Role of α- and ß-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease.

The urinary tract is highly innervated by autonomic nerves which are essential in urinary tract development, the production of growth factors, and the control of homeostasis. These neural signals may become dysregulated in several genitourinary (GU) disease states, both benign and malignant. Accordingly, the autonomic nervous system is a therapeutic target for several genitourinary pathologies including cancer, voiding dysfunction, and obstructing nephrolithiasis. Adrenergic receptors (adrenoceptors) are G-Protein coupled-receptors that are distributed throughout the body. The major function of α1-adrenoceptors is signaling smooth muscle contractions through GPCR and intracellular calcium influx. Pharmacologic intervention of α-and ß-adrenoceptors is routinely and successfully implemented in the treatment of benign urologic illnesses, through the use of α-adrenoceptor antagonists. Furthermore, cell-based evidence recently established the antitumor effect of α1-adrenoceptor antagonists in prostate, bladder and renal tumors by reducing neovascularity and impairing growth within the tumor microenvironment via regulation of the phenotypic epithelial-mesenchymal transition (EMT). There has been a significant focus on repurposing the routinely used, Food and Drug Administration-approved α1-adrenoceptor antagonists to inhibit GU tumor growth and angiogenesis in patients with advanced prostate, bladder, and renal cancer. In this review we discuss the current evidence on (a) the signaling events of the autonomic nervous system mediated by its cognate α- and ß-adrenoceptors in regulating the phenotypic landscape (EMT) of genitourinary organs; and (b) the therapeutic significance of targeting this signaling pathway in benign and malignant urologic disease. Video abstract.

Rodent navigation after dissociation of the allocentric and idiothetic representations of space.

Analysis of the neural mechanisms of place navigation requires isolation of the landmark dependent allocentric and self-motion related idiothetic orientation modes. To assess their importance, rats were trained on a rotating (360 degrees/min) arena to avoid foot shocks applied in either a room frame defined sector of the arena or an idiothetically defined region of the floor. Independence of the respective allocentric and idiothetic engrams was revealed by simultaneous avoidance of both locations. The possibility that idiothetic orientation was confounded by allocentric intramaze cues was examined in an apparatus consisting of an inner rotating disc surrounded by a stationary belt. As long as the rat was on the moving disc, position of the 60 degrees shock sector was stable on the disk but projected from it to different parts of the belt. When the rat moved to the belt the shock sector was now stable on the belt, but its projection to the disk travelled over its moving surface. The rat always found the shock sector in an idiothetically correct position but the mutual shifts of the disk and belt eliminated the utility of local cues like scent marks for the idiothetic solution of the task. Purely allocentric orientation was required in a place recognition task in which pressing a lever mounted on a rotating arena was rewarded only when the operandum moved through an allocentrically defined 60 degrees segment of its trajectory. Place recognition was manifest by increased bar pressing rates on approach to and inside the reward zone. These methods may reveal how hippocampal place cell activity correlates with both allocentric and idiothetic aspects of spatial orientation.

On-demand platform improves accuracy of the Morris water maze procedure.

In order to prevent chance finding of the hidden target in the Morris water tank task, the rigid underwater platform is replaced with a collapsible platform, resting at the bottom of the pool. A computerized videosystem tracks the rat's movement across the pool and raises the platform when the animal has stayed in the target area for a predetermined time. Acquisition of the task with the collapsible platform proceeds at a similar rate as with the rigid platform when the criterion conditions are easy (target distance 15 cm, target time 2.5 s), but gradually deteriorates when the target time increases to 10.0 s. Successful solution of the modified task requires accurate localization of the target under open loop conditions and is thus well suited for investigation of the fine structure of the cognitive maps and of their changes induced by lesions or drugs.

A multiple choice apparatus for electrophysiological investigations of spatial working memory in rats.

A multiple choice apparatus, minimizing the rat's movements and thus simplifying brain stimulation and/or recording in working memory experiments, consists of a dodecagonal enclosure (30 cm diameter, 100 cm high) with a horizontal platform assuming either an upper or a lower position, 43 or 65 cm below the top of the wall, respectively. The platform is moved between these two levels by a pneumatic system controlled by solid-state programming circuits. Each wall segment contains a choice window, 7 cm above the upper floor level, providing access to a recessed feeder. When the platform with a food-deprived rat moves into the upper position, the animal opens the hinged shutter of one window and gets the pellet. Five seconds later, a self-locking relay marks the visited window and the floor descends to the low position where it remains for a predetermined interval (e.g. 20 s), until it is raised again. The above cycle repeats as a long as different windows are chosen. When a choice is directed to an already visited window (error), the floor returns to the low position at once. During one trial, the animal is allowed 12 choices and the number of errors (i.e. choices directed to already entered windows) is recorded. In spite of the great reduction of kinaesthetic and vestibular signals and the almost complete elimination of visual extramaze cues, the working memory performance is similar to that in analogous radial maze.

Radial maze in the water tank: an aversively motivated spatial working memory task.

An 8-arm radial maze with 40 X 40 X 12 cm channels was inserted into a circular tank (120 cm in diameter, 60 cm high) filled 30 cm deep with 25 degrees C opaque water. Rats (n = 13) had to escape from the central area of the maze (30 cm in diameter) onto an invisible bench (1 cm below water surface) at the far end of each channel. Twenty sec after each choice the bench was collapsed and the animal was forced to choose again until all 8 channels had been visited. From the very beginning rats performed better than chance. The acquisition and performance of this aversively motivated radial maze test is similar as in conventional elevated 8-arm radial mazes.

An automated segmentation method for three-dimensional carotid ultrasound images.

We have developed an automated segmentation method for three-dimensional vascular ultrasound images. The method consists of two steps: an automated initial contour identification, followed by application of a geometrically deformable model (GDM). The formation of the initial contours requires the input of a single seed point by the user, and was shown to be insensitive to the placement of the seed within a structure. The GDM minimizes contour energy, providing a smoothed final result. It requires only three simple parameters, all with easily selectable values. The algorithm is fast, performing segmentation on a 336 x 352 x 200 volume in 25 s when running on a 100 MHz 9500 Power Macintosh prototype. The segmentation algorithm was tested on stenosed vessel phantoms with known geometry, and the segmentation of the cross-sectional areas was found to be within 3% of the true area. The algorithm was also applied to two sets of patient carotid images, one acquired with a mechanical scanner and the other with a freehand scanning system, with good results on both.

Vestibular navigation directed by the slope of terrain.

Slope of terrain is an important orienting gradient affecting the goal-directed locomotion of animals. Its significance was assessed in experiment 1 by training rats to find in darkness a feeder on the top of a low cone (80-cm base, 0- to 4-cm high). A computerized infrared tracking system monitoring the rat's position in darkness showed that the path length on the cone surface was inversely proportional to cone height. A device allowing continuous generation of slope-guided locomotion was used in experiment 2. This device consists of a 1-m arena, the floor of which can be supported at a point corresponding to the position of one of three equidistant feeders located 17 cm from its center. The arena is inclined by the locomotion of the rat to a plane passing through the elevated (2- or 4-cm) feeder, the rat's center of gravity, and a point at the edge of the arena resting on the floor. The multitude of such planes generated by the rat's locomotion forms the surface of a virtual cone, the top of which is formed by the feeder. Additional path (difference between distance traveled and shortest distance of the animal from the goal at the onset of inclination) is inversely related to the incline of the arena and is a sensitive measure of performance in this type of vestibular navigation.