Robitsek, R. J., Fortin, N. J., Koh, M. T., Gallagher, M. & Eichenbaum, H. Cognitive aging: a common decline of episodic recollection and spatial memory in rats. J. Neurosci. 28, 8945–8954 (2008).
Chudasama, Y., Doobay, V. M. & Liu, Y. Hippocampal–prefrontal cortical circuit mediates inhibitory response control in the rat. J. Neurosci. 32, 10915–10924 (2012).
Giustino, T. F. & Maren, S. The role of the medial prefrontal cortex in the conditioning and extinction of fear. Front. Behav. Neurosci. 9, 298 (2015).
Anderson, M. C., Bunce, J. G. & Barbas, H. Prefrontal–hippocampal pathways underlying inhibitory control over memory. Neurobiol. Learn. Mem. 134, 145–161 (2016).
Rich, E. L. & Shapiro, M. L. Prelimbic/infralimbic inactivation impairs memory for multiple task switches, but not flexible selection of familiar tasks. J. Neurosci. 27, 4747–4755 (2007).
Ragozzino, M. E., Detrick, S. & Kesner, R. P. Involvement of the prelimbic–infralimbic areas of the rodent prefrontal cortex in behavioral flexibility for place and response learning. J. Neurosci. 19, 4585–4594 (1999).
Ragozzino, M. E., Kim, J., Hassert, D., Minniti, N. & Kiang, C. The contribution of the rat prelimbic–infralimbic areas to different forms of task switching. Behav. Neurosci. 117, 1054–1065 (2003).
Brown, V. J. & Bowman, E. M. Rodent models of prefrontal cortical function. Trends Neurosci. 25, 340–343 (2002).
Marquis, J.-P., Killcross, S. & Haddon, J. E. Inactivation of the prelimbic, but not infralimbic, prefrontal cortex impairs the contextual control of response conflict in rats. Eur. J. Neurosci. 25, 559–566 (2007).
Guise, K. G. & Shapiro, M. Medial prefrontal cortex reduces memory interference by modifying hippocampal encoding. Neuron 94, 183–192.e8 (2017).
Rich, E. L. & Shapiro, M. Rat prefrontal cortical neurons selectively code strategy switches. J. Neurosci. 29, 7208–7219 (2009).
Durstewitz, D., Vittoz, N. M., Floresco, S. B. & Seamans, J. K. Abrupt transitions between prefrontal neural ensemble states accompany behavioral transitions during rule learning. Neuron 66, 438–448 (2010).
Karlsson, M. P., Tervo, D. G. R. & Karpova, A. Y. Network resets in medial prefrontal cortex mark the onset of behavioral uncertainty. Science 338, 135–139 (2012).
Ma, L., Hyman, J. M., Durstewitz, D., Phillips, A. G. & Seamans, J. K. A. Quantitative analysis of context-dependent remapping of medial frontal cortex neurons and ensembles. J. Neurosci. 36, 8258–8272 (2016).
Morrissey, M. D., Insel, N. & Takehara-Nishiuchi, K. Generalizable knowledge outweighs incidental details in prefrontal ensemble code over time. eLife 6, e22177 (2017).
Tomita, H., Ohbayashi, M., Nakahara, K., Hasegawa, I. & Miyashita, Y. Top-down signal from prefrontal cortex in executive control of memory retrieval. Nature 401, 699–703 (1999).
Buschman, T. J., Denovellis, E. L., Diogo, C., Bullock, D. & Miller, E. K. Synchronous oscillatory neural ensembles for rules in the prefrontal cortex. Neuron 76, 838–846 (2012).
Stokes, M. G. et al. Dynamic coding for cognitive control in prefrontal cortex. Neuron 78, 364–375 (2013).
Blackman, R. K. et al. Monkey prefrontal neurons reflect logical operations for cognitive control in a variant of the AX Continuous Performance Task (AX-CPT). J. Neurosci. 36, 4067–4079 (2016).
Miller, E. K., Freedman, D. J. & Wallis, J. D. The prefrontal cortex: categories, concepts and cognition. Phil. Trans. R. Soc. 357, 1123–1136 (2002).
Euston, D. R., Gruber, A. J. & McNaughton, B. L. The role of medial prefrontal cortex in memory and decision making. Neuron 76, 1057–1070 (2012).
Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev. Neurosci. 24, 167–202 (2001).
Rosene, D. & Van Hoesen, G. Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey. Science 198, 315–317 (1977).
Witter, M. P., Groenewegen, H. J., Lopes da Silva, F. H. & Lohman, A. H. Functional organization of the extrinsic and intrinsic circuitry of the parahippocampal region. Prog. Neurobiol. 33, 161–253 (1989).
Burwell, R. D., Witter, M. P. & Amaral, D. G. Perirhinal and postrhinal cortices of the rat: a review of the neuroanatomical literature and comparison with findings from the monkey brain. Hippocampus 5, 390–408 (1995).
Lavenex, P., Suzuki, W. A. & Amaral, D. G. Perirhinal and parahippocampal cortices of the macaque monkey: projections to the neocortex. J. Comp. Neurol. 447, 394–420 (2002).
Jay, T. M., Glowinski, J. & Thierry, A. M. Selectivity of the hippocampal projection to the prelimbic area of the prefrontal cortex in the rat. Brain Res. 505, 337–340 (1989).
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).
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).
Jadhav, S. P., Rothschild, G., Roumis, D. K. & Frank, L. M. Coordinated excitation and inhibition of prefrontal ensembles during awake hippocampal sharp-wave ripple events. Neuron 90, 113–127 (2016).
Dolleman-Van Der Weel, M. J. & Witter, M. P. Projections from the nucleus reuniens thalami to the entorhinal cortex, hippocampal field CA1, and the subiculum in the rat arise from different populations of neurons. J. Comp. Neurol. 364, 637–650 (1996).
Vertes, R. P. Analysis of projections from the medial prefrontal cortex to the thalamus in the rat, with emphasis on nucleus reuniens. J. Comp. Neurol. 442, 163–187 (2002).
Vertes, R. P. Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat. Neuroscience 142, 1–20 (2006).
Vertes, R. P., Hoover, W. B., Szigeti-Buck, K. & Leranth, C. Nucleus reuniens of the midline thalamus: link between the medial prefrontal cortex and the hippocampus. Brain Res. Bull. 71, 601–609 (2007).
Cassel, J.-C. et al. The reuniens and rhomboid nuclei: neuroanatomy, electrophysiological characteristics and behavioral implications. Prog. Neurobiol. 111, 34–52 (2013).
Ketz, N. A., Jensen, O. & O'Reilly, R. C. Thalamic pathways underlying prefrontal cortex–medial temporal lobe oscillatory interactions. Trends Neurosci. 38, 3–12 (2015).
Mitchell, A. S. et al. Advances in understanding mechanisms of thalamic relays in cognition and behavior. J. Neurosci. 34, 15340–15346 (2014).
Burwell, R. D. & Amaral, D. G. Cortical afferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. J. Comp. Neurol. 398, 179–205 (1998).
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).
Apergis-Schoute, J., Pinto, A. & Paré, D. Ultrastructural organization of medial prefrontal inputs to the rhinal cortices. Eur. J. Neurosci. 24, 135–144 (2006).
Agster, K. L. & Burwell, R. D. Cortical efferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. Hippocampus 19, 1159–1186 (2009).
Igarashi, K. M., Lu, L., Colgin, L. L., Moser, M.-B. & Moser, E. I. Coordination of entorhinal–hippocampal ensemble activity during associative learning. Nature 510, 143–147 (2014).
Keene, C. S. et al. Complementary functional organization of neuronal activity patterns in the perirhinal, lateral entorhinal, and medial entorhinal cortices. J. Neurosci. 36, 3660–3675 (2016).
Eichenbaum, H., Yonelinas, A. P. & Ranganath, C. The medial temporal lobe and recognition memory. Annu. Rev. Neurosci. 30, 123–152 (2007).
Barker, G. R. I., Bird, F., Alexander, V. & Warburton, E. C. Recognition memory for objects, place, and temporal order: a disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex. J. Neurosci. 27, 2948–2957 (2007). This study provides compelling evidence that ipsilateral pathways between the PFC and the hippocampus are essential for memory.
Hannesson, D. K., Howland, J. G. & Phillips, A. G. Interaction between perirhinal and medial prefrontal cortex is required for temporal order but not recognition memory for objects in rats. J. Neurosci. 24, 4596–4604 (2004).
Barker, G. R. I. et al. Separate elements of episodic memory subserved by distinct hippocampal–prefrontal connections. Nat. Neurosci. 20, 242–250 (2017).
Chao, O. Y., Huston, J. P., Li, J.-S., Wang, A.-L. & de Souza Silva, M. A. The medial prefrontal cortex–lateral entorhinal cortex circuit is essential for episodic-like memory and associative object-recognition. Hippocampus 26, 633–645 (2016).
Floresco, S. B., Seamans, J. K. & Phillips, A. G. Selective roles for hippocampal, prefrontal cortical, and ventral striatal circuits in radial-arm maze tasks with or without a delay. J. Neurosci. 17, 1880–1890 (1997).
Wang, G.-W. & Cai, J.-X. Disconnection of the hippocampal–prefrontal cortical circuits impairs spatial working memory performance in rats. Behav. Brain Res. 175, 329–336 (2006).
Siapas, A. G., Lubenov, E. V. & Wilson, M. A. Prefrontal phase locking to hippocampal theta oscillations. Neuron 46, 141–151 (2005).
Jones, M. W. & Wilson, M. A. Theta rhythms coordinate hippocampal–prefrontal interactions in a spatial memory task. PLoS Biol. 3, e402 (2005).
Sigurdsson, T., Stark, K. L., Karayiorgou, M., Gogos, J. A. & Gordon, J. A. Impaired hippocampal–prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464, 763–767 (2010).
Hyman, J. M., Zilli, E. A., Paley, A. M. & Hasselmo, M. E. Medial prefrontal cortex cells show dynamic modulation with the hippocampal theta rhythm dependent on behavior. Hippocampus 15, 739–749 (2005).
Hyman, J. M., Zilli, E. A., Paley, A. M. & Hasselmo, M. E. Working memory performance correlates with prefrontal–hippocampal theta interactions but not with prefrontal neuron firing rates. Front. Integr. Neurosci. 4, 2 (2010).
Benchenane, K. et al. Coherent theta oscillations and reorganization of spike timing in the hippocampal–prefrontal network upon learning. Neuron 66, 921–936 (2010). This study shows that oscillatory synchrony between the PFC and the hippocampus is essential for the organization of memory representations during learning.
Kim, J., Delcasso, S. & Lee, I. Neural correlates of object-in-place learning in hippocampus and prefrontal cortex. J. Neurosci. 31, 16991–17006 (2011).
Place, R., Farovik, A., Brockmann, M. & Eichenbaum, H. Bidirectional prefrontal–hippocampal interactions support context-guided memory. Nat. Neurosci. 19, 992–994 (2016) This study describes successive phases of interactions, whereby cueing by a context involves flow of information from the hippocampus to the PFC, whereas retrieval of context-appropriate memories involves flow of information from the PFC to the hippocampus.
O'Neill, P.-K., Gordon, J. A. & Sigurdsson, T. Theta oscillations in the medial prefrontal cortex are modulated by spatial working memory and synchronize with the hippocampus through its ventral subregion. J. Neurosci. 33, 14211–14224 (2013).
Backus, A. R., Schoffelen, J.-M., Szebényi, S., Hanslmayr, S. & Doeller, C. F. Hippocampal–prefrontal theta oscillations support memory integration. Curr. Biol. 26, 450–457 (2016).
Canolty, R. T. & Knight, R. T. The functional role of cross-frequency coupling. Trends Cogn. Sci. 14, 506–515 (2010).
Gordon, J. A. Oscillations and hippocampal–prefrontal synchrony. Curr. Opin. Neurobiol. 21, 486–491 (2011).
Colgin, L. L. Oscillations and hippocampal–prefrontal synchrony. Curr. Opin. Neurobiol. 21, 467–474 (2011).
Hallock, H. L., Wang, A. & Griffin, A. L. Ventral midline thalamus is critical for hippocampal–prefrontal synchrony and spatial working memory. J. Neurosci. 36, 8372–8389 (2016). This study provides strong evidence that the Re is crucial to oscillatory synchrony between the PFC and the hippocampus.
Thierry, A. M., Gioanni, Y., Dégénétais, E. & Glowinski, J. Hippocampo–prefrontal cortex pathway: anatomical and electrophysiological characteristics. Hippocampus 10, 411–419 (2000).
Spellman, T. et al. Hippocampal–prefrontal input supports spatial encoding in working memory. Nature 522, 309–314 (2015). This study provides compelling evidence of a role for the direct ventral hippocampus to PFC projection in the encoding of specific memories.
Ye, X., Kapeller-Libermann, D., Travaglia, A., Inda, M. C. & Alberini, C. M. Direct dorsal hippocampal–prelimbic cortex connections strengthen fear memories. Nat. Neurosci. 20, 52–61 (2017).
Xu, W. & Südhof, T. C. A neural circuit for memory specificity and generalization. Science 339, 1290–1295 (2013). This study provided the first evidence of a key role for the Re in prefrontal–hippocampal interactions that support memory.
Ito, H. T., Zhang, S.-J., Witter, M. P., Moser, E. I. & Moser, M.-B. A prefrontal–thalamo–hippocampal circuit for goal-directed spatial navigation. Nature 522, 50–55 (2015). This study provides compelling evidence that the Re is essential to the role of the PFC in guiding specificity of spatial memory representations in the hippocampus.
Rajasethupathy, P. et al. Projections from neocortex mediate top-down control of memory retrieval. Nature 526, 653–659 (2015).
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). This study shows that top-down control of memory by the PFC involves suppression of inappropriate memories in the hippocampus.
Jo, Y. S. & Lee, I. Disconnection of the hippocampal–perirhinal cortical circuits severely disrupts object–place paired associative memory. J. Neurosci. 30, 9850–9858 (2010).
Paz, R., Bauer, E. P. & Paré, D. Learning-related facilitation of rhinal interactions by medial prefrontal inputs. J. Neurosci. 27, 6542–6551 (2007).
Tse, D. et al. Schema-dependent gene activation and memory encoding in neocortex. Science 333, 891–895 (2011).
Zeithamova, D. & Preston, A. R. Flexible memories: differential roles for medial temporal lobe and prefrontal cortex in cross-episode binding. J. Neurosci. 30, 14676–14684 (2010).
Milivojevic, B., Vicente-Grabovetsky, A. & Doeller, C. F. Insight reconfigures hippocampal–prefrontal memories. Curr. Biol. 25, 821–830 (2015).
Bontempi, B., Laurent-Demir, C., Destrade, C. & Jaffard, R. Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature 400, 671–675 (1999).
Maviel, T., Durkin, T. P., Menzaghi, F. & Bontempi, B. Sites of neocortical reorganization critical for remote spatial memory. Science 305, 96–99 (2004).
Frankland, P. W., Bontempi, B., Talton, L. E., Kaczmarek, L. & Silva, A. J. The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 304, 881–883 (2004).
Lesburguères, E. et al. Early tagging of cortical networks is required for the formation of enduring associative memory. Science 331, 924–928 (2011).
Kitamura, T. et al. Engrams and circuits crucial for systems consolidation of a memory. Science 356, 73–78 (2017).
Li, Y. et al. A distinct entorhinal cortex to hippocampal CA1 direct circuit for olfactory associative learning. Nat. Neurosci. 20, 559–570 (2017).
Gordon, J. A. On being a circuit psychiatrist. Nat. Neurosci. 19, 1385–1386 (2016).
Preuss, T. M. Do rats have prefrontal cortex? The Rose–Woolsey–Akert program reconsidered. J. Cogn. Neurosci. 7, 1–24 (1995).
Uylings, H. B. M., Groenewegen, H. J. & Kolb, B. Do rats have a prefrontal cortex? Behav. Brain Res. 146, 3–17 (2003).
Uylings, H. B. & van Eden, C. G. Qualitative and quantitative comparison of the prefrontal cortex in rat and in primates, including humans. Prog. Brain Res. 85, 31–62 (1990).
Groenewegen, H. J. & Uylings, H. B. The prefrontal cortex and the integration of sensory, limbic and autonomic information. Prog. Brain Res. 126, 3–28 (2000).
Heilbronner, S. R., Rodriguez-Romaguera, J., Quirk, G. J., Groenewegen, H. J. & Haber, S. N. Circuit-based corticostriatal homologies between rat and primate. Biol. Psychiatry 80, 509–521 (2016).
Leonard, C. M. Finding prefrontal cortex in the rat. Brain Res. 1645, 1–3 (2016).
Birrell, J. M. & Brown, V. J. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J. Neurosci. 20, 4320–4324 (2000).
Dias, R., Robbins, T. W. & Roberts, A. C. Dissociation in prefrontal cortex of affective and attentional shifts. Nature 380, 69–72 (1996).
Dalley, J. W., Cardinal, R. N. & Robbins, T. W. Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci. Biobehav. Rev. 28, 771–784 (2004).
Chudasama, Y. Animal models of prefrontal-executive function. Behav. Neurosci. 125, 327–343 (2011).
Bizon, J. L., Foster, T. C., Alexander, G. E. & Glisky, E. L. Characterizing cognitive aging of working memory and executive function in animal models. Front. Aging Neurosci. 4, 19 (2012).
Benes, F. M., McSparren, J., Bird, E. D., SanGiovanni, J. P. & Vincent, S. L. Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch. Gen. Psychiatry. 48, 996–1001 (1991).
Weinberger, D. R. et al. Prefrontal neurons and the genetics of schizophrenia. Biol. Psychiatry 50, 825–844 (2001).
Heckers, S. & Konradi, C. Hippocampal pathology in schizophrenia. Curr. Top. Behav. Neurosci. 4, 529–553 (2010).
Lesh, T. A., Niendam, T. A., Minzenberg, M. J. & Carter, C. S. Cognitive control deficits in schizophrenia: mechanisms and meaning. Neuropsychopharmacology 36, 316–338 (2011).
Heckers, S. et al. Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nat. Neurosci. 1, 318–323 (1998).
Titone, D., Ditman, T., Holzman, P. S., Eichenbaum, H. & Levy, D. L. Transitive inference in schizophrenia: impairments in relational memory organization. Schizophr. Res. 68, 235–247 (2004).
Preston, A. R., Shohamy, D. & Tamminga, C. A. & Wagner, A. D. Hippocampal function, declarative memory, and schizophrenia: anatomic and functional neuroimaging considerations. Curr. Neurol. Neurosci. Rep. 5, 249–256 (2005).
Tamminga, C. A., Stan, A. D. & Wagner, A. D. The hippocampal formation in schizophrenia. Am. J. Psychiatry. 167, 1178–1193 (2010).
Ranganath, C., Minzenberg, M. J. & Ragland, J. D. The cognitive neuroscience of memory function and dysfunction in schizophrenia. Biol. Psychiatry 64, 18–25 (2008).
Armstrong, K., Williams, L. E. & Heckers, S. Revised associative inference paradigm confirms relational memory impairment in schizophrenia. Neuropsychology 26, 451–458 (2012).
Polyn, S. M. et al. Temporal context and the organisational impairment of memory search in schizophrenia. Cogn. Neuropsychiatry 20, 296–310 (2015).
Friston, K. J. & Frith, C. D. Schizophrenia: a disconnection syndrome? Clin. Neurosci. 3, 89–97 (1995).
Fletcher, P. The missing link: a failure of fronto–hippocampal integration in schizophrenia. Nat. Neurosci. 1, 266–267 (1998).
Meyer-Lindenberg, A. S. et al. Regionally specific disturbance of dorsolateral prefrontal–hippocampal functional connectivity in schizophrenia. Arch. Gen. Psychiatry. 62, 379–386 (2005).
Barch, D. M. et al. Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch. Gen. Psychiatry. 58, 280–288 (2001).
Samudra, N. et al. Alterations in hippocampal connectivity across the psychosis dimension. Psychiatry Res. 233, 148–157 (2015).
Hemsley, D. R. The schizophrenic experience: taken out of context? Schizophr. Bull. 31, 43–53 (2005).
Holmes, A. J. et al. Prefrontal functioning during context processing in schizophrenia and major depression: an event-related fMRI study. Schizophr. Res. 76, 199–206 (2005).
Reilly, J. L. et al. Impaired context processing is attributable to global neuropsychological impairment in schizophrenia and psychotic bipolar disorder. Schizophr. Bull. 43, 397–406 (2017).
Kamigaki, T. & Dan, Y. Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior. Nat. Neurosci. 20, 854–863 (2017).
The author acknowledges funding from the US National Institute of Mental Health (grant numbers MH094263, MH051570 and MH052090).
The author declares no competing financial interests.
- Oscillatory synchrony
Coordination of local field potential oscillations and spiking activity in two connected brain areas. Usually observed as a locking of the phase of oscillatory activity within a specific frequency band.
- Recognition memory
The ability to remember stimuli presented earlier, by later correctly recognizing those stimuli and by correctly rejecting other stimuli that were not previously experienced.
- Wisconsin Card Sorting Test
A card-sorting task in which participants must switch strategies to sort cards according to different parameters, such as rank, suit or colour.
- Nucleus reuniens
(Re). A midline nucleus at the centre of the thalamus that bidirectionally connects the prefrontal cortex with the hippocampus.
- Crossed lesions
Unilateral inactivation or lesion of each of two areas in opposing hemispheres, thus leaving each area intact in one hemisphere but eliminating ipsilateral connections between them.
- Theta oscillations
Oscillations in the local field potential or spiking activity in the 4–12 Hz frequency band originating in the medial septum.
- Local field potentials
Recorded electrical activity patterns that reflect both synaptic potentials and spiking activity of many neighbouring neurons within a brain area. Oscillatory patterns in local field potential reflect synchronous neural activity at particular frequencies.
- Phase shifts
Changes in the temporal coordination of spiking activity that, in many brain areas, is closely time-locked to the phase of a particular oscillation in the local field potential.
Oscillations in the local field potential in low (30–80 Hz) or high (80–140 Hz) frequency bands (defined differently among different studies).
- Post-learning consolidation
A prolonged period (hours to months) after learning, over which memories that are initially unstable become stable. This process is thought to involve the integration of new episodic memories into a semantic memory network.
- Circuit psychiatry
The use of powerful neurobiological tools to identify, monitor and manipulate specific brain circuits to advance knowledge of normal brain function and mental disorders.
About this article
Cite this article
Eichenbaum, H. Prefrontal–hippocampal interactions in episodic memory. Nat Rev Neurosci 18, 547–558 (2017). https://doi.org/10.1038/nrn.2017.74
Integrity of the uncinate fasciculus is associated with emotional pattern separation-related fMRI signals in the hippocampal dentate and CA3
Neurobiology of Learning and Memory (2021)
Tributyltin Exposure Is Associated With Recognition Memory Impairments, Alterations in Estrogen Receptor α Protein Levels, and Oxidative Stress in the Brain of Female Mice
Frontiers in Toxicology (2021)
Cerebral Cortex (2021)
Oscillation-Driven Memory Encoding, Maintenance, and Recall in an Entorhinal–Hippocampal Circuit Model
Cerebral Cortex (2021)