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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 conditioning3-8, 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 conditioning3-8. 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.
To examinetherelation betweensynapticplasticityand memory, we used cued-fear conditioning3-8 in rats, wherein a neutral conditioned stimulus (CS), such as a tone, when paired with an aversive unconditioned stimulus (US), resultsin atone-driven conditioned response (CR) indicating memory of the aversive stimulus. Temporally (but not non- temporally)pairinga tonewitha shockled to arobustCR(reduced lever pressing to a previously learned cued lever-press task9; Extended Data Fig. 1) during subsequent testing with a tone alone3-8 (Fig. 1a). To inves- tigate the synaptic basis underlying this associative memory, we replaced a tone with optogenetic stimulation of neural inputs to the lateral amyg- dala originating from auditory nuclei. We injected an adeno-associated virus (AAV) expressing a variant of the light-activated channel ChR2, °ChIEF, that can respond faithfully to 50-100 Hz stimuli10, into the medial geniculate nucleus and auditory cortex (Extended Data Fig. 2). After the channel reached axonal terminals in the lateral amygdala (Extended Data Fig. 3), a cannula permitting light delivery was placed targeting the dorsal tip of the lateral amygdala (Extended Data Fig. 4). An optical CS alone (a 2 min 10 Hz train of 2 ms pulses, see Methods) had no effect on lever pressing (Extended Data Fig. 5). However, tem- porally (but not non-termporally) pairing the optical CS with a foot shock (see Methods) led to a CR (Fig. 1b) that was sensitive to extinc- tion (see below) and blocked by NMDA receptor...