In Alzheimer’s disease (AD), hippocampus-dependent memories underlie an extensive decline. The neuronal ensemble encoding a memory, termed engram, is partially recapitulated during memory recall. Artificial activation of an engram can restore memory in a mouse model of early AD, but its fate and the factors that render the engram nonfunctional are yet to be revealed. Here, we used repeated two-photon in vivo imaging to analyze fosGFP transgenic mice (which express enhanced GFP under the Fos promoter) performing a hippocampus-dependent memory task. We found that partial reactivation of the CA1 engram during recall is preserved under AD-like conditions. However, we identified a novelty-like ensemble that interfered with the engram and thus compromised recall. Mimicking a novelty-like ensemble in healthy mice was sufficient to affect memory recall. In turn, reducing the novelty-like signal rescued the recall impairment under AD-like conditions. These findings suggest a novel mechanistic process that contributes to the deterioration of memories in AD.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
ΔFosB accumulation in hippocampal granule cells drives cFos pattern separation during spatial learning
Nature Communications Open Access 26 October 2022
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data that support the findings of this are available from the corresponding authors upon request.
The code used for analyzing the data in the current study is available from the corresponding authors upon request.
Semon, R. W. The Mneme (G. Allen & Unwin, 1921).
Josselyn, S. A., Köhler, S. & Frankland, P. W. Finding the engram. Nat. Rev. Neurosci. 16, 521–534 (2015).
Guzowski, J. F., McNaughton, B. L., Barnes, C. A. & Worley, P. F. Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nat. Neurosci. 2, 1120–1124 (1999).
Tayler, K. K., Tanaka, K. Z., Reijmers, L. G. & Wiltgen, B. J. Reactivation of neural ensembles during the retrieval of recent and remote memory. Curr. Biol. 23, 99–106 (2013).
Reijmers, L. G., Perkins, B. L., Matsuo, N. & Mayford, M. Localization of a stable neural correlate of associative memory. Science 317, 1230–1233 (2007).
Morgan, J. I., Cohen, D. R., Hempstead, J. L. & Curran, T. Mapping patterns of c-Fos expression in the central nervous system after seizure. Science 237, 192–197 (1987).
Sagar, S. M., Sharp, F. R. & Curran, T. Expression of c-Fos protein in brain: metabolic mapping at the cellular level. Science 240, 5–8 (1988).
Schoenenberger, P., Gerosa, D. & Oertner, T. G. Temporal control of immediate early gene induction by light. PLoS ONE 4, e8185 (2009).
Fleischmann, A. et al. Impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS. J. Neurosci. 23, 9116–9122 (2003).
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).
Prince, M. W. et al. World Alzheimer Report 2015. The Global Impact of Dementia: an Analysis of Prevalence, Incidence, Cost and Trends (Alzheimer’s Disease International, 2015).
Katzman, R. Editorial: the prevalence and malignancy of Alzheimer disease. A major killer. Arch. Neurol. 33, 217–218 (1976).
Palop, J. J. & Mucke, L. Epilepsy and cognitive impairments in Alzheimer disease. Arch. Neurol. 66, 435–440 (2009).
Kerchner, G. A. et al. Hippocampal CA1 apical neuropil atrophy in mild Alzheimer disease visualized with 7-T MRI. Neurology 75, 1381–1387 (2010).
Goshen, I. et al. Dynamics of retrieval strategies for remote memories. Cell 147, 678–689 (2011).
Larkin, M. C., Lykken, C., Tye, L. D., Wickelgren, J. G. & Frank, L. M. Hippocampal output area CA1 broadcasts a generalized novelty signal during an object–place recognition task. Hippocampus 24, 773–783 (2014).
Kumaran, D. & Maguire, E. A. Match mismatch processes underlie human hippocampal responses to associative novelty. J. Neurosci. 27, 8517–8524 (2007).
Lisman, J. E. & Otmakhova, N. A. Storage, recall, and novelty detection of sequences by the hippocampus: elaborating on the SOCRATIC model to account for normal and aberrant effects of dopamine. Hippocampus 11, 551–568 (2001).
Busche, M. A. et al. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 109, 8740–8745 (2012).
Busche, M. A. et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321, 1686–1689 (2008).
Attardo, A. et al. Long-term consolidation of ensemble neural plasticity patterns in hippocampal area CA1. Cell Rep. 25, 640–650.e642 (2018).
Tanaka, K. Z. et al. Cortical representations are reinstated by the hippocampus during memory retrieval. Neuron 84, 347–354 (2014).
Trouche, S. et al. Recoding a cocaine–place memory engram to a neutral engram in the hippocampus. Nat. Neurosci. 19, 564–567 (2016).
Liu, X. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012).
Ryan, T. J., Roy, D. S., Pignatelli, M., Arons, A. & Toggas, S. M. Engram cells retain memory under retrograde amnesia. Science 348, 1007–1013 (2015).
Roy, D. S. et al. Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease. Nature 531, 508–512 (2016).
Barth, A. L., Gerkin, R. C. & Dean, K. L. Alteration of neuronal firing properties after in vivo experience in a FosGFP transgenic mouse. J. Neurosci. 24, 6466–6475 (2004).
Jankowsky, J. L. et al. Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase. Hum. Mol. Genet. 13, 159–170 (2004).
Gu, L. et al. Long-term in vivo imaging of dendritic spines in the hippocampus reveals structural plasticity. J. Neurosci. 34, 13948–13953 (2014).
Mahringer, D. et al. Expression of c-Fos and Arc in hippocampal region CA1 marks neurons that exhibit learning-related activity changes. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/644526v1 (2019).
Palop, J. J. et al. Vulnerability of dentate granule cells to disruption of Arc expression in human amyloid precursor protein transgenic mice. J. Neurosci. 25, 9686–9693 (2005).
Rudinskiy, N. et al. Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer’s disease. Nat. Neurosci. 15, 1422–1429 (2012).
Zhang, P., Hirsch, E. C., Damier, P., Duyckaerts, C. & Javoy-Agid, F. c-Fos protein-like immunoreactivity: distribution in the human brain and over-expression in the hippocampus of patients with Alzheimer’s disease. Neuroscience 46, 9–21 (1992).
Anderson, A. J., Cummings, B. J. & Cotman, C. W. Increased immunoreactivity for Jun- and Fos-related proteins in Alzheimer’s disease: association with pathology. Exp. Neurol. 125, 286–295 (1994).
Tanaka, K. Z. et al. The hippocampal engram maps experience but not place. Science 361, 392–397 (2018).
Mau, W. et al. The same hippocampal CA1 population simultaneously codes temporal information over multiple timescales. Curr. Biol. 28, 1499–1508.e1494 (2018).
Schmid, L. C. et al. Dysfunction of somatostatin-positive interneurons associated with memory deficits in an Alzheimer’s disease model. Neuron 92, 114–125 (2016).
Kilgore, M. et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 35, 870–880 (2010).
Radulovic, J., Kammermeier, J. & Spiess, J. Relationship between Fos production and classical fear conditioning: effects of novelty, latent inhibition, and unconditioned stimulus preexposure. J. Neurosci. 18, 7452–7461 (1998).
Soltesz, I. & Losonczy, A. CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus. Nat. Neurosci. 21, 484–493 (2018).
Wilson, M. A. & McNaughton, B. L. Dynamics of the hippocampal ensemble code for space. Science 261, 1055–1058 (1993).
Karlsson, M. P. & Frank, L. M. Network dynamics underlying the formation of sparse, informative representations in the hippocampus. J. Neurosci. 28, 14271–14281 (2008).
Garner, A. R. et al. Generation of a synthetic memory trace. Science 335, 1513–1516 (2012).
Girardeau, G., Benchenane, K., Wiener, S. I., Buzsaki, G. & Zugaro, M. B. Selective suppression of hippocampal ripples impairs spatial memory. Nat. Neurosci. 12, 1222–1223 (2009).
Bittner, K. C. et al. Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons. Nat. Neurosci. 18, 1133–1142 (2015).
Basu, J. et al. A cortico–hippocampal learning rule shapes inhibitory microcircuit activity to enhance hippocampal information flow. Neuron 79, 1208–1221 (2013).
Basu, J. & Siegelbaum, S. A. The corticohippocampal circuit, synaptic plasticity, and memory. Cold Spring Harb. Perspect. Biol. 7, a021733 (2015).
Hsia, A. Y. et al. Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc. Natl Acad. Sci. USA 96, 3228–3233 (1999).
Siskova, Z. et al. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer’s disease. Neuron 84, 1023–1033 (2014).
Burgold, S. et al. In vivo multiphoton imaging reveals gradual growth of newborn amyloid plaques over weeks. Acta Neuropathol. 121, 327–335 (2011).
Zhu, P. et al. Silencing and un-silencing of tetracycline-controlled genes in neurons. PLoS ONE 2, e533 (2007).
Lopez, A. J. et al. Promoter-specific effects of DREADD modulation on hippocampal synaptic plasticity and memory formation. J. Neurosci. 36, 3588–3599 (2016).
Thevenaz, P., Ruttimann, U. E. & Unser, M. A pyramid approach to subpixel registration based on intensity. IEEE Trans. Image Process. 7, 27–41 (1998).
Bevington, P. R. & Robinson, D. K. Data Reduction and Error Analysis for the Physical Sciences 3rd edn (McGraw-Hill, 2003).
Pozzi, F., Di Matteo, T. & Aste, T. Exponential smoothing weighted correlations. Eur. Phys. J. B 85, 175 (2012).
Campbell, M. J., Walters, S. J. & Machin, D. Medical Statistics: a Textbook for the Health Sciences 4th edn (Wiley, 2007).
Friedrich, J., Zhou, P. & Paninski, L. Fast online deconvolution of calcium imaging data. PLoS Comput. Biol. 13, e1005423 (2017).
Giovannucci, A. et al. CaImAn an open source tool for scalable calcium imaging data analysis. eLife 8, e38173 (2019).
This work was supported by the DZNE, grants from the Deutsche Forschungsgemeinschaft (SFB 1089 C01 and B06), Centres of excellence in Neurodegeneration (CoEN 3018), the ERA-NET MicroSynDep and the MicroSchiz project. We thank P. Thevenaz and E. Meijering for the development of the ImageJ plugins stackreg and TurboReg. We acknowledge W. Wisden for providing the Addgene plasmids numbers 66794 and 66795. We thank B. Roth for providing the Addgene plasmid number 50475 and the Addgene viral prep number 44361. Addgene plasmid number 26973 was a gift from K. Deisseroth. We thank S. Wiegert, S. Remy, G. Petzold, R. Czajkowski and L. Ewell for helpful discussions on the manuscript, and thank the Light Microscope and Animal Facilities of DZNE for constant support.
The authors declare no competing interests.
Peer review information Nature Neuroscience thanks Takashi Kitamura and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a, Scheme of the experimental setting (left) and an exemplary two-photon in vivo image showing jRGECO1a and fosGFP expression (right). b, Fractions of jRGECO1a-expressing cells that are fosGFP−positive (fosGFP+) or -negative (fosGFP−). c, Event frequency of fosGFP+ and fosGFP- neurons. Data in b and c from 1953 jRGECO1a-expressing cells in n = 4 mice. d, Experimental timeline to assess fosGFP expression and its underlying neuronal activity, approximated by the Ca2+ event frequency. CE, novel context exposure; CTR, control. e–j, Exemplary two-photon images (left) and quantification (right) of UP (e, f), DOWN (g,h) and no change cells (i, j). k, l, Exemplary two-photon image of jRGECO1a-expressing CA1 neurons (k) and respective Ca2+ traces (l) of identified UP, DOWN and no change neurons marked in k. m, n, Ca2+ event frequency of UP, DOWN and no change neurons in the group of mice exposed to a novel context (CE, m) and those under continuous anesthesia (CTR, n). o, Experimental timeline to determine the onset of fosGFP expression upon contextual fear conditioning (cFC). p, Exemplary binary two-photon images (left) and quantification (right) of fosGFP expression onset (ON) and decay (OFF). Data in d–n from n = 4 CE and n = 6 CTR mice; c, two-sided Mann-Whitney test; f,h,j, two-sided unpaired t-test; m, n, one-way ANOVA with Holm-Sidak’s multiple comparison test; NS(P > 0.05); *P < 0.05; **P < 0.01; ***P < 0.001 for exact P values see Supplementary Table 1. Data in f, h and j are presented as mean ± SEM; each data point depicts the value of an individual mouse. Data in c, m and n show the median (bold line), 25%- and 75%-quartiles (dashed lines), minimum and maximum values (upper and lower end of violins). Scale bars, 50 µm (a, right), 5 µm (e, g, i), 25 µm (k, right).
a, Coronal mouse brain section showing the analyzed part (framed) of dorsal CA1. b, Quantification of endogenous c-Fos-positive (c-Fos+) and fosGFP-positive (fosGFP+) neurons in wild-type and fosGFP mice, respectively, and APP/PS1 and fosGFP-APP/PS1 mice; data from n = 9 wild-type, n = 6 fosGFP, n = 5 APP/PS1 and n = 9 fosGFP-APP/PS1 mice. c, Representative confocal images of c-Fos+ and fosGFP+ neurons in CA1 of fosGFP and fosGFP-APP/PS1 mice; for each mouse, five brain slices were stained and analyzed (see d), with similar results. d, Fraction of endogenous c-Fos+ nuclei that were simultaneously positive for fosGFP; data from n = 3 fosGFP and n = 3 fosGFP-APP/PS1 mice. e–g, Method to convert 8-bit raw data into binary images. Exemplary measurement of background fluorescence intensity (BG) in a fosGFP raw data image with manually placed circular masks (red, ∅ 7.45 μm) (e). Exemplary fosGFP raw data (f, left) and corresponding binary image (f, right). Circular masks (white) were manually placed above putatively fosGFP expressing nuclei to measure their fluorescence intensity (f, left). Nuclei with a fosGFP fluorescence intensity above or below threshold (TH) were defined as fosGFP+ or fosGFP-, respectively (g). h, Images showing the density of fosGFP+ neurons around MeXO4-stained Aß-plaques (yellow) and randomly placed virtual Aß-plaques in fosGFP-APP/PS1 and fosGFP mice, respectively; 250 ×250 μm excerpts of a 1.9 ×1.9 mm field of view; images were acquired once for each mouse; other excerpts show similar results. i, j, Density of fosGFP+ neurons in CA1 irrespective of Aß plaque distance (i), and in the proximity (<50 µm, near) or distant (>50 µm, far) to MeXO4-stained Aß-plaques (j) comparing fosGFP-APP/PS1 and fosGFP mice, respectively. k, Exemplary images of fosGFP-expressing neurons’ fluorescence intensities in CA1 of fosGFP and fosGFP-APP/PS1 mice; 250 ×250 μm excerpts of a 1.9 ×1.9 mm field of view; image was acquired once, other excerpts show similar results; white circles (radius = 50 µm) in h and k depict the area close to a MeXO4-positive Aβ-plaque (in fosGFP-APP/PS1 mice) or a virtual plaque (in fosGFP mice), respectively. l, m, Fluorescence intensity of fosGFP-expressing neurons in fosGFP and fosGFP-APP/PS1 mice regardless of Aß plaque distance (l), and in proximity (<50 µm, near) or distant (>50 µm, far) to MeXO4 stained Aß plaques (m); data in h–m from n = 8 fosGFP and n = 6 fosGFP-APP/PS1 mice; statistics were done over mice, except for l, m; data in l are from 2873 (fosGFP) and 2092 (fosGFP-APP/PS1) cells; data in m are from 1373 (fosGFP – near), 674 (fosGFP-APP/PS1-near), 1500 (fosGFP – far) and 1418 (fosGFP-APP/PS1 – far) cells; d, i, two-sided unpaired t-test; j, two-way ANOVA with Holm-Sidak’s correction for multiple comparisons; l, two-sided Mann-Whitney test; m, Kruskal-Wallis test with Dunn’s correction for multiple comparisons; *P < 0.05, **P < 0.01, ***P < 0.001, for exact P values see Supplementary Table 1. Data in b, d, i, j are presented as mean ± SEM; each data point depicts the value of an individual mouse. Data in l and m show the median (bold line), 25%- and 75%-quartiles (dashed lines), minimum and maximum values (upper and lower end of violins). Scale bars, 40 µm (c), 20 µm (e,f), 50 µm (h, k).
a, Experimental protocol for fear conditioning in context A: two minutes of exploration (pre-shock) are followed by three 0.5 mA foot shocks spaced by one minute intervals. Mouse was removed from the chamber one minute after the last foot shock (see also methods section). b, Freezing behavior of wild-type and APP/PS1 mice during conditioning. c, Experimental paradigm for testing short term memory (STM). d, Freezing behavior of wild-type and APP/PS1 mice during STM test, one hour after conditioning. e, f, Fraction of c-Fos-positive (c-Fos+) per DAPI-positiv (DAPI+) neurons (e) and density of DAPI+ neurons upon STM test (f). a, b, Data from n = 17 wild-type and n = 18 APP/PS1 mice; c–f, data from n = 4 wild-type and n = 4 APP/PS1 transgenic mice; b, two-way ANOVA with Holm-Sidak’s correction for multiple comparisons; d, f, two-sided unpaired t-test; e, two-sided Mann-Whitney test; **P < 0.01, for exact P values see Supplementary Table 1. Data are presented as mean ± SEM; each data point depicts the value of an individual mouse.
Inter-group comparison of the fold change of ON cells upon memory recall (d3–4 in A-A/B), corresponding to Fig. 1m–p. Data according to Fig. 1, n = 7 fosGFP A-A (G1), n = 6 fosGFP-APP/PS1 A-A (G2), n = 6 fosGFP A-B (G3) and n = 3 fosGFP-APP/PS1 A-B (G4) mice; data include BL and A-A/B imaging, comprising measurements from 4322 (G1), 5099 (G2), 3755 (G3) and 2195 (G4) cells, respectively; statistics were done over mice; two-way ANOVA with Holm-Sidak’s multiple comparisons test; NS (P > 0.05), for exact P values see Supplementary Table 1. Data are presented as mean ± SEM; each data point depicts the value of an individual mouse.
a, AAV-c-Fos-tTA and AAV-PTRE-tight-hChR2-EYFP were injected bilaterally into the hippocampus of APP/PS1 mice and wild-type littermates (left) before optical fibers were implanted to target CA1 (right). b, Experimental timeline. c, Representative confocal images showing hChR2-EYFP expression in wild-type (upper) and APP/PS1 mice (lower), respectively; for each mouse, four brain slices were stained and analyzed (see i, j), with similar results. d, e, Freezing during the stimulation protocol in context C, before (control, black) and after tagging (hChR2, green) of the same set of APP/PS1 (d, left) and wild-type mice (e, left). Average freezing during intervals without (off) and with (on) light stimulation in hChR2-tagged APP/PS1 (d, right) and wild-type (e, right) mice, respectively. f, g, Freezing during test I (f) and test II (g) comparing wild-type and APP/PS1 mice. h, Comparison of net freezing during light stimulation (on - off, average freezing during light on periods minus average freezing during light off periods) between wild-type and APP/PS1 mice. i, j, Density of hChR2-positive (hChR2+) cells regardless of Aß plaque distance (i), and in proximity (<50 µm, near) or distant (>50 µm, far) to MeXO4 stained Aß plaques in wild-type and APP/PS1 mice (j). Data from n = 6 wild-type and n = 8 APP/PS1 mice; d (right), e (right), two-sided paired t-test; f–j, two-sided unpaired t-test; ****P < 0.0001, ***P < 0.001, for exact P values see Supplementary Table 1. Data are presented as mean ± SEM; each data point depicts the value of an individual mouse.
a, b, Experimental approach. c, d, Overview (left) and zoom (right) of exemplary confocal images of coronal brain sections showing CA1 targeted expression of hM3D(Gq)-mCherry and c-Fos in vehicle- (c) and CNO-treated mice (d); for each mouse, four brain slices were stained and analyzed (see e), with similar results. e, Density of c-Fos-positive (c-Fos+) neurons in vehicle- and CNO-treated mice; the value of each mouse represents an average of four analyzed brain slices. f, Freezing behavior of vehicle- and CNO-treated mice. Data from n = 5 CNO-treated and n = 4 saline-treated mice; e, f, two-sided unpaired t-test; ****P < 0.0001, *P < 0.05, for exact P values see Supplementary Table 1. Data are presented as mean ± SEM; each data point depicts the value of an individual mouse. Scale bars, 500 µm (c, left), 50 µm (c, right).
a, b, Experimental approach. c, Density of c-Fos-positive (c-Fos+) neurons after memory retrieval; the value of each mouse represents an average of four analyzed brain slices. d, Freezing behavior of non-treated and non-labeled mice during recall on d8 (test). e, Overview (left) and zoom (right) of an exemplary confocal image of a coronal brain sections showing CA1 lacking expression of hM3D(Gq)-mCherry; for each mouse, four brain slices were stained and analyzed (see c), with similar results. Data from n = 5 wild-type mice. Data are presented as mean ± SEM; each data point depicts the value of an individual mouse. Scale bars, 500 µm (e, left), 50 µm (e, right).
Extended Data Fig. 8 Reduced endogenous c-Fos expression in hM4D(Gi)-positive CA1 pyramidal neurons.
a,b, Scheme of the experimental setting (a) and timeline (b) for reducing noise-like activity (ensemble of neurons active in context B) during memory recall of the conditioned context A (see Fig. 3g–k). c, d, Intensity distribution of endogenous c-Fos measured in the nuclei of hM4D(Gi)-mCherry-negative (mCherry-) and hM4D(Gi)-mCherry-positive (mCherry+) cells in both APP/PS1 (c) and wild-type mice (d). e, Quantification of hM4D(Gi)-mCherry expression in wild-type and APP/PS1 mice. Data from n = 5 wild-type and n = 3 APP/PS1 mice; c, d, two-sided Mann-Whitney test; e, two-sided unpaired t-test; NS (P > 0.05); ****P < 0.0001, for statistical details and exact P values see Supplementary Table 1. Data in c and d show the median (bold line), 25%- and 75%-quartiles (dashed lines), minimum and maximum values (upper and lower end of violins). Data in e are presented as mean ± SEM; each data point depicts the value of an individual mouse.
a, Travelled distance in context B (left) and freezing in the conditioned context A (right) comparing vehicle- and CNO-treated wild-type mice expressing hM4D(Gi). Data in a from n = 4 vehicle- and n = 8 CNO-treated wild-type mice. b, Travelled distances in context B comparing wild-type and APP/PS1 mice expressing hM4D(Gi) (left) or lacking DREADD expression (right); data in b (left) from n = 8 wild-type and n = 10 APP/PS1 mice; data in b (right) from n = 4 wild-type and n = 4 APP/PS1 mice. c, Experimental timeline (left). Travelled distance in context B (middle) and freezing in the conditioned context A (right) comparing vehicle- and CNO-treated wild-type mice. Data in c from n = 6 vehicle-treated and n = 7 CNO-treated wild-type mice. a (left), two-sided Mann-Whitney test; a (right), b, c, two-sided unpaired t-test; NS (P > 0.05), for exact P values see Supplementary Table 1. Data are presented as mean ± SEM; each data point depicts the value of an individual mouse.
a, b, Experimental setup (a) and timeline (b) to determine the influence of either hM4D(Gi) expression or sham injection (just AAV-c-Fos-tTA) on memory recall. c, Exemplary confocal images showing hM4D(Gi)-mCherry expression in groups A, B and C; for each mouse, four brain slices were stained, with similar results. d, Freezing behavior of groups A, B and C during memory test. Data from n = 6 group A, n = 6 group B and n = 6 group C mice. d, one-way ANOVA with Holm-Sidaks multiple comparison test; NS (P > 0.05), for exact P values see Supplementary Table 1. Data are presented as mean ± SEM; each data point depicts the value of an individual mouse. Scale bars, 500 µm (c, left), 50 µm (c, right).
About this article
Cite this article
Poll, S., Mittag, M., Musacchio, F. et al. Memory trace interference impairs recall in a mouse model of Alzheimer’s disease. Nat Neurosci 23, 952–958 (2020). https://doi.org/10.1038/s41593-020-0652-4
This article is cited by
Nature Reviews Neuroscience (2022)
ΔFosB accumulation in hippocampal granule cells drives cFos pattern separation during spatial learning
Nature Communications (2022)
Construction and implementation of a college talent cultivation system under deep learning and data mining algorithms
The Journal of Supercomputing (2022)
Nature Neuroscience (2020)