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Optogenetic Reactivation of Memory Ensembles in the Retrosplenial Cortex Induces Systems Consolidation

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Optogenetic Reactivation of Memory Ensembles in the Retrosplenial Cortex Induces Systems Consolidation Optogenetic reactivation of memory ensembles in the retrosplenial cortex induces systems consolidation André F. de Sousaa,b, Kiriana K. Cowansageb, Ipshita Zutshic,d, Leonardo M. Cardozob,d,e, Eun J. Yoob, Stefan Leutgebc,f, and Mark Mayfordb,1 aDoctoral Program in Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA 92037; bPsychiatry Department, University of California, San Diego, La Jolla, CA 92093; cNeurobiology Section and Center for Neural Circuits and Behavior, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093; dNeurosciences Graduate Program, University of California, San Diego, La Jolla, CA; eFundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Ministry of Education of Brazil, DF 70040-020 Brasília, Brazil; and fKavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA 92093 Edited by Thomas C. Südhof, Stanford University School of Medicine, Stanford, CA, and approved February 13, 2019 (received for review October 26, 2018) The neural circuits underlying memory change over prolonged is unclear; however, some models propose that spontaneous periods after learning, in a process known as systems consolida- postlearning reactivation of the neural ensembles involved in tion. Postlearning spontaneous reactivation of memory-related memory encoding gradually promotes neocortical ensemble mat- neural ensembles is thought to mediate this process, although a uration and systems consolidation through activity-dependent causal link has not been established. Here we test this hypothesis synaptic plasticity within these circuits (7, 8, 20). In support of in mice by using optogenetics to selectively reactivate neural this hypothesis, correlative studies in both humans and animal ensembles representing a contextual fear memory (sometimes models have demonstrated coherent reactivation of learning- referred to as engram neurons). High-frequency stimulation of related neural activity during offline brain states (i.e., sleep and these ensembles in the retrosplenial cortex 1 day after learning quiet awake states) (21–23), and disruption of high-frequency produced a recent memory with features normally observed in rhythmic activity associated with this ensemble reactivation in consolidated remote memories, including higher engagement of rodents impairs performance in spatial tasks (24, 25). However, neocortical areas during retrieval, contextual generalization, and there is no evidence that reactivation of neural ensembles repre- decreased hippocampal dependence. Moreover, this effect was senting a memory is directly involved in systems consolidation. NEUROSCIENCE only present if memory ensembles were reactivated during sleep Demonstration of such causal relation requires either selective or light anesthesia. These results provide direct support for inhibition (loss of function) or activation (gain of function) of postlearning memory ensemble reactivation as a mechanism of neural ensembles representing a specific memory to evaluate its systems consolidation, and show that this process can be accelera- effect on the consolidation process. ted by ensemble reactivation in an unconscious state. In this study, we adopted a gain-of-function strategy to test the role of the reactivation of neocortical memory ensembles in engram | memory consolidation | retrosplenial cortex | fear conditioning | systems consolidation. We used a cfos-based genetic tagging system replay (cfos-tTA/tetO-ChEF transgenic mouse) to express a channelrho- dopsin variant (ChEF) selectively in neurons naturally activated he ability to encode and retrieve episodic memories requires during CFC (26), and subsequently stimulated these ensembles in Tcoordinated activity in diverse brain areas, including the the retrosplenial cortex (RSC), using high-frequency optogenetic thalamus, neocortex, and areas of the medial-temporal lobe such stimulation (Fig. 1). The RSC is well suited to contribute to the as the hippocampus (HPC) (1–3). At the time of learning, syn- consolidation process, as it is connected to both the hippocampus aptic plasticity is thought to occur in a subset of neurons that are activated during the experience and become part of the neural Significance ensemble representing the specific memory, sometimes referred to as the memory engram (4). These changes occur rapidly with This study examines a question in memory research that has memory encoding, and are essential for the initial formation and been extant since the observation of temporally graded ret- maintenance of memory (5, 6). As time passes, memory en- rograde amnesia in patient HM after temporal lobe resection; sembles throughout the brain are further stabilized and modified namely, how does the circuit structure underlying memory through a process known as systems memory consolidation, change over prolonged periods after initial learning, such that which is thought to be necessary for the maintenance, in- recent memories require the hippocampus whereas older re- tegration, and correct categorization of new information (7, 8). mote memories do not? We use optogenetic reactivation of the This process is usually slow (months to years in humans and neurons active naturally during initial learning (engram neu- weeks to months in rodents) and changes the relative contribu- rons) to show that postlearning neural replay can produce this tion of different brain areas for memory retrieval. Studies from shift in memory. Interestingly, this was only observed in both humans and rodents show that the hippocampus is prefer- sleeping, not awake, mice. This is consistent with a model in entially engaged during learning and recent memory retrieval, which natural activity in memory ensemble during offline pe- whereas neocortical areas are more active when a remote riods results in the circuit change to remote memory. memory is retrieved (9–11). In addition, some neocortical areas involved in remote memory are not necessary for recent memory Author contributions: A.F.d.S. and M.M. designed research; A.F.d.S., I.Z., L.M.C., and E.J.Y. retrieval (9, 12), whereas the hippocampus is generally dispens- performed research; K.K.C. and S.L. contributed new reagents/analytic tools; A.F.d.S. and able for remote memory retrieval (13–16), although some recent I.Z. analyzed data; and A.F.d.S. and M.M. wrote the paper. studies have challenged this idea (12, 17). Interestingly, these The authors declare no conflict of interest. broad changes at the neural circuit level are often accompanied This article is a PNAS Direct Submission. by changes in the quality of memory. For example, humans tend Published under the PNAS license. to lose details of episodic memories as time passes (18), and 1To whom correspondence should be addressed. Email: [email protected]. rodents are unable to discriminate between two different con- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. texts in a remote retrieval trial in the context fear conditioning 1073/pnas.1818432116/-/DCSupplemental. (CFC) paradigm (19). The mechanism underlying these changes www.pnas.org/cgi/doi/10.1073/pnas.1818432116 PNAS Latest Articles | 1of6 Downloaded by guest on September 23, 2021 A B HPC infusions c-fosc-fos prom. tTAtTA Recall 1 Recall 2 DOX DOX Ctx. Ctx. LED Ctx. arc A 24h A 5h 24h A 60’ counts tetOtetO ChEF tetO ChEF ChEF tetO ChEF DOX NoNo expression expression ExpressionExpression ) C D 4 5 80 * Saline + LED 4 Saline + LED 60 Saline * Sal ine *** 3 Drug + LED * ** Drug + LED 40 2 Drug Drug 1 20 Arc/ROI area (x10 0 0 Infl Prl ACC RSC HPC CP Recall 1 Recall 2 (dCA1) E F 150 WT TG HPC/ACC ** ** infusions 100 Ctx. LED Ctx. 50 A 24h 24h A 0 DOX of% Saline freezing Fig. 1. Optogenetic reactivation of RSC memory ensembles produces a recent memory with characteristics of a remote memory. (A) Schematic of the cfos- tTA/tetO-ChEF double-transgenic mouse line. (B) Experimental protocol used in RSC ensemble reactivation and HPC inactivation. (C) Freezing levels of TG animals before (recall 1, 24 h after training) and after (recall 2, 48 h after training) light-emitting diode (LED) stimulation and HPC infusions. (saline+LED, n = 6; saline, n = 6; drug + LED, n = 9; drug, n = 9). (D) arc-positive cells in selected brain areas after recall 2 (saline+LED, n = 6; saline, n = 5; drug + LED, n = 5; drug, n = 6). (E) Experimental protocol used in RSC ensemble reactivation and HPC/ACC inactivation. (F) Freezing levels of WT and TG animals after LED stimulation and HPC or − − − − − − − − ACCdruginfusions(WT/ACC, n = 6; WT/HPC , n = 10; WT/ACC /HPC , n = 7; TG/ACC , n = 6; TG/HPC , n = 9; TG/ACC /HPC , n = 6). Drug, CNQX+TTX; Infl, infralimbic cortex; Prl, prelimbic cortex; ACC, anterior cingulate cortex; HPC, hippocampus; CP, caudate putamen. In all panels, bars represent mean ± SEM. *P < 0.05; ** P < 0.01; ***P < 0.001. and neocortical areas required for remote memory, and is nec- day, animals were exposed to the training context for a brief essary for both recent and remote CFC memory retrieval (27), and recall trial and distributed into four groups matched by freezing we have previously shown that the cfos-positive neurons activated levels (Fig. 1B). To achieve a stable “offline” brain state during with learning carry a component of the original CFC memory stimulation of memory ensembles, two groups were lightly se- trace (26). We found that posttraining stimulation of the RSC dated with isoflurane anesthesia (SI Appendix, Fig. S1) while
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