miR Profile of Chronic Right Ventricular Pacing: a Pilot Study in Children with Congenital Complete Atrioventricular Block.

Chronic ventricular pacing can lead to pacing-induced cardiomyopathy (PICM). Clinical data alone is insufficient to predict who will develop PICM. Our study aimed to evaluate the circulating miR profile associated with chronic right ventricular pacing in children with congenital complete AV block (CCAVB) and to identify candidate miRs for longitudinal monitoring. Clinical data and blood were collected from chronically paced children (N = 9) and compared with non-paced controls (N = 13). miR microarrays from the buffy coat revealed 488 differentially regulated miRs between groups. Pathway analysis predicted both adaptive and maladaptive miR signaling associated with chronic pacing despite preserved ventricular function. Greater profibrotic signaling (miRs-92a, 130, 27, 29) and sodium and calcium channel dysregulation (let-7) were seen in those paced > 10 years with the most dyregulation seen in a patient with sudden death vs. those paced < 10 years. These miRs may help to identify early adverse remodeling in this population.

Criteria for Early Pacemaker Implantation in Patients With Postoperative Heart Block After Congenital Heart Surgery.

BACKGROUND: Guidelines recommend observation for atrioventricular node recovery until postoperative days (POD) 7 to 10 before permanent pacemaker placement (PPM) in patients with heart block after congenital cardiac surgery. To aid in surgical decision-making for early PPM, we established criteria to identify patients at high risk of requiring PPM. METHODS: We reviewed all cases of second degree and complete heart block (CHB) on POD 0 from August 2009 through December 2018. A decision tree model was trained to predict the need for PPM amongst patients with persistent CHB and prospectively validated from January 2019 through March 2021. Separate models were developed for all patients on POD 0 and those without recovery by POD 4. RESULTS: Of the 139 patients with postoperative heart block, 68 required PPM. PPM was associated with older age (3.2 versus 1.0 years; P=0.018) and persistent CHB on POD 0 (versus intermittent CHB or second degree heart block; 87% versus 58%; P=0.001). Median days [IQR] to atrioventricular node recovery was 2 [0-5] and PPM was 9 [6-11]. Of the 100 cases of persistent CHB (21 in the validation cohort), 59 (59%) required PPM. A decision tree model identified 4 risk factors for PPM in patients with persistent CHB: (1) aortic valve replacement, subaortic stenosis repair, or Konno procedure; (2) ventricular L-looping; (3) atrioventricular valve replacement; (4) and absence of preoperative antiarrhythmic agent (in POD 0 model only). The POD 4 model specificity was 0.89 [0.67-0.99] and positive predictive value was 0.94 [95% CI 0.81-0.98], which was stable in prospective validation (positive predictive value 1.0). CONCLUSIONS: A data-driven analysis led to actionable criteria to identify patients requiring PPM. Patients with left ventricular outflow tract surgery, atrioventricular valve replacement, or ventricular L-Looping could be considered for PPM on POD 4 to reduce risks of temporary pacing and improve care efficiency.

Optogenetic inhibition of dorsal medial prefrontal cortex attenuates stress-induced reinstatement of palatable food seeking in female rats.

Relapse to maladaptive eating habits during dieting is often provoked by stress. Recently, we identified a role of dorsal medial prefrontal cortex (mPFC) neurons in stress-induced reinstatement of palatable food seeking in male rats. It is unknown whether endogenous neural activity in dorsal mPFC drives stress-induced reinstatement in female rats. Here, we used an optogenetic approach, in which female rats received bilateral dorsal mPFC microinjections of viral constructs coding light-sensitive eNpHR3.0-eYFP or control eYFP protein and intracranial fiber optic implants. Rats were food restricted and trained to lever press for palatable food pellets. Subsequently, pellets were removed, and lever pressing was extinguished; then the effect of bilateral dorsal mPFC light delivery on reinstatement of food seeking was assessed after injections of the pharmacological stressor yohimbine (an α-2 andrenoceptor antagonist) or pellet priming, a manipulation known to provoke food seeking in hungry rats. Dorsal mPFC light delivery attenuated yohimbine-induced reinstatement of food seeking in eNpHR3.0-injected but not eYFP-injected rats. This optical manipulation had no effect on pellet-priming-induced reinstatement or ongoing food-reinforced responding. Dorsal mPFC light delivery attenuated yohimbine-induced Fos immunoreactivity and disrupted neural activity during in vivo electrophysiological recording in awake rats. Optical stimulation caused significant outward currents and blocked electrically evoked action potentials in eNpHR3.0-injected but not eYFP-injected mPFC hemispheres. Light delivery alone caused no significant inflammatory response in mPFC. These findings indicate that intracranial light delivery in eNpHR3.0 rats disrupts endogenous dorsal mPFC neural activity that plays a role in stress-induced relapse to food seeking in female rats.

Medial prefrontal cortex neuronal activation and synaptic alterations after stress-induced reinstatement of palatable food seeking: a study using c-fos-GFP transgenic female rats.

Relapse to maladaptive eating habits during dieting is often provoked by stress and there is evidence for a role of ovarian hormones in stress responses and feeding. We studied the role of these hormones in stress-induced reinstatement of food seeking and medial prefrontal cortex (mPFC) neuronal activation in c-fos-GFP transgenic female rats, which express GFP in strongly activated neurons. Food-restricted ovariectomized or sham-operated c-fos-GFP rats were trained to lever-press for palatable food pellets. Subsequently, lever-pressing was extinguished and reinstatement of food seeking and mPFC neuronal activation was assessed after injections of the pharmacological stressor yohimbine (0.5-2 mg/kg) or pellet priming (1-4 noncontingent pellets). Estrous cycle effects on reinstatement were also assessed in wild-type rats. Yohimbine- and pellet-priming-induced reinstatement was associated with Fos and GFP induction in mPFC; both reinstatement and neuronal activation were minimally affected by ovarian hormones in both c-fos-GFP and wild-type rats. c-fos-GFP transgenic rats were then used to assess glutamatergic synaptic alterations within activated GFP-positive and nonactivated GFP-negative mPFC neurons following yohimbine-induced reinstatement of food seeking. This reinstatement was associated with reduced AMPA receptor/NMDA receptor current ratios and increased paired-pulse facilitation in activated GFP-positive but not GFP-negative neurons. While ovarian hormones do not appear to play a role in stress-induced relapse of food seeking in our rat model, this reinstatement was associated with unique synaptic alterations in strongly activated mPFC neurons. Our paper introduces the c-fos-GFP transgenic rat as a new tool to study unique synaptic changes in activated neurons during behavior.

Effect of fenfluramine on reinstatement of food seeking in female and male rats: implications for the predictive validity of the reinstatement model.

RATIONALE AND OBJECTIVES: Relapse to old unhealthy eating habits while dieting is often provoked by stress or acute exposure to palatable foods. We adapted a rat reinstatement model, which is used to study drug relapse, to study mechanisms of relapse to palatable food seeking induced by food-pellet priming (non-contingent exposure to a small amount of food pellets) or injections of yohimbine (an alpha-2 adrenoceptor antagonist that causes stress-like responses in humans and non-humans). Here, we assessed the predictive validity of the food reinstatement model by studying the effects of fenfluramine, a serotonin releaser with known anorectic effects, on reinstatement of food seeking. METHODS: We trained food-restricted female and male rats to lever-press for 45-mg food pellets (3-h sessions) and first assessed the effect of fenfluramine (0.75, 1.5, and 3.0 mg/kg, i.p.) on food-reinforced responding. Subsequently, we extinguished the food-reinforced responding and tested the effect of fenfluramine (1.5 and 3.0 mg/kg) on reinstatement of food seeking induced by yohimbine injections (2 mg/kg, i.p.) or pellet priming (four non-contingent pellets). RESULTS: Fenfluramine decreased yohimbine- and pellet-priming-induced reinstatement. As expected, fenfluramine also decreased food-reinforced responding, but a control condition in which we assessed fenfluramine's effect on high-rate operant responding indicated that the drug's effect on reinstatement was not due to performance deficits. CONCLUSIONS: The present data support the predictive validity of the food reinstatement model and suggest that this model could be used to identify medications for prevention of relapse induced by stress or acute exposure to palatable food during dietary treatments.

Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats.

RATIONALE AND OBJECTIVES: Relapse to alcohol use during abstinence or maladaptive eating habits during dieting is often provoked by stress. The anxiogenic drug yohimbine, which causes stress-like responses in humans and non-humans, reliably reinstates alcohol and food seeking in a rat relapse model. Yohimibine is a prototypical alpha-2 adrenoceptor antagonist, but results from studies on noradrenaline's role in yohimbine-induced reinstatement of drug and food seeking are inconclusive. Here, we further addressed this issue by studying the effect of the alpha-1 adrenoceptor antagonist prazosin and the alpha-2 adrenoceptor agonist guanfacine on yohimbine-induced reinstatement. METHODS: In exp. 1, we trained rats to self-administer alcohol (12% w/v, 1 h/day), and after extinction of alcohol-reinforced lever pressing, we tested prazosin's (0.5, 1.0, and 2.0 mg/kg, i.p.) or guanfacine's (0.125, 0.25, and 0.5 mg/kg, i.p.) effect on yohimbine (1.25 mg/kg, i.p.)-induced reinstatement; we also examined prazosin's effect on intermittent-footshock-stress-induced reinstatement. In exp. 2, we trained food-restricted rats to self-administer 45 mg food pellets and first examined prazosin's or guanfacine's effects on food-reinforced responding, and then, after extinction of lever presses, on yohimbine-induced reinstatement. RESULTS: Prazosin (0.5-2.0 mg/kg) blocked yohimbine-induced reinstatement of food and alcohol seeking, as well as footshock-induced reinstatement of alcohol seeking. Guanfacine attenuated yohimbine-induced reinstatement of alcohol seeking at the highest dose (0.5 mg/kg), but its effect on yohimbine-induced reinstatement of food seeking was not significant. Neither prazosin nor guanfacine affected high-rate food-reinforced responding. CONCLUSIONS: Results demonstrate an important role of postsynaptic alpha-1 adrenoceptors in stress-induced reinstatement of alcohol and food seeking.

Role of dorsal medial prefrontal cortex dopamine D1-family receptors in relapse to high-fat food seeking induced by the anxiogenic drug yohimbine.

In humans, relapse to maladaptive eating habits during dieting is often provoked by stress. In rats, the anxiogenic drug yohimbine, which causes stress-like responses in both humans and nonhumans, reinstates food seeking in a relapse model. In this study, we examined the role of medial prefrontal cortex (mPFC) dopamine D1-family receptors, previously implicated in stress-induced reinstatement of drug seeking, in yohimbine-induced reinstatement of food seeking. We trained food-restricted rats to lever press for 35% high-fat pellets every other day (9-15 sessions, 3 h each); pellet delivery was accompanied by a discrete tone-light cue. We then extinguished operant responding for 10-16 days by removing the pellets. Subsequently, we examined the effect of yohimbine (2 mg/kg, i.p.) on reinstatement of food seeking and Fos (a neuronal activity marker) induction in mPFC. We then examined the effect of systemic injections of the D1-family receptor antagonist SCH23390 (10 µg/kg, s.c.) on yohimbine-induced reinstatement and Fos induction, and that of mPFC SCH23390 (0.5 and 1.0 µg/side) injections on this reinstatement. Yohimbine-induced reinstatement was associated with strong Fos induction in the dorsal mPFC and with weaker Fos induction in the ventral mPFC. Systemic SCH23390 injections blocked both yohimbine-induced reinstatement and mPFC Fos induction. Dorsal, but not ventral, mPFC injections of SCH23390 decreased yohimbine-induced reinstatement of food seeking. In addition, dorsal mPFC SCH23390 injections decreased pellet-priming-induced reinstatement, but had no effect on ongoing high-fat pellet self-administration or discrete-cue-induced reinstatement. Results indicate a critical role of dorsal mPFC dopamine D1-family receptors in stress-induced relapse to palatable food seeking, as well as relapse induced by acute re-exposure to food taste, texture, and smell.

Anhedonia in postpartum rats.

Postpartum depression (PPD) is a debilitating illness, yet little is known about its causes. The purpose of this study was to examine a major symptom of depression during the postpartum period, anhedonia, by comparing sucrose preference in female rats that had undergone actual pregnancy or hormone-simulated pregnancy (HSP) to their respective controls. Whereas HSP rats showed significantly less preference than vehicle control rats for 1% sucrose solution during the first three weeks of the "postpartum" period, previously pregnant females showed only slightly depressed sucrose preference for the first 1-2 days postpartum, compared to non-pregnant controls. Habituation to 1% sucrose during the pregnancy period, which increased preference upon later testing in previously pregnant rats tested on postpartum day 2, did not significantly increase preference in HSP rats, suggesting that depressed preference in the latter group was not due to neophobia. Pre-treatment with desipramine did not prevent suppressed sucrose preference in HSP rats, and preference was even further suppressed following chronic sertraline treatment. These results suggest that estradiol withdrawal following HSP may cause anhedonia during the early "postpartum" period. In contrast, females that have undergone actual pregnancy are less likely to show this effect, suggesting that postpartum hormonal changes other than the dramatic decline in estradiol may buffer its negative mood effects.