Background The current effective treatment options for posttraumatic stress disorder (PTSD) are limited and therefore the need to explore new treatment strategies is critical. Pharmacological inhibition of the renin-angiotensin system is a common approach to treat hypertension and emerging evidence highlights the importance of this pathway in stress and anxiety. A recent clinical study from our laboratory provides evidence supporting a role for the renin-angiotensin system in the regulation of the stress response in patients diagnosed with PTSD. Methods Using an animal model of PTSD and the selective angiotensin receptor type 1 (AT1) antagonist losartan, we investigated the acute and long-term effects of AT1 receptor inhibition on fear memory and baseline anxiety. Following losartan treatment, we performed classical Pavlovian fear conditioning pairing auditory cues with footshocks and examined extinction behavior, gene expression changes in the brain as well as neuroendocrine and cardiovascular responses. Results Following cued fear conditioning, both acute and 2-week administration of losartan enhanced the consolidation of extinction memory but had no effect on fear acquisition, baseline anxiety, blood pressure and neuroendocrine stress measures. Gene expression changes in the brain were also altered in mice treated with losartan for 2 weeks, in particular reduced amygdala AT1 receptor and bed nucleus stria terminalis c-Fos mRNA levels. Conclusions These data suggest that AT1 receptor antagonism enhances the extinction of fear memory and therefore maybe a beneficial therapy for PTSD patients who have impairments in extinction of aversive memories.

Summary Using an array-based approach after auditory fear-conditioning, and microRNA (miRNA) sponge-mediated inhibition, we identified a role for miR-34a within the basolateral amygdala (BLA) in fear memory consolidation. Luciferase assays and bioinformatics suggested the Notch pathway as a target of miR-34a. mRNA and protein levels of Notch receptors and ligands are down-regulated in a time- and learning-specific manner after fear conditioning in the amygdala. Systemic and stereotaxic manipulations of the Notch pathway indicated that Notch signaling in the BLA suppresses fear memory consolidation. Impairment of fear memory consolidation after inhibition of miR-34a within the BLA is rescued by inhibiting Notch signaling. Together, these data suggest that within the BLA, a transient decrease in Notch signaling, via miR-34a regulation, is important for the consolidation of fear memory. This work expands the idea that developmental molecules have roles in adult behavior, and that existing interventions targeting them hold promise for treating neuropsychiatric disorders.

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The development and function of the brain require tight control of gene expression. Genome architecture is thought to play a critical regulatory role in gene expression, but the mechanisms governing genome architecture in the brain in vivo remain poorly understood. Here, we report that conditional knockout of the chromatin remodeling enzyme Chd4 in granule neurons of the mouse cerebellum increases accessibility of gene regulatory sites genome-wide in vivo. Conditional knockout of Chd4 promotes recruitment of the architectural protein complex cohesin preferentially to gene enhancers in granule neurons in vivo. Importantly, in vivo profiling of genome architecture reveals that conditional knockout of Chd4 strengthens interactions among developmentally repressed contact domains as well as genomic loops in a manner that tightly correlates with increased accessibility, enhancer activity, and cohesin occupancy at these sites. Collectively, our findings define a role for chromatin remodeling in the control of genome architecture organization in the mammalian brain.