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Memory consolidation drives the enhancement of remote cocaine memory via prefrontal circuit

Molecular Psychiatry (2024)Cite this article

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Abstract

Remote memory usually decreases over time, whereas remote drug-cue associated memory exhibits enhancement, increasing the risk of relapse during abstinence. Memory system consolidation is a prerequisite for remote memory formation, but neurobiological underpinnings of the role of consolidation in the enhancement of remote drug memory are unclear. Here, we found that remote cocaine-cue associated memory was enhanced in rats that underwent self-administration training, together with a progressive increase in the response of prelimbic cortex (PrL) CaMKII neurons to cues. System consolidation was required for the enhancement of remote cocaine memory through PrL CaMKII neurons during the early period post-training. Furthermore, dendritic spine maturation in the PrL relied on the basolateral amygdala (BLA) input during the early period of consolidation, contributing to remote memory enhancement. These findings indicate that memory consolidation drives the enhancement of remote cocaine memory through a time-dependent increase in activity and maturation of PrL CaMKII neurons receiving a sustained BLA input.

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Fig. 1: PrL CaMKII neuron activity time-dependently increases along with the enhancement of remote cocaine memory.
Fig. 2: Inhibition of PrL CaMKII neurons prevents the enhancement and consolidation of remote cocaine memory.
Fig. 3: Enhancement of remote cocaine memory does not require BLA CaMKII neurons.
Fig. 4: Chronic inhibition of the BLA-PrL circuit during the early period of consolidation prevents the enhancement of remote cocaine memory.
Fig. 5: Chronic inhibition of the BLA input during the early period of consolidation impairs the dendritic spine density and maturation of PrL CaMKII neurons.

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References

  1. Ryan TJ, Frankland PW. Forgetting as a form of adaptive engram cell plasticity. Nat Rev Neurosci. 2022;23:173–86.

    Article  PubMed  CAS  Google Scholar 

  2. Xue YX, Deng JH, Chen YY, Zhang LB, Wu P, Huang GD, et al. Effect of selective inhibition of reactivated nicotine-associated memories with propranolol on nicotine craving. JAMA Psychiatry. 2017;74:224–32.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wright WJ, Graziane NM, Neumann PA, Hamilton PJ, Cates HM, Fuerst L, et al. Silent synapses dictate cocaine memory destabilization and reconsolidation. Nat Neurosci. 2020;23:32–46.

    Article  PubMed  CAS  Google Scholar 

  4. Shin CB, Templeton TJ, Chiu AS, Kim J, Gable ES, Vieira PA, et al. Endogenous glutamate within the prelimbic and infralimbic cortices regulates the incubation of cocaine-seeking in rats. Neuropharmacology. 2018;128:293–300.

    Article  PubMed  CAS  Google Scholar 

  5. Ma YY, Lee BR, Wang X, Guo C, Liu L, Cui R, et al. Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron. 2014;83:1453–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Parvaz MA, Moeller SJ, Goldstein RZ. Incubation of cue-induced craving in adults addicted to cocaine measured by electroencephalography. JAMA Psychiatry. 2016;73:1127–34.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Frankland PW, Bontempi B. The organization of recent and remote memories. Nat Rev Neurosci. 2005;6:119–30.

    Article  PubMed  CAS  Google Scholar 

  8. Fukushima H, Zhang Y, Archbold G, Ishikawa R, Nader K, Kida S. Enhancement of fear memory by retrieval through reconsolidation. Elife. 2014;3:e02736.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kitamura T, Ogawa SK, Roy DS, Okuyama T, Morrissey MD, Smith LM, et al. Engrams and circuits crucial for systems consolidation of a memory. Science. 2017;356:73–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Lee JH, Kim WB, Park EH, Cho JH. Neocortical synaptic engrams for remote contextual memories. Nat Neurosci. 2023;26:259–73.

    Article  PubMed  CAS  Google Scholar 

  11. Dixsaut L, Graff J. Brain-wide screen of prelimbic cortex inputs reveals a functional shift during early fear memory consolidation. Elife. 2022;11:e78542.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Kol A, Adamsky A, Groysman M, Kreisel T, London M, Goshen I. Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning. Nat Neurosci. 2020;23:1229–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Rich MT, Huang YH, Torregrossa MM. Plasticity at thalamo-amygdala synapses regulates cocaine-cue memory formation and extinction. Cell Rep. 2019;26:1010–20.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hsiang HL, Epp JR, van den Oever MC, Yan C, Rashid AJ, Insel N, et al. Manipulating a “cocaine engram” in mice. J Neurosci. 2014;34:14115–27.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Xue YX, Luo YX, Wu P, Shi HS, Xue LF, Chen C, et al. A memory retrieval-extinction procedure to prevent drug craving and relapse. Science. 2012;336:241–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Luo YX, Xue YX, Liu JF, Shi HS, Jian M, Han Y, et al. A novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking. Nat Commun. 2015;6:7675–89.

    Article  PubMed  CAS  Google Scholar 

  17. Bruno CA, O’Brien C, Bryant S, Mejaes JI, Estrin DJ, Pizzano C, et al. pMAT: An open-source software suite for the analysis of fiber photometry data. Pharm Biochem Behav. 2021;201:173093.

    Article  CAS  Google Scholar 

  18. Lu L, Uejima JL, Gray SM, Bossert JM, Shaham Y. Systemic and central amygdala injections of the mGluR(2/3) agonist LY379268 attenuate the expression of incubation of cocaine craving. Biol Psychiatry. 2007;61:591–8.

    Article  PubMed  CAS  Google Scholar 

  19. Lu L, Wang X, Wu P, Xu C, Zhao M, Morales M, et al. Role of ventral tegmental area glial cell line-derived neurotrophic factor in incubation of cocaine craving. Biol Psychiatry. 2009;66:137–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Wang C, Yue H, Hu Z, Shen Y, Ma J, Li J, et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science. 2020;367:688–94.

    Article  PubMed  CAS  Google Scholar 

  21. Sebastian V, Estil JB, Chen D, Schrott LM, Serrano PA. Acute physiological stress promotes clustering of synaptic markers and alters spine morphology in the hippocampus. PLoS One. 2013;8:e79077.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Muller CP, Quednow BB, Lourdusamy A, Kornhuber J, Schumann G, Giese KP. CaM Kinases: From memories to addiction. Trends Pharm Sci. 2016;37:153–66.

    Article  PubMed  Google Scholar 

  23. DeNardo LA, Liu CD, Allen WE, Adams EL, Friedmann D, Fu L, et al. Temporal evolution of cortical ensembles promoting remote memory retrieval. Nat Neurosci. 2019;22:460–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Xia F, Richards BA, Tran MM, Josselyn SA, Takehara-Nishiuchi K, Frankland PW. Parvalbumin-positive interneurons mediate neocortical-hippocampal interactions that are necessary for memory consolidation. Elife. 2017;6:1–25.

    Article  CAS  Google Scholar 

  25. Gomez JL, Bonaventura J, Lesniak W, Mathews WB, Sysa-Shah P, Rodriguez LA, et al. Chemogenetics revealed: DREADD occupancy and activation via converted clozapine. Science. 2017;357:503–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Tye KM, Janak PH. Amygdala neurons differentially encode motivation and reinforcement. J Neurosci. 2007;27:3937–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Klavir O, Prigge M, Sarel A, Paz R, Yizhar O. Manipulating fear associations via optogenetic modulation of amygdala inputs to prefrontal cortex. Nat Neurosci. 2017;20:836–44.

    Article  PubMed  CAS  Google Scholar 

  28. Carelli RM, Williams JG, Hollander JA. Basolateral amygdala neurons encode cocaine self-administration and cocaine-associated cues. J Neurosci. 2003;23:8204–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Josselyn SA, Tonegawa S. Memory engrams: Recalling the past and imagining the future. Science. 2020;367:eaaw4325.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Ebrahimi S, Okabe S. Structural dynamics of dendritic spines: Molecular composition, geometry and functional regulation. Biochim Biophys Acta. 2014;1838:2391–8.

    Article  PubMed  CAS  Google Scholar 

  31. Gawin FHKH. Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Arch Gen Psychiatry. 1986;43:107–13.

    Article  PubMed  CAS  Google Scholar 

  32. Grimm JW, Hope BT, Wise RA, Shaham Y. Incubation of cocaine craving after withdrawal. Nature. 2001;412:141–2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Liu X, Yuan K, Lu T, Lin X, Zheng W, Xue Y, et al. Preventing incubation of drug craving to treat drug relapse: From bench to bedside. Mol Psychiatry. 2023;28:1415–29.

    Article  PubMed  Google Scholar 

  34. Venniro M, Reverte I, Ramsey LA, Papastrat KM, D’Ottavio G, Milella MS, et al. Factors modulating the incubation of drug and non-drug craving and their clinical implications. Neurosci Biobehav Rev. 2021;131:847–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Bedi G, Preston KL, Epstein DH, Heishman SJ, Marrone GF, Shaham Y, et al. Incubation of cue-induced cigarette craving during abstinence in human smokers. Biol Psychiatry. 2011;69:708–11.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wang G, Shi J, Chen N, Xu L, Li J, Li P, et al. Effects of length of abstinence on decision-making and craving in methamphetamine abusers. PLoS One. 2013;8:1–7.

    Google Scholar 

  37. Li P, Wu P, Xin X, Fan YL, Wang GB, Wang F, et al. Incubation of alcohol craving during abstinence in patients with alcohol dependence. Addict Biol. 2015;20:513–22.

    Article  PubMed  Google Scholar 

  38. Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, et al. Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA. 1996;93:12040–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Yue JL, Yuan K, Bao YP, Meng SQ, Shi L, Fang Q, et al. The effect of a methadone-initiated memory reconsolidation updating procedure in opioid use disorder: A translational study. EBioMedicine. 2022;85:104283.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Tronson NC, Taylor JR. Addiction: A drug-induced disorder of memory reconsolidation. Curr Opin Neurobiol. 2013;23:573–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Grimm JW, Harkness JH, Ratliff C, Barnes J, North K, Collins S. Effects of systemic or nucleus accumbens-directed dopamine D1 receptor antagonism on sucrose seeking in rats. Psychopharmacology. 2011;216:219–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Pickens CL, Golden SA, Adams-Deutsch T, Nair SG, Shaham Y. Long-lasting incubation of conditioned fear in rats. Biol Psychiatry. 2009;65:881–6.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Matos MR, Visser E, Kramvis I, van der Loo RJ, Gebuis T, Zalm R, et al. Memory strength gates the involvement of a CREB-dependent cortical fear engram in remote memory. Nat Commun. 2019;10:2315.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Galaj E, Ranaldi R. Neurobiology of reward-related learning. Neurosci Biobehav Rev. 2021;124:224–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Gueye AB, Allain F, Samaha AN. Intermittent intake of rapid cocaine injections promotes the risk of relapse and increases mesocorticolimbic BDNF levels during abstinence. Neuropsychopharmacology. 2019;44:1027–35.

    Article  PubMed  CAS  Google Scholar 

  46. Markou A, Li J, Tse K, Li X. Cue-induced nicotine-seeking behavior after withdrawal with or without extinction in rats. Addict Biol. 2018;23:111–9.

    Article  PubMed  CAS  Google Scholar 

  47. Hyman SE, Malenka RC. Addiction and the brain: The neurobiology of compulsion and its persistence. Nat Rev Neurosci. 2001;2:695–703.

    Article  PubMed  CAS  Google Scholar 

  48. Yehuda R, Hoge CW, McFarlane AC, Vermetten E, Lanius RA, Nievergelt CM, et al. Post-traumatic stress disorder. Nat Rev Dis Prim. 2015;1:15057.

    Article  PubMed  Google Scholar 

  49. Lesburgueres E, Gobbo OL, Alaux-Cantin S, Hambucken A, Trifilieff P, Bontempi B. Early tagging of cortical networks is required for the formation of enduring associative memory. Science. 2011;331:924–8.

    Article  PubMed  CAS  Google Scholar 

  50. Squire LR, Genzel L, Wixted JT, Morris RG. Memory consolidation. Cold Spring Harb Perspect Biol. 2015;7:a021766.

    Article  PubMed  PubMed Central  Google Scholar 

  51. West EA, Saddoris MP, Kerfoot EC, Carelli RM. Prelimbic and infralimbic cortical regions differentially encode cocaine-associated stimuli and cocaine-seeking before and following abstinence. Eur J Neurosci. 2014;39:1891–902.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Nicolas C, Russell TI, Pierce AF, Maldera S, Holley A, You ZB, et al. Incubation of cocaine craving after intermittent-access self-administration: Sex differences and estrous cycle. Biol Psychiatry. 2019;85:915–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Ferreira R, Brandao ML, Nobre MJ. 5-HT1A receptors of the prelimbic cortex mediate the hormonal impact on learned fear expression in high-anxious female rats. Horm Behav. 2016;84:84–96.

    Article  PubMed  CAS  Google Scholar 

  54. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: From actions to habits to compulsion. Nat Neurosci. 2005;8:1481–9.

    Article  PubMed  CAS  Google Scholar 

  55. Janak PH, Tye KM. From circuits to behaviour in the amygdala. Nature. 2015;517:284–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y. Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci. 2005;8:212–9.

    Article  PubMed  CAS  Google Scholar 

  57. Tonegawa S, Morrissey MD, Kitamura T. The role of engram cells in the systems consolidation of memory. Nat Rev Neurosci. 2018;19:485–98.

    Article  PubMed  CAS  Google Scholar 

  58. Barrientos C, Knowland D, Wu MMJ, Lilascharoen V, Huang KW, Malenka RC, et al. Cocaine-induced structural plasticity in input regions to distinct cell types in nucleus accumbens. Biol Psychiatry. 2018;84:893–904.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Mashhoon Y, Wells AM, Kantak KM. Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior. Pharm Biochem Behav. 2010;96:347–53.

    Article  CAS  Google Scholar 

  60. Ghazizadeh A, Hong S, Hikosaka O. Prefrontal cortex represents long-term memory of object values for months. Curr Biol. 2018;28:2206–17.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the STI2030-Major Projects (no. 2021ZD0200800), and National Natural Science Foundation of China (no. 82288101 and no. 81901352). All schematic images were created with BioRender.com.

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Author notes

  1. These authors contributed equally: Xiaoxing Liu, Tangsheng Lu.

Authors and Affiliations

  1. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 100191, Beijing, China

    Xiaoxing Liu, Xuan Chen, Wei Yan, Le Shi, Kai Yuan & Lin Lu

  2. National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence Research, Peking University, 100191, Beijing, China

    Tangsheng Lu, Shihao Huang, Wen Zhang, Shiqiu Meng, Yanping Bao, Yanxue Xue, Jie Shi, Ying Han & Lin Lu

  3. Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China

    Tangsheng Lu & Shihao Huang

  4. Xinxiang Medical University, Xinxiang, 453003, China

    Xuan Chen

  5. Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, 100871, Beijing, China

    Wei Zheng & Lin Lu

  6. Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder, Chinese Academy of Medical Sciences (No. 2018RU006), Dongcheng, Beijing, China

    Lin Lu

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Contributions

LL, YH, YX, XL, and TL designed the study. XL, TL, KY, XC, SH, and WZheng performed the experiments. XL, TL, YH, and YB analyzed the data. XL and TL prepared the first draft of the manuscript. WZhang, SM, WY, LS, JS, KY, YX, YH, and LL revised the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Yanxue Xue, Ying Han or Lin Lu.

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Liu, X., Lu, T., Chen, X. et al. Memory consolidation drives the enhancement of remote cocaine memory via prefrontal circuit. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-023-02364-w

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