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’.

Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala

“…It is currently not clear whether this within-session extinction also persists between sessions, but this would be worthy of future investigation. Consistent with this suggestion, previous research has shown that inhibition of Class I HDACs can enhance fear extinction memory (Bahari-Javan et al, 2012;Bredy and Barad, 2008;Graff et al, 2014;Lattal et al, 2007;Stafford et al, 2012;Whittle et al, 2013). Although systemic pharmacological HDAC3 inhibition fails to enhance cued fear extinction (Bowers et al, 2015), site-specific HDAC3 inhibition restricted to the hippocampus or amygdala might reveal an important role of HDAC3 in fear extinction memory.…”

An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials

“…Importantly, DCS reverses deficits in fear extinction caused by the single prolonged stress model that is hypothesized to more thoroughly instantiate PTSD-like symptoms and the accompanying underlying pathology (51, 52). Similarly, DCS enhances extinction in 129S1/SvImJ (S1), an alternative genetic mouse model of PTSD that exhibits persistent impairment of fear extinction (53). …”

“…DBS is demonstrably efficacious for the treatment of Parkinson’s Disease, its original indication, and is now being investigated for the treatment of and depression, obsessive compulsive disorder (OCD), and PTSD (7, 222, 224–226). At the pre-clinical level, several studies find enhanced cued fear extinction with DBS of the ventral striatum that may be mediated by enhanced BDNF expression (53, 227, 228). Others find decreased PTSD-like symptoms and cued fear expression in rats with DBS of the amygdala (229–231).…”

Learning not to Fear: Neural Correlates of Learned Safety

“…More critically, large pre-or posttraining electrolytic lesions of the Nac did not affect the acquisition or expression of learned safety or learned fear (Josselyn et al, 2005). However, an indirect role for the Nac in fear extinction has recently been proposed based on the observation that deep-brain stimulation of the Nac rescued an impairment of deficient extinction retrieval in a genetic mouse model and this effect has been attributed to an interaction between the Nac and the corticolimbic extinction circuitry (Whittle et al, 2013). Similarly, deep brain stimulation of specific zone dorsomedial of the ventral striatum has been described to augment extinction of conditioned fear in rats (Rodriguez-Romaguera et al, 2012).…”