Alpha1-adrenergic receptor blockade in the ventral tegmental area attenuates acquisition of cocaine-induced pavlovian associative learning.

Activity of the alpha1-adrenergic receptor (α1-AR) in the ventral tegmental area (VTA) modulates dopaminergic activity, implying its modulatory role in the behavioral functions of the dopamine (DA) system. Indeed, intra-VTA α1-AR blockade attenuates conditioned stimulus dependent behaviors such as drug seeking responses signifying a role of the noradrenergic signaling in the VTA in conditioned behaviors. Importantly, the role of the VTA α1-AR activity in Pavlovian associative learning with positive outcomes remains unknown. Here, we aimed to examine how intra-VTA α1-AR blockade affects acquisition of cocaine-induced Pavlovian associative learning in the conditioned place preference (CPP) paradigm. The impact of α1-AR blockade on cocaine-reinforced operant responding and cocaine-evoked ultrasonic vocalizations (USVs) was also studied. In addition, both α1-AR immunoreactivity in the VTA and its role in phasic DA release in the nucleus accumbens (NAc) were assessed. We demonstrated cellular localization of α1-AR expression in the VTA, providing a neuroanatomical substrate for the α1-AR mechanism. We showed that prazosin (α1-AR selective antagonist; 1 µg/0.5 µl) microinfusion attenuated electrically evoked DA transients in the NAc and dose-dependently (0.1-1 µg/0.5 µl) prevented the acquisition of cocaine CPP but did not affect cocaine-reinforced operant responding nor cocaine-induced positive affective state (measured as USVs). We propose that the VTA α1-AR signaling is necessary for the acquisition of Pavlovian associative learning but does not encode hedonic value. Thus, α1-AR signaling in the VTA might underlie salience encoding of environmental stimuli and reflect an ability of alerting/orienting functions, originating from bottom-up information processing to guide behaviors.

Deep learning fetal ultrasound video model match human observers in biometric measurements.

Objective.This work investigates the use of deep convolutional neural networks (CNN) to automatically perform measurements of fetal body parts, including head circumference, biparietal diameter, abdominal circumference and femur length, and to estimate gestational age and fetal weight using fetal ultrasound videos.Approach.We developed a novel multi-task CNN-based spatio-temporal fetal US feature extraction and standard plane detection algorithm (called FUVAI) and evaluated the method on 50 freehand fetal US video scans. We compared FUVAI fetal biometric measurements with measurements made by five experienced sonographers at two time points separated by at least two weeks. Intra- and inter-observer variabilities were estimated.Main results.We found that automated fetal biometric measurements obtained by FUVAI were comparable to the measurements performed by experienced sonographers The observed differences in measurement values were within the range of inter- and intra-observer variability. Moreover, analysis has shown that these differences were not statistically significant when comparing any individual medical expert to our model.Significance.We argue that FUVAI has the potential to assist sonographers who perform fetal biometric measurements in clinical settings by providing them with suggestions regarding the best measuring frames, along with automated measurements. Moreover, FUVAI is able perform these tasks in just a few seconds, which is a huge difference compared to the average of six minutes taken by sonographers. This is significant, given the shortage of medical experts capable of interpreting fetal ultrasound images in numerous countries.

Noradrenergic and corticosteroid receptors regulate somatic and motivational symptoms of morphine withdrawal.

Somatic and motivational symptoms accompanying opiate withdrawal are considered one of the major reasons for relapse to opiate-seeking and opiate-taking behaviors. These symptoms are accompanied by the activation of stress-related processes including hypothalamic-pituitary-adrenal axis activity and noradrenergic (NA) signaling. In particular, the NA system plays an important role in the expression of somatic signs of opiate withdrawal, whereas glucocorticoid (GR) and mineralocorticoid receptors (MR) are activated during opiate abstinence. The purpose of our study was to examine the roles of α1-, α2-, and ß-adrenoceptors (ARs) as well as GR and MR, in the formation and expression of physiological and motivational symptoms of morphine withdrawal. We showed that systemic pretreatment with the selective α1-AR antagonist prazosin (0-1 mg/kg), the selective α2-AR antagonist RX821002 (0-2 mg/kg), the selective ß-adrenergic antagonist, propranolol (0-10 mg/kg), or the selective MR antagonist spironolactone (0-50 mg/kg), but not the selective GR antagonist mifepristone (0-40 mg/kg), decreased somatic symptoms of naloxone-precipitated morphine withdrawal in mice chronically treated with morphine. In contrast, only propranolol pretreatment attenuated the dysphoric affective state accompanying naloxone-precipitated morphine withdrawal as assessed in the conditioned place aversion (N-CPA) paradigm. Together, our results demonstrate the important roles of noradrenergic receptors in the modulation of somatic, but not motivational/affective, symptoms of morphine withdrawal. In addition MR but not GR regulates the expression of only somatic symptoms of morphine withdrawal.

Alpha1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses.

Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha1-adrenergic receptor (α1-AR) signaling in the VTA affects conditioned fear. The role of α1-AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α1-AR blockade in the mammillary bodies (MB) - a brain region with α1-AR expression adjacent to the VTA. Intra-VTA but not intra-MB α1-AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α1-AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α1-AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α1-AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α1-AR signaling in the regulation of stress responsiveness and fear memory.