CA1 and CA3 differentially support spontaneous retrieval of episodic contexts within human hippocampal subfields

Halle R Dimsdale-Zucker, Maureen Ritchey, Arne D Ekstrom, Andrew P Yonelinas, Charan Ranganath, Halle R Dimsdale-Zucker, Maureen Ritchey, Arne D Ekstrom, Andrew P Yonelinas, Charan Ranganath

Abstract

The hippocampus plays a critical role in spatial and episodic memory. Mechanistic models predict that hippocampal subfields have computational specializations that differentially support memory. However, there is little empirical evidence suggesting differences between the subfields, particularly in humans. To clarify how hippocampal subfields support human spatial and episodic memory, we developed a virtual reality paradigm where participants passively navigated through houses (spatial contexts) across a series of videos (episodic contexts). We then used multivariate analyses of high-resolution fMRI data to identify neural representations of contextual information during recollection. Multi-voxel pattern similarity analyses revealed that CA1 represented objects that shared an episodic context as more similar than those from different episodic contexts. CA23DG showed the opposite pattern, differentiating between objects encountered in the same episodic context. The complementary characteristics of these subfields explain how we can parse our experiences into cohesive episodes while retaining the specific details that support vivid recollection.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Experimental approach. Participants encoded objects uniquely located within one of two spatial locations (spatial contexts) across a series of 20 videos (episodic contexts). Next, they were scanned while performing an object recognition test which required differentiating old and new objects presented without any contextual information. We used representational similarity analyses (RSA) to examine the similarity of voxel patterns elicited by each recollected object relative to other recollected objects that were studied in the same (or different) spatial and episodic context. This figure is not included under the Creative Commons licence for the article; all rights reserved
Fig. 2
Fig. 2
Pattern similarity in CA1 and CA23DG is sensitive to episodic context. Pattern similarity was higher in left CA1 for items studied in the same video (Same Video Same House) than for items in different videos (Different Video Same House). Left CA23DG showed a reversal of this pattern such that pattern similarity was higher for items studied between videos vs. within the same video. Neither CA1 nor CA23DG patterns were sensitive to spatial context similarity alone

References

    1. Davachi L. Item, context and relational episodic encoding in humans. Curr. Opin. Neurobiol. 2006;16:693–700. doi: 10.1016/j.conb.2006.10.012.
    1. Eichenbaum H, Yonelinas AP, Ranganath C. The medial temporal lobe and recognition memory. Annu. Rev. Neurosci. 2007;30:123–152. doi: 10.1146/annurev.neuro.30.051606.094328.
    1. Kesner RP, Rolls ET. A computational theory of hippocampal function, and tests of the theory: new developments. Neurosci. Biobehav. Rev. 2015;48:92–147. doi: 10.1016/j.neubiorev.2014.11.009.
    1. Guzowski JF, Knierim JJ, Moser EI. Ensemble dynamics of hippocampal regions CA3 and CA1. Neuron. 2004;44:581–584. doi: 10.1016/j.neuron.2004.11.003.
    1. Hasselmo ME, Eichenbaum H. Hippocampal mechanisms for the context-dependent retrieval of episodes. Neural Netw. 2005;18:1172–1190. doi: 10.1016/j.neunet.2005.08.007.
    1. Levy WB. A sequence predicting CA3 is a flexible associator that learns and uses context to solve hippocampal-like tasks. Hippocampus. 1996;6:579–590. doi: 10.1002/(SICI)1098-1063(1996)6:6<579::AID-HIPO3>;2-C.
    1. O’Reilly RC, Norman KA. Hippocampal and neocortical contributions to memory: advances in the complementary learning systems framework. Trends Cogn. Sci. 2002;6:505–510. doi: 10.1016/S1364-6613(02)02005-3.
    1. Kraus BJ, Robinson RJ, White JA, Eichenbaum H, Hasselmo ME. Hippocampal ‘time cells’: time versus path integration. Neuron. 2013;78:1090–1101. doi: 10.1016/j.neuron.2013.04.015.
    1. Salz DM, et al. Time cells in hippocampal area CA3. J. Neurosci. 2016;36:7476–7484. doi: 10.1523/JNEUROSCI.0087-16.2016.
    1. Kyle CT, Smuda DN, Hassan AS, Ekstrom AD. Roles of human hippocampal subfields in retrieval of spatial and temporal context. Behav. Brain Res. 2015;278C:549–558. doi: 10.1016/j.bbr.2014.10.034.
    1. Lee I, Jerman TS, Kesner RP. Disruption of delayed memory for a sequence of spatial locations following CA1- or CA3-lesions of the dorsal hippocampus. Neurobiol. Learn. Mem. 2005;84:138–147. doi: 10.1016/j.nlm.2005.06.002.
    1. Leutgeb S, Leutgeb JK. Pattern separation, pattern completion, and new neuronal codes within a continuous CA3 map. Learn. Mem. 2007;14:745–757. doi: 10.1101/lm.703907.
    1. Kriegeskorte N, Mur M, Bandettini P. Representational similarity analysis - connecting the branches of systems neuroscience. Front. Syst. Neurosci. 2008;2:4. doi: 10.3389/neuro.01.016.2008.
    1. McKenzie S, et al. Hippocampal representation of related and opposing memories develop within distinct, hierarchically organized neural schemas. Neuron. 2014;83:202–215. doi: 10.1016/j.neuron.2014.05.019.
    1. Diana RA, Yonelinas AP, Ranganath C. Imaging recollection and familiarity in the medial temporal lobe: a three-component model. Trends Cogn. Sci. 2007;11:379–386. doi: 10.1016/j.tics.2007.08.001.
    1. Johnson JD, Rugg MD. Recollection and the reinstatement of encoding-related cortical activity. Cereb. Cortex. 2007;17:2507–2515. doi: 10.1093/cercor/bhl156.
    1. Gordon AM, Rissman J, Kiani R, Wagner AD. Cortical reinstatement mediates the relationship between content-specific encoding activity and subsequent recollection decisions. Cereb. Cortex. 2014;24:3350–3364. doi: 10.1093/cercor/bht194.
    1. Marr D. Simple memory: a theory for archicortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 1971;262:23–81. doi: 10.1098/rstb.1971.0078.
    1. Todd MT, Nystrom LE, Cohen JD. Confounds in multivariate pattern analysis: theory and rule representation case study. Neuroimage. 2013;77:157–165. doi: 10.1016/j.neuroimage.2013.03.039.
    1. Mizuseki K, Royer S, Diba K, Buzsáki G. Activity dynamics and behavioral correlates of CA3 and CA1 hippocampal pyramidal neurons. Hippocampus. 2012;22:1659–1680. doi: 10.1002/hipo.22002.
    1. Lee I, Rao G, Knierim JJ. A double dissociation between hippocampal subfields: differential time course of CA3 and CA1 place cells for processing changed environments. Neuron. 2004;42:803–815. doi: 10.1016/j.neuron.2004.05.010.
    1. Roth ED, Yu X, Rao G, Knierim JJ. Functional differences in the backward shifts of CA1 and CA3 place fields in novel and familiar environments. PLoS ONE. 2012;7:e36035. doi: 10.1371/journal.pone.0036035.
    1. Gusev PA, Cui C, Alkon DL, Gubin AN. Topography of Arc/Arg3.1 mRNA expression in the dorsal and ventral hippocampus induced by recent and remote spatial memory recall: dissociation of CA3 and CA1 activation. J. Neurosci. 2005;25:9384–9397. doi: 10.1523/JNEUROSCI.0832-05.2005.
    1. Farovik A, Dupont LM, Eichenbaum H. Distinct roles for dorsal CA3 and CA1 in memory for sequential nonspatial events. Learn. Mem. 2010;17:12–17. doi: 10.1101/lm.1616209.
    1. Ji J, Maren S. Differential roles for hippocampal areas CA1 and CA3 in the contextual encoding and retrieval of extinguished fear. Learn. Mem. 2008;15:244–251. doi: 10.1101/lm.794808.
    1. Stokes J, Kyle C, Ekstrom AD. Complementary roles of human hippocampal subfields in differentiation and integration of spatial context. J. Cogn. Neurosci. 2015;27:546–559. doi: 10.1162/jocn_a_00736.
    1. MacDonald CJ, Lepage KQ, Eden UT, Eichenbaum H. Hippocampal ‘time cells’ bridge the gap in memory for discontiguous events. Neuron. 2011;71:737–749. doi: 10.1016/j.neuron.2011.07.012.
    1. Mankin EA, et al. Neuronal code for extended time in the hippocampus. Proc. Natl Acad. Sci. USA. 2012;109:19462–19467. doi: 10.1073/pnas.1214107109.
    1. Pastalkova E, Itskov V, Amarasingham A, Buzsáki G. Internally generated cell assembly sequences in the rat hippocampus. Science. 2008;321:1322–1327. doi: 10.1126/science.1159775.
    1. Allen TA, Salz DM, McKenzie S, Fortin NJ. Nonspatial sequence coding in CA1 neurons. J. Neurosci. 2016;36:1547–1563. doi: 10.1523/JNEUROSCI.2874-15.2016.
    1. Chen J, Cook PA, Wagner AD. Prediction strength modulates responses in human area CA1 to sequence violations. J. Neurophysiol. 2015;114:1227–1238. doi: 10.1152/jn.00149.2015.
    1. Hoge J, Kesner RP. Role of CA3 and CA1 subregions of the dorsal hippocampus on temporal processing of objects. Neurobiol. Learn. Mem. 2007;88:225–231. doi: 10.1016/j.nlm.2007.04.013.
    1. Hunsaker MR, Fieldsted PM, Rosenberg JS, Kesner RP. Dissociating the roles of dorsal and ventral CA1 for the temporal processing of spatial locations, visual objects, and odors. Behav. Neurosci. 2008;122:643–650. doi: 10.1037/0735-7044.122.3.643.
    1. Kesner RP, Hunsaker MR, Ziegler W. The role of the dorsal CA1 and ventral CA1 in memory for the temporal order of a sequence of odors. Neurobiol. Learn. Mem. 2010;93:111–116. doi: 10.1016/j.nlm.2009.08.010.
    1. Manns JR, Howard MW, Eichenbaum H. Gradual changes in hippocampal activity support remembering the order of events. Neuron. 2007;56:530–540. doi: 10.1016/j.neuron.2007.08.017.
    1. Stark E, Roux L, Eichler R, Buzsáki G. Local generation of multineuronal spike sequences in the hippocampal CA1 region. Proc. Natl Acad. Sci. USA. 2015;112:10521–10526. doi: 10.1073/pnas.1508785112.
    1. Brown TI, Hasselmo ME, Stern CE. A high-resolution study of hippocampal and medial temporal lobe correlates of spatial context and prospective overlapping route memory. Hippocampus. 2014;24:819–839. doi: 10.1002/hipo.22273.
    1. Hunsaker MR, Lee B, Kesner RP. Evaluating the temporal context of episodic memory: the role of CA3 and CA1. Behav. Brain Res. 2008;188:310–315. doi: 10.1016/j.bbr.2007.11.015.
    1. Wang F, Diana RA. Temporal context processing within hippocampal subfields. Neuroimage. 2016;134:261–269. doi: 10.1016/j.neuroimage.2016.03.048.
    1. Chanales, A. J., Oza, A., Favila, S. E. & Kuhl, B. A. Overlap among spatial memories triggers repulsion of hippocampal representations. Curr. Biol.27, 2307–2317.e5 (2017).
    1. Favila SE, Chanales AJH, Kuhl BA. Experience-dependent hippocampal pattern differentiation prevents interference during subsequent learning. Nat. Commun. 2016;7:11066. doi: 10.1038/ncomms11066.
    1. LaRocque KF, et al. Global similarity and pattern separation in the human medial temporal lobe predict subsequent memory. J. Neurosci. 2013;33:5466–5474. doi: 10.1523/JNEUROSCI.4293-12.2013.
    1. Schlichting ML, Mumford JA, Preston AR. Learning-related representational changes reveal dissociable integration and separation signatures in the hippocampus and prefrontal cortex. Nat. Commun. 2015;6:8151. doi: 10.1038/ncomms9151.
    1. Yassa MA, Stark CEL. Pattern separation in the hippocampus. Trends Neurosci. 2011;34:515–525. doi: 10.1016/j.tins.2011.06.006.
    1. Kim, G., Norman, K. A. & Turk-Browne, N. B. Neural differentiation of incorrectly predicted memories. J. Neurosci.10.1523/jneurosci.3272-16.2017 (2017).
    1. Kyle, C. T., Stokes, J. D., Lieberman, J. S., Hassan, A. S. & Ekstrom, A. D. Successful retrieval of competing spatial environments in humans involves hippocampal pattern separation mechanisms. eLife4, e10499 (2015).
    1. Schapiro AC, Kustner LV, Turk-Browne NB. Shaping of object representations in the human medial temporal lobe based on temporal regularities. Curr. Biol. 2012;22:1622–1627. doi: 10.1016/j.cub.2012.06.056.
    1. Aly M, Turk-Browne NB. Attention promotes episodic encoding by stabilizing hippocampal representations. Proc. Natl Acad. Sci. USA. 2016;113:E420–E429. doi: 10.1073/pnas.1518931113.
    1. Aly M, Turk-Browne NB. Attention stabilizes representations in the human hippocampus. Cereb. Cortex. 2016;26:783–796.
    1. Tulving E. Précis of elements of episodic memory. Behav. Brain Sci. 1984;7:223–238. doi: 10.1017/S0140525X0004440X.
    1. Burgess N, Maguire EA, O’Keefe J. The human hippocampus and spatial and episodic memory. Neuron. 2002;35:625–641. doi: 10.1016/S0896-6273(02)00830-9.
    1. Eichenbaum H, Cohen NJ. Can we reconcile the declarative memory and spatial navigation views on hippocampal function? Neuron. 2014;83:764–770. doi: 10.1016/j.neuron.2014.07.032.
    1. Ranganath C. A unified framework for the functional organization of the medial temporal lobes and the phenomenology of episodic memory. Hippocampus. 2010;20:1263–1290. doi: 10.1002/hipo.20852.
    1. Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage. 2012;59:2142–2154. doi: 10.1016/j.neuroimage.2011.10.018.
    1. Mazaika, P., Whitfield-Gabrieli, S. & Cooper, J. C. (2005) Detection and repair of transient artifacts in fMRI data. Poster presented at Human Brain Mapping.
    1. Yushkevich PA, et al. Nearly automatic segmentation of hippocampal subfields in in vivo focal T2-weighted MRI. Neuroimage. 2010;53:1208–1224. doi: 10.1016/j.neuroimage.2010.06.040.
    1. Ekstrom AD, et al. Advances in high-resolution imaging and computational unfolding of the human hippocampus. Neuroimage. 2009;47:42–49. doi: 10.1016/j.neuroimage.2009.03.017.
    1. Zeineh MM, Engel SA, Bookheimer SY. Application of cortical unfolding techniques to functional MRI of the human hippocampal region. NeuroImage. 2000;11:668–683. doi: 10.1006/nimg.2000.0561.
    1. Yushkevich PA, et al. Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: towards a harmonized segmentation protocol. Neuroimage. 2015;111:526–541. doi: 10.1016/j.neuroimage.2015.01.004.
    1. Bates, D. lme4: Mixed-effects Modeling with R (Springer, Madison, WI, 2010).
    1. Yushkevich PA, et al. Automated volumetry and regional thickness analysis of hippocampal subfields and medial temporal cortical structures in mild cognitive impairment. Hum. Brain Mapp. 2015;36:258–287. doi: 10.1002/hbm.22627.
    1. Bates, D., Mächler, M., Bolker, B. & Walker, S. Fitting linear mixed-effects models using lme4. 67, 1–48 (2015).
    1. Barr DJ, Levy R, Scheepers C, Tily HJ. Random effects structure for confirmatory hypothesis testing: Keep it maximal. J. Mem. Lang. 2013;68:255–278. doi: 10.1016/j.jml.2012.11.001.
    1. Luke, S. G. Evaluating significance in linear mixed-effects models in R. Behav. Res. Methods10.3758/s13428-016-0809-y (2016).
    1. Winter, B. Linear models and linear mixed effects models in R with linguistic applications. arXiv (2013).
    1. Dunlap WP, Cortina JM, Vaslow JB, Burke MJ. Meta-analysis of experiments with matched groups or repeated measures designs. Psychol. Methods. 1996;1:170–177. doi: 10.1037/1082-989X.1.2.170.
    1. Yonelinas AP. The nature of recollection and familiarity: a review of 30 years of research. J. Mem. Lang. 2002;46:441–517. doi: 10.1006/jmla.2002.2864.
    1. Mumford JA, Turner BO, Ashby FG, Poldrack RA. Deconvolving BOLD activation in event-related designs for multivoxel pattern classification analyses. Neuroimage. 2012;59:2636–2643. doi: 10.1016/j.neuroimage.2011.08.076.
    1. Ritchey M, Montchal ME, Yonelinas AP, Ranganath C. Delay-dependent contributions of medial temporal lobe regions to episodic memory retrieval. eLife. 2015;4:e05025. doi: 10.7554/eLife.05025.
    1. Frankó E, Insausti AM, Artacho-Pérula E, Insausti R, Chavoix C. Identification of the human medial temporal lobe regions on magnetic resonance images: human medial temporal lobe landmarks. Hum. Brain Mapp. 2014;35:248–256. doi: 10.1002/hbm.22170.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi