Neuronal Allocation to a Hippocampal Engram - PubMed (original) (raw)
Neuronal Allocation to a Hippocampal Engram
Sungmo Park et al. Neuropsychopharmacology. 2016 Dec.
Abstract
The dentate gyrus (DG) is important for encoding contextual memories, but little is known about how a population of DG neurons comes to encode and support a particular memory. One possibility is that recruitment into an engram depends on a neuron's excitability. Here, we manipulated excitability by overexpressing CREB in a random population of DG neurons and examined whether this biased their recruitment to an engram supporting a contextual fear memory. To directly assess whether neurons overexpressing CREB at the time of training became critical components of the engram, we examined memory expression while the activity of these neurons was silenced. Chemogenetically (hM4Di, an inhibitory DREADD receptor) or optogenetically (iC++, a light-activated chloride channel) silencing the small number of CREB-overexpressing DG neurons attenuated memory expression, whereas silencing a similar number of random neurons not overexpressing CREB at the time of training did not. As post-encoding reactivation of the activity patterns present during initial experience is thought to be important in memory consolidation, we investigated whether post-training silencing of neurons allocated to an engram disrupted subsequent memory expression. We found that silencing neurons 5 min (but not 24 h) following training disrupted memory expression. Together these results indicate that the rules of neuronal allocation to an engram originally described in the lateral amygdala are followed in different brain regions including DG, and moreover, that disrupting the post-training activity pattern of these neurons prevents memory consolidation.
Figures
Figure 1
CREB overexpression in DG neurons training preferentially biases their allocation to an engram supporting contextual fear memory (chemogenetic studies). (a) HSV vector microinjection produces strong localized infection of DG principal neurons. Example image from mouse brain 4 days post microinjection. (b) vCREB-hM4Di and hM4Di vectors infected a similar number of DG neurons. vhM4Di (_n_=15 sections from 5 mice), vCREB-hM4Di (_n_=15 sections from 5 mice). (c) DG neurons expressing hM4Di show endogenous levels of CREB protein, whereas DG neurons expressing vCREB-hM4Di show high levels of CREB. GFP (green, GFP, infected neuron), CREB (red, CREB protein expression). (d) Pre-test chemogenetic silencing of neurons that overexpressed CREB during training inhibits subsequent memory expression (CNO in mice expressing vCREB-hM4Di). Silencing a similar number of random neurons (expressing hM4Di without vCREB) failed to disrupt memory expression. These results indicate that the neurons overexpressing CREB are preferentially allocated to an engram. hM4Di and VEH (_n_=20); hM4Di and CNO (_n_=22); vCREB-hM4Di and VEH (_n_=23); vCREB-hM4Di and CNO (_n_=24). Data presented are mean±SEM. n.s., not statistically different, **p<0.01.
Figure 2
CREB overexpression in DG neurons preferentially biases their allocation to an engram supporting contextual fear memory. Optogenetically silencing their activity during a memory test selectively impairs memory expression. (a) Microinjection of vCREB-hM4Di produces strong localized transgene expression in DG principal neurons. (b) Blue light (BL+) silencing decreases freezing in mice with vCREB-iC++ vector but not in mice expressing iC++ vector alone, regardless of order of light presentation during test (BL+, BL−) (c). (b) vCREB-iC++ (_n_=14), iC++ (_n_=10), (c) vCREB-iC++ (_n_=9), iC++ (_n_=10). Data presented are mean±SEM. n.s., not statistically different, **p<0.01, ***p<0.001.
Figure 3
Post-training inhibition of DG neurons allocated to an engram disrupts subsequent contextual fear memory expression. (a) Silencing of neurons expressing vCREB-iC++ 5 min following training decreases subsequent freezing at test, even in the absence of blue light during the test. However, silencing neurons expressing iC++ alone (5 min post training) had no effect on subsequent memory test. vCREB-iC++ and post-training light (n =11), vCREB-iC++ and no light (_n_=5), iC++ and post-training light (_n_=6). (b) Silencing neurons expressing vCREB-iC++ 24 h following training does not impair freezing during the test in the absence of light. vCREB-iC++ and 24 h post-training light (_n_=10). Data presented are mean±SEM. n.s., not statistically different, *p<0.05, **p<0.01, ***p<0.001.
Similar articles
- The role of neuronal excitability, allocation to an engram and memory linking in the behavioral generation of a false memory in mice.
Lau JMH, Rashid AJ, Jacob AD, Frankland PW, Schacter DL, Josselyn SA. Lau JMH, et al. Neurobiol Learn Mem. 2020 Oct;174:107284. doi: 10.1016/j.nlm.2020.107284. Epub 2020 Aug 1. Neurobiol Learn Mem. 2020. PMID: 32745601 Free PMC article. - Excitability mediates allocation of pre-configured ensembles to a hippocampal engram supporting contextual conditioned threat in mice.
Mocle AJ, Ramsaran AI, Jacob AD, Rashid AJ, Luchetti A, Tran LM, Richards BA, Frankland PW, Josselyn SA. Mocle AJ, et al. Neuron. 2024 May 1;112(9):1487-1497.e6. doi: 10.1016/j.neuron.2024.02.007. Epub 2024 Mar 5. Neuron. 2024. PMID: 38447576 - Bidirectional switch of the valence associated with a hippocampal contextual memory engram.
Redondo RL, Kim J, Arons AL, Ramirez S, Liu X, Tonegawa S. Redondo RL, et al. Nature. 2014 Sep 18;513(7518):426-30. doi: 10.1038/nature13725. Epub 2014 Aug 27. Nature. 2014. PMID: 25162525 Free PMC article. - Inception of a false memory by optogenetic manipulation of a hippocampal memory engram.
Liu X, Ramirez S, Tonegawa S. Liu X, et al. Philos Trans R Soc Lond B Biol Sci. 2013 Dec 2;369(1633):20130142. doi: 10.1098/rstb.2013.0142. Print 2014 Jan 5. Philos Trans R Soc Lond B Biol Sci. 2013. PMID: 24298144 Free PMC article. Review. - Finding the engram.
Josselyn SA, Köhler S, Frankland PW. Josselyn SA, et al. Nat Rev Neurosci. 2015 Sep;16(9):521-34. doi: 10.1038/nrn4000. Nat Rev Neurosci. 2015. PMID: 26289572 Review.
Cited by
- Higher-order interactions between hippocampal CA1 neurons are disrupted in amnestic mice.
Yan C, Mercaldo V, Jacob AD, Kramer E, Mocle A, Ramsaran AI, Tran L, Rashid AJ, Park S, Insel N, Redish AD, Frankland PW, Josselyn SA. Yan C, et al. Nat Neurosci. 2024 Sep;27(9):1794-1804. doi: 10.1038/s41593-024-01713-4. Epub 2024 Jul 19. Nat Neurosci. 2024. PMID: 39030342 - Phospholipase C beta 1 in the dentate gyrus gates fear memory formation through regulation of neuronal excitability.
Lee J, Jeong Y, Park S, Kim S, Oh H, Jin JA, Sohn JW, Kim D, Shin HS, Heo WD. Lee J, et al. Sci Adv. 2024 Jul 5;10(27):eadj4433. doi: 10.1126/sciadv.adj4433. Epub 2024 Jul 3. Sci Adv. 2024. PMID: 38959322 Free PMC article. - Comparing behaviours induced by natural memory retrieval and optogenetic reactivation of an engram ensemble in mice.
Park S, Ko SY, Frankland PW, Josselyn SA. Park S, et al. Philos Trans R Soc Lond B Biol Sci. 2024 Jul 29;379(1906):20230227. doi: 10.1098/rstb.2023.0227. Epub 2024 Jun 10. Philos Trans R Soc Lond B Biol Sci. 2024. PMID: 38853560 - Engram mechanisms of memory linking and identity.
Choucry A, Nomoto M, Inokuchi K. Choucry A, et al. Nat Rev Neurosci. 2024 Jun;25(6):375-392. doi: 10.1038/s41583-024-00814-0. Epub 2024 Apr 25. Nat Rev Neurosci. 2024. PMID: 38664582 Review. - Sleep-dependent engram reactivation during hippocampal memory consolidation associated with subregion-specific biosynthetic changes.
Wang L, Park L, Wu W, King D, Vega-Medina A, Raven F, Martinez J, Ensing A, McDonald K, Yang Z, Jiang S, Aton SJ. Wang L, et al. iScience. 2024 Mar 4;27(4):109408. doi: 10.1016/j.isci.2024.109408. eCollection 2024 Apr 19. iScience. 2024. PMID: 38523798 Free PMC article.
References
- Blanchard RJ, Blanchard DC (1969). Crouching as an index of fear. J Comp Physiol Psychol 67: 370–375. - PubMed
- Bolles RC, Fanselow MS (1982). Endorphins and behavior. Annu Rev Psychol 33: 87–101. - PubMed
- Buzsáki G (1989). Two-stage model of memory trace formation: a role for “noisy” brain states. Neuroscience 31: 551–570. - PubMed
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials