Reorganization of learning-associated prefrontal synaptic plasticity between the recall of recent and remote fear extinction memory

Abstract

We have previously shown that fear extinction is accompanied by an increase of synaptic efficacy in inputs from the ventral hippocampus (vHPC) and mediodorsal thalamus (MD) to the medial prefrontal cortex (mPFC) and that disrupting these changes to mPFC synaptic transmission compromises extinction processes. The aim of this study was to examine whether these extinction-related changes undergo further plasticity as the memory of extinction becomes more remote. Changes in synaptic efficacy in both vHPC-mPFC and MD-mPFC inputs were consequently analyzed when the memory was either 1 d or 7 d old. Increases of synaptic efficacy in the vHPC-mPFC pathway were observed when the memory was 1 d old, but not 7 d after initial extinction. In contrast, potentiation of synaptic efficacy in the MD-mPFC pathway increased over time. In rats that received low-frequency vHPC stimulation immediately after extinction, both vHPC-mPFC and MD-mPFC inputs failed to develop potentiation, and the recall of extinction (both recent and remote memories) was impaired. These findings suggest that post-extinction potentiation in vHPC-mPFC inputs may be necessary for both the recall of recent memory and post-extinction potentiation in the MD-mPFC inputs. This late potentiation process may be required for the recall of remote extinction memory.

Figure 1.

Diagrams showing electrode placements (filled circles) in the mediodorsal thalamus (MD) and ventral hippocampus (vHPC) for stimulation (A), and mostly in the ventral part of the prelimbic area (PrL) of the medial prefrontal cortex for field potential recordings (B).

Figure 2.

Changes (mean ± SEM percentage relative to baseline) in the amplitude of hippocampal-prefrontal field potential (mPFC FP) during baseline (BL1 and BL2), pre-extinction training (PreExt), and at 1 and 7 d post-extinction delays (1d-post and 7d-post) in rats that received or did not receive hippocampal low-frequency stimulation (NLFS and LFS groups). (Left) Representative prefrontal field potentials recorded during baseline establishment and during 1 d after training. Changes in field potential amplitude were measured between the two dotted lines. FC indicates fear conditioning; FE, fear extinction. *P < 0.05 (NLFS vs. LFS).

Figure 3.

Changes (mean ± SEM percentage relative to baseline) in the amplitude of mediodorsal thalamic-prefrontal field potential (mPFC FP) during baseline (BL1 and BL2), pre-extinction training (PreExt), and at 1 and 7 d post-extinction delays (1d-post and 7d-post) in rats that received or did not receive hippocampal low-frequency stimulation (NLFS and LFS groups). (Left) Representative prefrontal field potentials recorded during baseline establishment and during 1 d after training. Changes in field potential amplitude were measured between the two dotted lines. FC, fear conditioning; FE, fear extinction. *P < 0.05; **P < 0.01 (NLFS vs. LFS).

Figure 4.

(Left, extinction training). Freezing behavior (mean ± SEM) before the first CS presentation (pre-Ext), and during the first (early extinction, EE) and last (late extinction, LE) five CS presentations of extinction training (15 tone-alone presentations). (Right, retention tests) Freezing before and during each retention test (1d-post and 7d-post; five tone-alone presentations/test) in rats that received or did not receive hippocampal low-frequency stimulation (NLFS and LFS groups). **P = 0.01; ***P < 0.0001 (NLFS vs. LFS).