Knockdown of Corticotropin Releasing Hormone Receptor 1 (CRF1) in the Rostral Peri‐Cellular Region of the Locus Coeruleus (LC) Normalizes Anxiety‐Like Behavior in Female Rats Subjected to Coronary Ischemia and Reperfusion (IR)

Abstract

After myocardial infarction (MI), patients often develop post‐traumatic stress disorder (PTSD), an anxiety disorder characterized by deficits in extinction of learned fear. Women develop more severe symptoms of PTSD, and severity of Post‐MI PTSD symptoms is predictive of further cardiovascular morbidity. Excessive noradrenergic drive in the medial prefrontal cortex (mPFC) has been implicated in PTSD. Neural projections from the amygdala release CRF in the rostral peri‐cellular region of the LC, and CRF stimulates LC neurons to release norepinephrine in mPFC to modulate fear extinction. Here, we examined the role of peri‐LC CRF in PTSD‐like behavior in a rat model of MI. Female and male rats were trained to fear a tone and then subjected to IR or sham surgery 1 week later. Two weeks later, rats were given bilateral LC injections of a viral vector encoding a shRNA sequence targeting the rat CRF1 receptor, or a scrambled sequence. Six weeks later, cumulative freezing behavior was measured during 10 extinction trials. One day later, rats were anesthetized with ketamine and perfused for in situ detection of CRF1 mRNA. IR impaired left ventricular (LV) function more in males than females (23.3±3.1 [n=17] vs 33.7±4.4% [n=18] fractional shortening). Females with more severe LV damage (fractional shortening ≤40%) took longer to extinguish fear than sham females (99.7±12.3 [n=4] vs. 41.6±7.3 seconds [n=6], P<0.01). Treatment with anti‐CRF1 shRNA reversed deficits in extinction among IR females with more severe LV damage (43.3±7.7 seconds [n=6], P<0.05). Males showed similar trends that were not significant (82.9±16.0 [n=9] vs. 57.1±9.7 [n=10] and 58.6±14.4 seconds [n=9]). Rostral Peri‐LC CRF1 mRNA was elevated by 66% (P<0.01) in sham females compared to sham males. ShRNA treatment reduced rostral peri‐LC CRF1 mRNA by 22.9% (P<0.05) and 42% (P<0.01) in female and male sham rats respectively, but did not affect caudal LC CRF1 mRNA levels. Female and male IR rats showed reduced rostral (but not caudal) peri‐LC CRF1 mRNA levels compared to their respective sham controls (−58%, P<0.01 and −38%, P<0.05 respectively). ShRNA treatment did not further reduce peri‐LC CRF1 mRNA levels in IR rats. Rostral peri‐LC CRF1 mRNA levels were inversely related to cumulative freezing in females treated with the scrambled sequence (P<0.01). Together, the data indicate that rostral peri‐LC CRF contributes to deficits in fear extinction in female rats after IR. The data are also consistent with the possibility that fear‐induced release of CRF in the rostral peri‐LC region acutely suppresses CRF1 gene expression.Support or Funding InformationAmerican Heart Association GRNT20380765, Cardiovascular Research Institute, Loyola University ChicagoThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.