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Spaced Training Enhances Memory and Prefrontal Ensemble Stability in Mice

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Spaced Training Enhances Memory and Prefrontal Ensemble Stability in Mice bioRxiv preprint doi: https://doi.org/10.1101/2020.12.17.417451; this version posted December 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 2 Spaced training enhances memory and prefrontal ensemble stability in mice 1,2 1 1 1 3 Annet Glas , Mark H¨ubener , Tobias Bonhoeffer , Pieter M. Goltstein 4 Author Affiliations 1 5 Max Planck Institute of Neurobiology, Martinsried, Germany 2 6 Graduate School of Systemic Neurosciences, Martinsried, Germany 7 Lead Contacts 8 Tobias Bonhoeffer, [email protected] 9 Pieter Goltstein, [email protected] 10 Summary 11 Memory is substantially improved when learning is distributed over time, an effect called \spacing effect". So 12 far it has not been studied how spaced learning affects neuronal ensembles presumably underlying memory. 13 In the present study, we investigate whether trial spacing increases the stability or size of neuronal ensembles. 14 Mice were trained in the \everyday memory" task, an appetitive, naturalistic, delayed matching-to-place task. 15 Spacing trials by 60 minutes produced more robust memories than training with shorter or longer intervals. 16 c-Fos labeling and chemogenetic inactivation established the necessity of the dorsomedial prefrontal cortex 17 (dmPFC) for successful memory storage. In vivo calcium imaging of excitatory dmPFC neurons revealed that 18 longer trial spacing increased the similarity of the population activity pattern on subsequent encoding trials 19 and upon retrieval. Conversely, trial spacing did not affect the size of the total neuronal ensemble or the size 20 of subpopulations dedicated to specific task-related behaviors and events. Thus, spaced learning promotes 21 reactivation of prefrontal neuronal ensembles processing episodic-like memories. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.17.417451; this version posted December 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 22 Introduction 23 Extending the period between individual learning events can considerably strengthen a memory and increase 1 24 its lifespan, a phenomenon called the \spacing effect" . This phenomenon has been described across a wide 2 3 4 25 range of species, from mollusk to man . In mice, spaced training can strengthen associative episodic-like , 5 6 26 motor , and spatial memories. The effectiveness of spacing learning is thought to be mediated by molecular 2 27 and synaptic processes , which involve activation and expression of key signaling proteins and transcription 2; 6; 7 5; 8 28 factors , leading to increased synaptic plasticity . It has not yet been studied, whether and how 29 increasing the spacing of learning events affects neuronal ensembles representing an individual memory. 30 During a learning experience, a subset of neurons is activated as a result of their intrinsic excitability and 9; 10; 11; 12 31 external sensory drive . The memory itself is thought to be encoded by synaptic connections that 13; 14; 15 32 are newly formed or strengthened within this neuronal ensemble . Subsequently, memories can be 16; 17 33 consolidated by further functional and structural synaptic remodeling, enabling long-term retention . 34 For retrieval of a memory, neurons that are part of the ensemble need to be reactivated in a pattern similar 11; 18; 19 35 to that during memory encoding . 36 The working hypothesis for the present work is that the molecular and synaptic mechanisms underlying 2 37 the spacing effect can influence two characteristics of neuronal ensembles, i.e. the size or reactivation pattern 38 of the ensemble, during memory encoding, storage, and retrieval. The reasoning is that when learning occurs 39 over multiple optimally spaced trials, molecular signaling initiated in the first trial can extend the temporal 10; 20 40 window of enhanced neuronal excitability and thereby increase the likelihood of the same ensemble being 41 reactivated in subsequent trials. As such, spaced training would more effectively strengthen the ensemble's 21; 22 42 internal synaptic connectivity and by local competitive circuit interactions result in a sparser, but more 23; 24; 25 26 43 reliably activated assembly . Sparseness would safeguard the specificity of the represented memory , 44 while stronger connectivity would render the memory more resilient to homeostatic mechanisms that can 27 45 result in forgetting and thereby increase the probability of retrieval. Conversely, as the group of excitable 10 46 neurons drifts over time , consecutive learning experiences could activate different sets of neurons. Spacing 28 47 learning experiences over extended periods could therefore allocate a memory to overlapping sets of neurons . 48 Within this framework, the memory enhancing effect of spaced training could be mediated by representing a 4; 11 49 learning experience with a larger neuronal ensemble . 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.17.417451; this version posted December 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 50 To determine whether and how trial spacing changes the way neuronal ensembles represent learned 7 51 experiences, we implemented the \everyday memory" task, a naturalistic delayed matching-to-place task . 52 The instilled episodic-like memories are typically forgotten within 24 hours, but spaced training reliably 7 53 prolongs the period over which the memories can be retrieved . Efficient execution of the everyday memory 54 task relies on functions that have been attributed to the dorsal medial prefrontal cortex (dmPFC), including 29 30 55 behavioral flexibility and learning against a background of relevant prior knowledge . Moreover, rodent 56 prefrontal cortex is, in concert with hippocampus, involved in the encoding and retrieval of episodic-like 31; 32 57 memories , providing an attractive system for examining the relation between neuronal ensemble activity 58 and memory strength. 59 Here we report that trial spacing improves memory and is accompanied with enhanced reactivation of 60 the neuronal ensembles in dmPFC. Increasing trial spacing in the everyday memory task enhanced memory 61 retrieval, yet impaired memory encoding. In vivo calcium imaging with a miniaturized microscope revealed 62 that trial spacing results in more similar reactivation of the ensemble between encoding trials and upon 63 memory retrieval. Conversely, trial spacing did not affect the size of the ensemble, suggesting that trial 64 spacing primarily affects the synaptic strength within the neuronal ensemble but not its size. 65 Results 66 Studying episodic-like memory in an \everyday memory" task. We trained female mice (n = 20) in 7 67 repeated sessions of an \everyday memory" task (see Method Summary, Figure 1A, B, Video 1; ). Each 68 training session consisted of three encoding trials (ETs; separated by an \encoding intertrial interval") and 69 three retrieval trials (RTs). During each encoding trial, mice entered the radial arm maze from a start box, 70 explored the maze and retrieved a buried chocolate reward by digging in one of two available, odor-masked 71 sandwells (i.e. the \rewarded" sandwell; Figure S1A{C). Upon completion of the final encoding trial, mice 72 were kept in their home cage for an extended delay period (\retrieval delay"), after which the three retrieval 73 trials (RTs) were conducted. During retrieval trials, mice had to revisit the previously rewarded sandwell. 74 Simultaneously, mice had to refrain from digging at the previously non-rewarded sandwell, as well as four 75 new non-rewarded sandwells (\non-cued" sandwells). 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.17.417451; this version posted December 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A Behavioral arena B Encoding Retrieval Encoding trial (ET) Retrieval trial (RT) ET1 ET2 ET3 RT1 RT2 RT3 Rewarded sandwell Non-rewarded sandwell Non-cued sandwell Start box Encoding intertrial interval (ETi) 0.5 | 10 | 30 | 60 min Retrieval delay (RTd) 2.5 | 24 hrs ET | RT C Encoding Retrieval D Retrieval across session blocks i d *** ** 100 1 2 3 4 5 100 1 100 5 0.5 | 2.5 10 | 2.5 80 80 4 80 30 | 2.5 60 60 3 60 60 | 2.5 0.5 | 24 Errors 40 Errors 40 2 40 10 | 24 20 20 1 20 Performance index Performance index Performance index 30 | 24 60 | 24 0 0 0 0 0 ET1 ET2 ET3 RT1 RT2 RT3 E Retrieval F Encoding G Retention H Probe trials *** *** *** *** *** *** *** * ** * * 100 100 250 100 75 80 80 200 50 60 60 150 25 0 40 40 100 -25 Retention index -50 Performance index 20 Performance index 20 50 -75 Occupancy difference score Occupancy difference 0 0 0 -100 ET1 ET2 ET3 RTd 2.5 hrs 24 hrs RTd 2.5 hrs 24 hrs ETi (min) 0.5 0.5 10 10 30 30 60 60 RTd (hrs) 2.5 24 2.5 24 2.5 24 2.5 24 Figure 1. Trial spacing enhances memory retrieval, yet impairs memory encoding on the ev- eryday memory task. A Schematic of behavioral training setup. B Schematic of session structure. Sandwell locations were altered on each session. C Performance improved across encoding (left) and retrieval trials 2 -15 -4 (right; ET1 vs.
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