Fear Erasure in Mice Requires Synergy Between Antidepressant Drugs and Extinction Training

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Science  23 Dec 2011:
Vol. 334, Issue 6063, pp. 1731-1734
DOI: 10.1126/science.1214592

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  1. Fig. 1

    Chronic Flx treatment before fear conditioning leads to fear erasure when combined with extinction training. (A) Flx treatment started 3 weeks before and continued throughout the experiment. (B) Control and Flx groups (n = 31 to 34 mice per group) exhibited similar levels of fear acquisition (extinction day 1, first block of 2 CS) and extinction (extinction day 2, last block of 2 CS). One week later (n = 21 per group) only control group showed spontaneous recovery and fear renewal. In the fear renewal test, the Flx-extinction group froze less than either control-extinction or Flx–no-extinction group (NoExt, n = 5). *P < 0.05, **P < 0.01, ***P < 0.001. Error bars indicate mean ± SEM.

  2. Fig. 2

    Extinction training is effective in combination with chronic Flx treatment after fear conditioning. (A) After fear conditioning and 2 weeks of Flx treatment, mice were subjected to fear renewal (protocol I) or fear reinstatement (protocol II). 5 US indicates five unsignaled foot shocks. (B) Fear renewal: Control and Flx groups (n = 10 per group) exhibited similar levels of fear acquisition and extinction. One week later, only control group showed elevated spontaneous recovery and significant fear renewal. The Flx-extinction group froze less than either control-extinction or Flx–no-extinction groups (NoExt, n = 7). (C) Fear reinstatement: Although both groups exhibited increased levels of freezing when compared with the extinguished levels, the Flx group showed lower levels of fear reinstatement (P < 0.05). N = 8 per group. *P < 0.05, **P < 0.01. Error bars indicate mean ± SEM.

  3. Fig. 3

    Flx treatment enhances plasticity in the fear memory circuitry. (A) Representative PNNs and parvalbumin (PV) immunostaining in the BLA. Arrows, double-positive neurons. (B to D) Chronic Flx decreased the percentage of PNN-containing neurons with parvalbumin (B), increased PSA-NCAM expression (C), and decreased KCC2 levels (D) in the fear circuit. N = 6 per group. (E) Input-output function for fEPSPs in LA evoked by EC stimulation. Flx treatment increased the average amplitude of fEPSPs above control levels. N = 12 to 15 per group. (F) Effect of high-frequency stimulation (two 1-s stimuli at 100 Hz) of EC afferents on LA fEPSPs. In control animals, EC tetanization caused short-term synaptic potentiation, but there was no potentiation at 1 hour; conversely, in fluoxetine-treated animals tetanization resulted in LTP at 1 hour. N = 8 per group. Inset shows example traces before and 1 hour after tetanization. *P < 0.05, **P < 0.01 versus respective control group. Error bars indicate mean ± SEM.

  4. Fig. 4

    BDNF regulates fear memory erasure. (A) Chronic Flx after fear conditioning increased the BDNF exon-1 and total BDNF mRNA levels in the BLA and BDNF exon-1 level in the hippocampus (HIP) but not in the prefrontal cortex (mPFC). N = 6 to 8 per group. (B) Flx prevented fear renewal in BDNF+/+ mice (see protocol I, Fig. 2A) but failed to erase fearful memory in BDNF+/− mice. N = 10 or 11 per group. (C) BDNF-virus experiment: After successful fear acquisition and extinction, doxycycline treatment was terminated to induce BDNF overexpression in amygdala, which resulted in a significant reduction in freezing level in the fear renewal test. N = 6 or 7 per group. *P < 0.05, **P < 0.01, ***P < 0.001 versus control groups. Error bars indicate means ± SEM.

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