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Engineering a memory with LTD and LTP

Nature volume 511, pages 348–352 (2014)Cite this article

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Abstract

It has been proposed that memories are encoded by modification of synaptic strengths through cellular mechanisms such as long-term potentiation (LTP) and long-term depression (LTD)1. However, the causal link between these synaptic processes and memory has been difficult to demonstrate2. Here we show that fear conditioning3,4,5,6,7,8, a type of associative memory, can be inactivated and reactivated by LTD and LTP, respectively. We began by conditioning an animal to associate a foot shock with optogenetic stimulation of auditory inputs targeting the amygdala, a brain region known to be essential for fear conditioning3,4,5,6,7,8. Subsequent optogenetic delivery of LTD conditioning to the auditory input inactivates memory of the shock. Then subsequent optogenetic delivery of LTP conditioning to the auditory input reactivates memory of the shock. Thus, we have engineered inactivation and reactivation of a memory using LTD and LTP, supporting a causal link between these synaptic processes and memory.

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Figure 1: Fear conditioning with tone or optogenetics.
Figure 2: LTD inactivates and LTP reactivates memory.
Figure 3: LTP produces conditioned response only after prior paired conditioning.
Figure 4: In vivo electrophysiological responses to 10 Hz, LTD and LTP protocols.
Figure 5: Optical LTD protocol significantly reduces auditory fear conditioning; optical LTP does not reverse extinction.

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Acknowledgements

We thank J. Isaacson, L. Squire and members of the Malinow laboratory for suggestions. This study was supported by NIH MH049159 and Cure Alzheimer’s Foundation grants to R.M. and NIH grant NS27177 to R.T.; R.T. is an Investigator of the HHMI.

Author information

Author notes

  1. Sadegh Nabavi and Rocky Fox: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience and Section of Neurobiology, Center for Neural Circuits and Behavior, University of California at San Diego, 92093, California, USA

    Sadegh Nabavi, Rocky Fox, Christophe D. Proulx & Roberto Malinow

  2. Department of Pharmacology, University of California at San Diego, 92093, California, USA

    John Y. Lin & Roger Y. Tsien

  3. Howard Hughes Medical Institute, University of California at San Diego, 92093, California, USA

    Roger Y. Tsien

Authors
  1. Sadegh Nabavi
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  4. John Y. Lin
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  6. Roberto Malinow
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Contributions

S.N. and R.M. designed the experiments and wrote the manuscript. S.N., R.F. and R.M. analysed the data. S.N., R.F. and C.D.P. performed the experiments. J.Y.L. and R.Y.T. provided the oChIEF-tdTomato construct.

Corresponding author

Correspondence to Roberto Malinow.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Freezing correlates well with reduction in lever presses to previously learned task.

Plot of per cent freezing versus per cent reduction in lever presses to previously learned task. Best fit line indicates significant positive correlation (R2 = 0.4; P < 0.01; F test). Data includes results from 3 manipulations (paired optical CS-shock conditioning, optical LTD and optical LTP). The per cent change in lever presses to previously learned task (60% ± 9%) was significantly greater than change in per cent freezing (20% ± 5%; n = 21; P < 0.001, paired Student’s t-test).

Extended Data Figure 2 In vivo optically evoked synaptic responses in lateral amygdala.

Field responses to 10 Hz (top) and 100 Hz optical stimulation (middle, bottom), obtained from animal infected with AAV-oChIEF in auditory regions four weeks before recording. Note that the responses follow stimulation faithfully.

Extended Data Figure 3 Expression of oChIEF in auditory regions reaches lateral amygdala.

a, b, Diagram (left) and epifluorescent image (right) of coronal section of rat brain indicating areas expressing AAV-oChIEF-tdTomato 3–4 weeks after in vivo injection in auditory cortex (a) and medial geniculate nucleus (b). c, Axonal expression of AAV-oChIEF-tdTomato in lateral amygdala (dashed white line); approximate placement of cannula and light (blue) indicated. Scale bars, 500 μm.

Extended Data Figure 4 Optic fibre locations in representative group of rats used in the behavioural assays.

Histologically assessed optic fibre tip location for rats which responded (blue circles; upper panel, right, is one example) or did not respond (orange circles; lower panel, right, is one example) to optical conditioning. The arrow on the panels shows the location of the tip of optic fibre. Lateral amygdala is indicated by dashed line. Note that the ventricle opened during tissue sectioning in the lower image. Scale bars, 500 μm.

Extended Data Figure 5 The 10 Hz test protocol does not produce CR.

Test for CR (blue) in naïve animals (n = 8), as measured by changes in lever presses normalized to baseline period. Subsequent delivery of paired optical CS and shock produced CR in these animals (not shown). Each point represents data collected over 1 min.

Extended Data Figure 6 Systemic NMDA receptor blockade during conditioning blocks ODI-induced conditioned response.

a, Animals (n = 5) were injected with MK801 (see Methods) and given optical CS paired with foot shock and subsequently tested one day later for CR. b, The same group of animals was then given optical CS paired with foot shock (in the absence of MK801) and subsequently tested one day later for CR. c, MK801 significantly blocked conditioning.

Extended Data Figure 7 LTD and LTP remove and reactivate memory.

a–e, Data from an individual rat, measuring lever presses per minute before, during (blue) and after optical CS, one day after paired conditioning of optical CS and shock (a), one day after subsequent optical LTD protocol (b), one day after subsequent optical LTP protocol (c), one day after subsequent second optical LTD protocol (d) and one day after subsequent second optical LTP protocol (e). f, Graph of lever presses during first minute into optical CS one day after delivery of indicated conditioning protocols.

Extended Data Figure 8 The effects of LTD and LTP are rapid and long-lasting.

a, Animals (n = 5) were tested for CR one day following pairing of optical CS with shock. b, c, Within one hour of testing, animals received optical LTD protocol and were tested for CR 20 min (b) and three days (c) later. d, e, Following day three, testing animals received optical LTP protocol and were tested for CR 20 min (d) and three days (e) later. f, Graph of normalized lever presses for the first minute of optical CS following indicated protocols.

Extended Data Figure 9 Optically evoked in vivo and in vitro stimuli produce similar electrophysiological responses.

Animals were injected in vivo with AAV-oChIEF-tdTomato in auditory regions 4 weeks before recordings. Left, in vivo electrophysiological response obtained from glass electrode placed in lateral amygdala and evoked by light pulse delivered through fibre optic cable placed 500 μm above tip of glass electrode. Right, in vitro brain slice electrophysiological response obtained from glass electrode placed in lateral amygdala and evoked by light pulse delivered through fibre optic cable placed above the brain slice. Black trace is before and red trace after bath application of 10 μM NBQX. Scale bars, 1 mV, 10 ms.

Extended Data Figure 10 LTD reverses LTP and LTP reverses LTD of in vivo optical responses in amygdala.

a, Plot of baseline normalized fEPSP in vivo optically evoked responses (n = 5 from 5 rats) following optical LTP (100 Hz) and optical LTD (1 Hz). b, Same as a for a separate group of recordings (n = 5) following optical LTD (1 Hz) and optical LTP (100 Hz). All comparisons to baseline period.

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Nabavi, S., Fox, R., Proulx, C. et al. Engineering a memory with LTD and LTP. Nature 511, 348–352 (2014). https://doi.org/10.1038/nature13294

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