Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction

Abstract

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory.

Effects of a histone deacetylase 3 inhibitor on extinction and reinstatement of cocaine self-administration in rats

“…It is therefore possible that context-induced reinstatement for cocaine seeking behavior and context-specific extinction may be particularity susceptible to HDAC3 modulation. Further experiments should evaluate how HDAC inhibitors work in a variety of circuits that may recruit different neurotransmitters (Whittle et al 2016). …”

Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet

“…Second, we reasoned that short-term exposure to an obesogenic diet would reduce the neuronal activation in corticolimbic regions implicated in fear extinction and anxiolytic effects. Finally, given the robust effects of obesogenic diets on the HPA axis and dopamine systems (Boitard et al, 2015;Khazen et al, 2019;Reyes, 2012;Sharma et al, 2013), and the modulatory actions of these factors on mPFC-amygdala circuit function (Fadok et al, 2009b;Jovanovic et al, 2010;2020;Veer et al, 2012;Whittle et al, 2016), we hypothesized that the obesogenic diet would increase the HPA tone while reducing dopamine receptor expression in the mPFC.…”

Environmental variables that ameliorate extinction learning deficits in the 129S1/SvlmJ mouse strain

“…[25][26][27] Efforts to elucidate the differences in extinction learning between 129S1 and C57BL/6 mice have led to a greater understanding of neurophysiological and genetic substrates responsible for the expression and suppression of fear. 24,27,31 Interestingly, a recent study used linkage crosses between 129S1 and C57BL/6 mice combined with quantitative trait loci analysis to identify a panel of genes in the amygdala that show expression differences that correlate to the extinction learning deficits. 29 The extinction learning deficits in the 129S1 can be ameliorated by dietary zinc restriction, 30 deep brain stimulation of the nucleus accumbens, 23 pharmacological treatment with the α2-adrenoreceptor antagonist, yohimbine, the selective serotonin reuptake inhibitor, fluoxetine, or the dopamine precursor, L-dopa.…”

“…29 The extinction learning deficits in the 129S1 can be ameliorated by dietary zinc restriction, 30 deep brain stimulation of the nucleus accumbens, 23 pharmacological treatment with the α2-adrenoreceptor antagonist, yohimbine, the selective serotonin reuptake inhibitor, fluoxetine, or the dopamine precursor, L-dopa. 24,27,31 Interestingly, a recent study used linkage crosses between 129S1 and C57BL/6 mice combined with quantitative trait loci analysis to identify a panel of genes in the amygdala that show expression differences that correlate to the extinction learning deficits. 29 Of the genes identified, the expression of Ppid, a gene that is functionally coupled to the glucocorticoid receptor, was found to reduce extinction learning deficits in 129S1 mice when its expression was increased.…”