Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model

Abstract

Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in S1 mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with d-cycloserine (N-methly-d-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Fig. 1

Comparison of “normal” and “weak” fear conditioning paradigms during fear conditioning (Cond.), extinction training (Ext.) and extinction retrieval (Ext. Ret.). A) Schematic of experimental design. B) No differences in freezing were observed during fear conditioning or fear expression between “normal” and “weak” fear conditioned groups. During extinction training, “weak” fear conditioned mice displayed reduced freezing compared to “normal” fear conditioned mice. No differences in freezing behaviour were observed between “normal” and “weak” fear conditioned mice during extinction retrieval. 0 = baseline/pre-tone freezing levels. *p < 0.05 “normal” vs. “weak” fear conditioned groups.

Fig. 2

DBS of the AcbC during extinction training reduces fear in S1 mice. A) Schematic of experimental design. B) Sham and DBS groups did not differ in freezing during “stronger” fear conditioning (Cond.). DBS did not alter fear expression as no differences were observed in the DBS group during the first CS-block in which the stimulator was off and the first CS-block (CS-block 2) when the stimulator was on. Freezing did not differ between Sham and DBS groups during the remainder of extinction training (Ext.). Lower freezing was observed in DBS mice during an extinction retrieval session (Ext. Ret.). C) Schematic diagram showing electrode placement in the AcbC. Diagram adapted from Franklin and Paxinos (2008). Sham stimulated mice are shown as filled circles and DBS stimulated mice are shown as white filled circles. Level indicated is mm from Bregma. 0 = baseline/pre-tone freezing levels. *p < 0.001 Sham vs. DBS.

Fig. 3

VPA, administered prior to extinction training, rescues impaired extinction acquisition and deficient extinction consolidation/expression in S1 mice. A) Schematic of experimental design. B) During extinction training (Ext.), freezing was lower in VPA treated S1 mice than VEH S1 mice on CS presentation blocks 2–8. Lower freezing was observed in VPA treated S1 mice during extinction retrieval (Ext. Ret.). No differences in freezing was observed between VEH and VPA groups during “normal” fear conditioning (Cond.). 0 = baseline/pre-tone freezing levels. *p < 0.05 VEH vs. VPA.

Fig. 4

AMN082, administered prior to extinction training, rescues impaired extinction learning and deficient extinction consolidation/retrieval in S1 mice. A) Schematic of experimental design. B) During extinction training (Ext.), freezing was lower in AMN082 treated S1 mice than VEH S1 mice on CS presentation blocks 3–8. Lower freezing was observed in AMN082 treated S1 mice during extinction retrieval (Ext. Ret.). No differences in freezing were observed between VEH and AMN082 groups during “normal” fear conditioning (Cond.). 0 = baseline/pre-tone freezing levels. *p < 0.05 VEH vs. AMN082.

Fig. 5

PEPA, administered prior to extinction training, does not rescue deficient extinction acquisition or deficit extinction consolidation/retrieval in S1 mice. A) Schematic of experimental design. B) Freezing responses did not differ between VEH or 10 or 30 mg/kg MS-275 groups during “normal” fear conditioning (Cond.), extinction training (Ext.) or an extinction retrieval session (Ext. Ret.). 0 = baseline/pre-tone freezing levels.

Fig. 6

MS-275, administered prior to extinction training (arrow), does not rescue deficient extinction acquisition or deficit extinction consolidation/retrieval in S1 mice. A) Schematic of experimental design. B) Freezing responses did not differ between VEH or 5 or 10 mg/kg MS-275 groups during “normal” fear conditioning (Cond.), extinction training (Ext.) or an extinction retrieval session (Ext. Ret.). 0 = baseline/pre-tone freezing levels.

Fig. 7

Post extinction administration of DCS or MS-275 rescues impaired extinction consolidation/retrieval in S1 mice. A) Schematic of experimental design. B) Lower freezing was observed during a retrieval test (Ext. Ret.) when DCS or MS-275 was administered immediately following successful extinction (arrow). Groups did not differ in freezing responses either during “weak” fear conditioning (Cond.) or during extinction training (Ext.). 0 = baseline/pre-tone freezing levels. *p < 0.05 VEH vs. DCS; ^#p < 0.01 VEH vs. MS-275.