Abstract
Inhibition of the angiotensin type 1 receptor (AT1R) has been shown to decrease fear responses in both humans and rodents. These effects are attributed to modulation of extinction learning, however the contribution of AT1R to alternative memory processes remains unclear. Using classic Pavlovian conditioning combined with radiotelemetry and whole-genome RNA sequencing, we evaluated the effects of the AT1R antagonist losartan on fear memory reconsolidation. Following the retrieval of conditioned auditory fear memory, animals were given a single intraperitoneal injection of losartan or saline. In response to the conditioned stimulus (CS), losartan-treated animals exhibited significantly less freezing at 24 h and 1 week; an effect that was dependent upon memory reactivation and independent of conditioned cardiovascular reactivity. Using an unbiased whole-genome RNA sequencing approach, transcriptomic analysis of the basolateral amygdala (BLA) identified losartan-dependent differences in gene expression during the reconsolidation phase. These findings demonstrate that post-retrieval losartan modifies behavioral and transcriptomic markers of conditioned fear memory, supporting an important regulatory role for this receptor in reconsolidation and as a potential pharmacotherapeutic target for maladaptive fear disorders such as PTSD.
Highlights
Life-threatening traumatic events can lead to the formation of maladaptive fear memories and the development of mental health disorders such as posttraumatic stress disorder (PTSD)
To determine whether blockade of angiotensin type 1 receptor (AT1R) during the window of reconsolidation alters the maintenance of conditioned auditory fear memory, mice were fear conditioned and 24 h later received a single-conditioned stimulus (CS) retrieval cue followed by a losartan injection (Fig. 1a)
Our findings demonstrate that losartan administration shortly after memory retrieval attenuates freezing behavior and modifies differentially expressed genes in the basolateral amygdala, while leaving conditioned cardiovascular responses intact
Summary
Life-threatening traumatic events (e.g., military combat, assault, or natural disaster) can lead to the formation of maladaptive fear memories and the development of mental health disorders such as posttraumatic stress disorder (PTSD). Pre-clinical research demonstrates that peripheral AT1R inhibition with losartan[3,4,5] or deletion of AT1R from select neuronal populations facilitates fear memory extinction[6]. Memory retrieval can initiate a distinct, protein synthesis-dependent mnemonic process called reconsolidation, during which reactivated memories become temporarily labile and susceptible to updating[13]. Reconsolidation provides a time-limited window of vulnerability to selectively weaken or enhance a previously consolidated memory[14]. Because interference with reconsolidation can have amnesic effects on the reactivated memory, this process could potentially be manipulated to benefit a range of psychiatric conditions, including
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