Extinction of Fear Memory Attenuates Conditioned Cardiovascular Fear Reactivity

Post-traumatic stress disorder (PTSD) is characterized by a heightened emotional and physiological state and an impaired ability to suppress or extinguish traumatic fear memories. Exaggerated physiological responses may contribute to increased cardiovascular disease (CVD) risk in this population, but whether treatment for PTSD can offset CVD risk remains unknown. To further evaluate physiological correlates of fear learning, we used a novel pre-clinical conditioned cardiovascular testing paradigm and examined the effects of Pavlovian fear conditioning and extinction training on mean arterial pressure (MAP) and heart rate (HR) responses. We hypothesized that a fear conditioned cardiovascular response could be detected in a novel context and attenuated by extinction training. In a novel context, fear conditioned mice exhibited marginal increases in MAP (∼3 mmHg) and decreases in HR (∼20 bpm) during CS presentation. In a home cage context, the CS elicited significant increases in both HR (100 bpm) and MAP (20 mmHg). Following extinction training, the MAP response was suppressed while CS-dependent HR responses were variable. These pre-clinical data suggest that extinction learning attenuates the acute MAP responses to conditioned stimuli over time, and that MAP and HR responses may extinguish at different rates. These results suggest that in mouse models of fear learning, conditioned cardiovascular responses are modified by extinction training. Understanding these processes in pre-clinical disease models and in humans with PTSD may be important for identifying interventions that facilitate fear extinction and attenuate hyper-physiological responses, potentially leading to improvements in the efficacy of exposure therapy and PTSD–CVD comorbidity outcomes

A microanalytical capillary electrophoresis mass spectrometry assay for quantifying angiotensin peptides in the brain

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. The renin-angiotensin system (RAS) of the brain produces a series of biologically active angiotensinogen-derived peptides involved in physiological homeostasis and pathophysiology of disease. Despite significant research efforts to date, a comprehensive understanding of brain RAS physiology is lacking. A significant challenge has been the limited set of bioanalytical assays capable of detecting angiotensin (Ang) peptides at physiologically low concentrations (2–15 fmol/g of wet tissue) and sufficient chemical specificity for unambiguous molecular identifications. Additionally, a complex brain anatomy calls for microanalysis of specific tissue regions, thus further taxing sensitivity requirements for identification and quantification in studies of the RAS. To fill this technology gap, we here developed a microanalytical assay by coupling a laboratory-built capillary electrophoresis (CE) nano-electrospray ionization (nano-ESI) platform to a high-resolution mass spectrometer (HRMS). Using parallel reaction monitoring, we demonstrated that this technology achieved confident identification and quantification of the Ang peptides at approx. 5 amol to 300 zmol sensitivity. This microanalytical assay revealed differential Ang peptide profiles between tissues that were micro-sampled from the subfornical organ and the paraventricular nucleus of the hypothalamus, important brain regions involved in thirst and water homeostasis and neuroendocrine regulation to stress. Microanalytical CE-nano-ESI-HRMS extends the analytical toolbox of neuroscience to help better understand the RAS

Examining the cardiovascular response to fear extinction in a trauma-exposed sample

Background: Trauma and symptoms of posttraumatic stress disorder (PTSD) have repeatedly been linked to impaired cardiovascular functioning. Poor fear extinction is a well-established biomarker of PTSD that may provide insight into mechanisms underlying cardiovascular risk. The current study probed the cardiovascular response to extinction in a sample of trauma-exposed individuals. Methods: Participants were 51 trauma-exposed women who underwent a fear conditioning paradigm. Heart rate (HR) during extinction was examined in response to a conditioned stimulus that was previously paired with an aversive unconditioned stimulus (CS+) and one that was never paired (CS-). Heart rate variability (HRV) was calculated at baseline and during the extinction session. Results: Consistent with fear bradycardia, initial HR deceleration (.5-2s) after CS + onset occurred during early extinction and appeared to extinguish over time. Higher baseline HRV was significantly associated with greater fear bradycardia during early extinction. Conclusions: This is the first study to demonstrate a pattern of fear bradycardia in early extinction, which was associated with higher HRV levels and decreased over the course of the extinction phase. These results suggest that increased fear bradycardia may be indicative of greater vagal control (i.e., HRV), both of which are psychophysiological biomarkers that may influence cardiovascular and autonomic disease risk in trauma-exposed individuals

Examining the cardiovascular response to fear extinction in a trauma-exposed sample

© 2020 Elsevier Ltd Background: Trauma and symptoms of posttraumatic stress disorder (PTSD) have repeatedly been linked to impaired cardiovascular functioning. Poor fear extinction is a well-established biomarker of PTSD that may provide insight into mechanisms underlying cardiovascular risk. The current study probed the cardiovascular response to extinction in a sample of trauma-exposed individuals. Methods: Participants were 51 trauma-exposed women who underwent a fear conditioning paradigm. Heart rate (HR) during extinction was examined in response to a conditioned stimulus that was previously paired with an aversive unconditioned stimulus (CS+) and one that was never paired (CS-). Heart rate variability (HRV) was calculated at baseline and during the extinction session. Results: Consistent with fear bradycardia, initial HR deceleration (.5-2s) after CS + onset occurred during early extinction and appeared to extinguish over time. Higher baseline HRV was significantly associated with greater fear bradycardia during early extinction. Conclusions: This is the first study to demonstrate a pattern of fear bradycardia in early extinction, which was associated with higher HRV levels and decreased over the course of the extinction phase. These results suggest that increased fear bradycardia may be indicative of greater vagal control (i.e., HRV), both of which are psychophysiological biomarkers that may influence cardiovascular and autonomic disease risk in trauma-exposed individuals

Evaluation of an angiotensin Type 1 receptor blocker on the reconsolidation of fear memory

© 2020, The Author(s). 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

Angiotensin II Type 2 Receptor-Expressing Neurons in the Central Amygdala Influence Fear-Related Behavior

BACKGROUND: The renin-angiotensin system has been implicated in posttraumatic stress disorder; however, the mechanisms responsible for this connection and the therapeutic potential of targeting the renin-angiotensin system in posttraumatic stress disorder remain unknown. Using an angiotensin receptor bacterial artificial chromosome (BAC) and enhanced green fluorescent protein (eGFP) reporter mouse, combined with neuroanatomical, pharmacological, and behavioral approaches, we examined the role of angiotensin II type 2 receptor (AT METHODS: Dual immunohistochemistry with retrograde labeling was used to characterize AT RESULTS: AT CONCLUSIONS: These findings suggest that CeM A