Recoding a cocaine-place memory engram to a neutral engram in the hippocampus

Abstract

The hippocampus provides the brain's memory system with a subset of neurons holding a map-like representation of each environment experienced. We found in mice that optogenetic silencing those neurons active in an environment unmasked a subset of quiet neurons, enabling the emergence of an alternative map. When applied in a cocaine-paired environment, this intervention neutralized an otherwise long-lasting drug-place preference, showing that recoding a spatial memory engram can alleviate associated maladaptive behavior.

Figure 1. Activity-dependent tagging of CA1 neurons

(a) c-fos-tTA mice were bilaterally injected with a TRE3G-ArchT-GFP virus and implanted with tetrodes and optic fibers in the dorsal CA1. (b) c-fos::ArchT tagged, but not c-fos::ArchT control, mice were transiently taken off Dox to tag CA1 neurons recruited in the circle with tTA-TRE3G interaction-driven ArchT expression. Ensemble recordings and light-delivery were performed in subsequent days in the circle and square enclosures. (c) ArchT-GFP expressing neurons in the pyramidal cell layer of a tagged, but not a control, mouse. Stratum oriens (or.), pyramidale (pyr.), radiatum (rad.). Cell nuclei stained with Dapi. Scale bars: 30μm. (d) Raster plots showing spike times relative to 30s light-pulses for three neurons simultaneously recorded from the same tetrode. The top (1.59Hz versus 0.01Hz) but not the bottom (0.43Hz versus 0.40Hz) neuron was photo-silenced whereas the middle neuron increased its firing (0.38Hz versus 1.51Hz). (e) Firing rate light-response (mean±s.e.m) of all CA1 principal neurons recorded and grouped according to their light-modulation (as in d).

Figure 2. Photo-silencing of tagged neurons enabled alternative neurons to emerge and provide an alternative map

(a,b) Baseline (light-OFF) firing rate (a) and spatial coherence (b) of tagged and alternative neurons from tagged mice exploring the circle (mean±s.e.m). *P<0.05, **P<0.01, ***P<0.001: comparison to Day 1. (c,d) Example raster plots and spatial rate maps of simultaneously recorded neurons on Day 2 (c) and Day 6 (d). Distinct neurons were recorded on each day; one cell per row. Spatial rate maps are scaled to the peak firing rate (Hz; top right of each map) or 1Hz for low-firing cells. Warm colors (red) correspond to the cell’s place field. (e) Example weight vectors representing simultaneously recorded assembly-patterns detected from 25ms co-fluctuation of (light-OFF) spike discharge in the circle. (f) Average single-neuron contribution to the temporal expression of assembly-patterns during the first and the second three-day blocks using 25-ms time windows (mean±s.e.m). **P<0.01, ***P<0.001.

Figure 3. CA1 photo-recoding revoked an otherwise long-lasting cocaine-place memory

(a) Cocaine-conditioned place preference paradigm. Mice explored the entire apparatus (Pre-test) before the preferred compartment was paired with saline (+S) and the other with cocaine (+C) administration, followed by a place-preference test (Test 1). Then tagged, but not control, c-fos::ArchT mice were transiently taken off Dox to tag active CA1 neurons and all mice received cocaine in the cocaine-paired compartment. CA1 light was delivered to all c-fos::ArchT mice during subsequent (drug-free) re-exposure to the cocaine-paired compartment, followed by a second place-preference test (Test 2). (b) Example paths for c-fos::ArchT tagged and control mice during Pre-test, Test 1 and Test 2. (c) Cocaine-place preference score (mean±s.e.m). During each test drug-free mice had access to the entire apparatus and their place preference was scored as the difference between the time spent in the cocaine-paired compartment minus that in the saline-paired compartment over their sum. Within-group comparison to Pre-test: ***P<0.001. Test 2, between-group comparison: ###P<0.001.