Engram Size Varies with Learning and Reflects Memory Content and Precision

Research Articles: Behavioral/Cognitive Engram size varies with learning and reflects memory content and precision https://doi.org/10.1523/JNEUROSCI.2786-20.2021 Cite as: J. Neurosci 2021; 10.1523/JNEUROSCI.2786-20.2021 Received: 3 November 2020 Revised: 7 February 2021 Accepted: 25 February 2021 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 Leake et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Title: Engram size varies with learning and reflects memory content and precision 2 3 Abbreviated title: Engram size reflects learning and memory precision 4 5 Authors: Jessica Leake1,2,7, Raphael Zinn1,2,7, Laura H Corbit3, Michael S Fanselow4,5,6, 6 Bryce Vissel1,2 7 8 1 Centre for Neuroscience and Regenerative Medicine, Faculty of Science, University of 9 Technology Sydney, Sydney, NSW, 2007, Australia 10 2 St Vincent’s Centre for Applied Medical Research, Sydney, NSW, 2011, Australia 11 3 Department of Psychology, The University of Toronto, Toronto, ON, M5S 1A1, Canada 12 4 Staglin Center for Brain and Behavioral Health, University of California, Los Angeles, Los 13 Angeles, CA 90095, USA 14 5 Department of Psychology, University of California, Los Angeles, Los Angeles, CA 90095, 15 USA 16 6 Department of Psychiatry and Biobehavioral Sciences, University of California, Los 17 Angeles, Los Angeles, CA 90095, USA 18 7 These authors contributed equally to the work 19 20 21 Corresponding Author information: 22 Professor Bryce Vissel 23 Email: [email protected] 24 25 Number of pages: 18 26 Number of figures: 6 27 Word count abstract: 250 words 28 Word count introduction: 638 words 29 Word count discussion: 1492 words 30 31 Conflict of interest statement: The authors declare no competing financial interests. 32 33 Acknowledgements: 34 35 This work was supported by Boyarsky Family Trust, the Howland-Rose Foundation, Doug 36 Battersby and family, David King and family, John Schaffer, Lady Fairfax Charitable Trust, 37 Stanley and Charmaine Roth and we recognise Iain Gray in honour of Kylie. Funding was 38 also provided by the NHMRC (grant 1083569) and the ARC (DP200102445) and NIMH 39 RO1-62122 (MSF). The funders had no role in the planning, writing, study analysis, decision 40 to publish, or preparation of the manuscript. 41 42 43 44 45 46 47 48 49 50 1 51 Abstract 52 53 Memories are rarely acquired under ideal conditions, rendering them vulnerable to 54 profound omissions, errors and ambiguities. Consistent with this, recent work using context 55 fear conditioning has shown that memories formed after inadequate learning time display a 56 variety of maladaptive properties, including overgeneralization to similar contexts. However, 57 the neuronal basis of such poor learning and memory imprecision remains unknown. Using c- 58 fos to track neuronal activity in male mice, we examined how these learning-dependent 59 changes in context fear memory precision are encoded in hippocampal ensembles. We found 60 that the total number of c-fos encoding cells did not correspond with learning history but 61 instead more closely reflected the length of the session immediately preceding c-fos 62 measurement. However, using a c-fos driven tagging method (TRAP2 mouse line), we found 63 that the degree of learning and memory specificity corresponded with neuronal activity in a 64 subset of dentate gyrus cells that were active during both learning and recall. Comprehensive 65 memories acquired after longer learning intervals were associated with more double-labelled 66 cells. These were preferentially reactivated in the conditioning context compared to a similar 67 context, paralleling behavioural discrimination. Conversely, impoverished memories 68 acquired after shorter learning intervals were associated with fewer double-labelled cells. 69 These were reactivated equally in both contexts, corresponding with overgeneralization. 70 Together, these findings provide two surprising conclusions. First, engram size varies with 71 learning. Second, larger engrams support better neuronal and behavioural 72 discrimination. These findings are incorporated into a model that describes how neuronal 73 activity is influenced by previous learning and present experience, thus driving behaviour. 74 75 76 Significance Statement 77 78 Memories are not always formed under ideal circumstances. This is especially true in 79 traumatic situations, such as car accidents, where individuals have insufficient time to 80 process what happened around them. Such memories have the potential to overgeneralize to 81 irrelevant situations, producing inappropriate fear and contributing to disorders like post- 82 traumatic stress disorder. However, it is unknown how such poorly-formed fear memories are 83 encoded within the brain. We find that restricting learning time results in fear memories that 84 are encoded by fewer hippocampal cells. Moreover, these fewer cells are inappropriately 85 reactivated in both dangerous and safe contexts. These findings suggest that fear memories 86 formed at brief periods overgeneralize because they lack the detail-rich information necessary 87 to support neuronal discrimination. 88 89 90 91 92 93 94 95 96 97 98 99 100 2 101 Introduction 102 103 Developing a comprehensive cognitive map of an environmental context takes time. 104 This is because contexts are composed of many disparate features, only a fraction of which 105 can be attended to at any moment. To encode such multimodal stimuli into memory, animals 106 must sample their features and integrate them into unified representations within 107 hippocampal networks (Fanselow, 1986; Fanselow, 2000; Rudy and O'Reilly, 2001). This 108 process commences rapidly, as indicated by increased immediate early gene (IEG) expression 109 and the emergence of place fields within seconds of entering a novel context (Pevzner et al., 110 2012). Yet once initiated, the same process continues for many minutes, with progressive 111 increases in hippocampal IEGs and full stabilization of hippocampal place fields only after 112 several minutes of context exploration (Frank et al., 2004; Leutgeb et al., 2004; Leake et al., 113 2017; Colon and Poulos, 2020). This extended period of hippocampal activity suggests that 114 encoding the entire context may take considerably longer than developing an initial 115 representation. Thus, interrupting the learning process could result in memories impoverished 116 in contextual detail. 117 Recent research (Zinn et al., 2020) has shown that this rapid initiation and delayed 118 completion of contextual learning can have profound adaptive consequences. Using 119 contextual fear conditioning in mice, we demonstrated that the precision of contextual fear 120 memory is critically dependent on the time animals spend in the context prior to shock 121 (placement shock interval; PSI). Animals conditioned at longer PSIs were able to 122 differentiate between the conditioning context and a similar context. However, as the PSI was 123 shortened, fear became increasingly generalized and resistant to extinction. These 124 observations are potentially interesting because overgeneralized and persistent fear is 125 characteristic of post-traumatic stress disorder (PTSD) and other psychiatric disorders 126 (Dunsmoor and Paz, 2015). This suggests that incomplete contextual encoding could be one 127 mechanism through which maladaptive fear arises (Jacobs and Nadel, 1985; Brewin et al., 128 2010; Brewin, 2014). 129 Given the potential implications of forming incomplete memories, the goal of the 130 present study was to investigate how time-dependent changes in contextual memory precision 131 are neurally encoded within hippocampal networks. Theoretical models (Treves and Rolls, 132 1994; Krasne et al., 2015) and empirical research (Liu et al., 2012; Denny et al., 2014; Ryan 133 et al., 2015) have demonstrated that memories for specific contexts are encoded within sparse 134 hippocampal cell populations. When reexposed to the same context, features of that 135 environment trigger reactivation of the original cellular ensemble, resulting in memory recall. 136 However, when exposed to a different environment, a largely non-overlapping cell 137 population is activated and differentiation occurs (Chawla et al., 2005; Deng et al., 2013; 138 Yokoyama and Matsuo, 2016). Here we examined how the extent of initial contextual 139 learning affects these processes. We predicted that PSI would alter the number of cells 140 activated and incorporated into the memory during learning and retrieval. At shorter PSIs, 141 animals would have less time for environmental sampling, resulting in acquisition of fewer 142 contextual details and recruitment of fewer cells into the memory trace. This in turn would 143 influence the degree to which the same cells would be reactivated across contexts. 144 To test these possibilities, mice were conditioned at a range of PSIs and c-fos 145 expression was used an indicator of context-encoding related activity within hippocampal

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