Reduced tubuloglomerular feedback activity and absence of its synchronization in a connexin40 knockout rat.

Introduction: Tubuloglomerular feedback (TGF) is the negative feedback component of renal blood flow (RBF) autoregulation. Neighbouring nephrons often exhibit spontaneous TGF oscillation and synchronization mediated by endothelial communication, largely via connexin40 (Cx40). Methods: We had a knockout (KO) rat made that lacks Cx40. One base pair was altered to create a stop codon in exon 1 of Gja5, the gene that encodes Cx40 (the strain is WKY-Gja55em1Mcwi). Blood pressure (BP)-RBF transfer functions probed RBF dynamics and laser speckle imaging interrogated the dynamics of multiple efferent arterioles that reach the surface (star vessels). Results: The distribution of wild type (WT), heterozygote, and KO pups at weaning approximated the Mendelian ratio of 1:2:1; growth did not differ among the three strains. The KO rats were hypertensive. BP-RBF transfer functions showed low gain of the myogenic mechanism and a smaller TGF resonance peak in KO than in WT rats. Laser speckle imaging showed that myogenic mechanism had higher frequency in KO than in WT rats, but similar maximum spectral power. In contrast, the TGF frequency was similar while peak power of its oscillation was much smaller in KO than in WT rats. In WT rats, plots of instantaneous TGF phase revealed BP-independent TGF synchronization among star vessels. The synchronization could be both prolonged and widespread. In KO rats TGF synchronization was not seen, although BP transients could elicit short-lived TGF entrainment. Discussion: Despite the reduced TGF spectral power in KO rats, there was sufficient TGF gain to induce oscillations and therefore enough gain to be effective locally. We conclude that failure to synchronize is dependent, at least in part, on impaired conducted vasomotor responses.

Scaling of sensorimotor delays in terrestrial mammals.

Whether an animal is trying to escape from a predator, avoid a fall or perform a more mundane task, the effectiveness of its sensory feedback is constrained by sensorimotor delays. Here, we combine electrophysiological experiments, systematic reviews of the literature and biophysical models to determine how delays associated with the fastest locomotor reflex scale with size in terrestrial mammals. Nerve conduction delay is one contributor, and increases strongly with animal size. Sensing, synaptic and neuromuscular junction delays also contribute, and we approximate each as a constant value independent of animal size. Muscle's electromechanical and force generation delays increase more moderately with animal size than nerve conduction delay, but their total contribution exceeds that of the four neural delays. The sum of these six component delays, termed total delay, increases with animal size in proportion to M0.21-large mammals experience total delays 17 times longer than small mammals. The slower movement times of large animals mostly offset their long delays resulting in a more modest, but perhaps still significant, doubling of their total delay relative to movement duration when compared with their smaller counterparts. Irrespective of size, sensorimotor delay is likely a challenge for all mammals, particularly during fast running.

Sensorimotor responsiveness and resolution in the giraffe.

The ability of an animal to detect and respond to changes in the environment is crucial to its survival. However, two elements of sensorimotor control - the time required to respond to a stimulus (responsiveness) and the precision of stimulus detection and response production (resolution) - are inherently limited by a competition for space in peripheral nerves and muscles. These limitations only become more acute as animal size increases. In this paper, we investigated whether the physiology of giraffes has found unique solutions for maintaining sensorimotor performance in order to compensate for their extreme size. To examine responsiveness, we quantified three major sources of delay: nerve conduction delay, muscle electromechanical delay and force generation delay. To examine resolution, we quantified the number and size distribution of nerve fibers in the sciatic nerve. Rather than possessing a particularly unique sensorimotor system, we found that our measurements in giraffes were broadly comparable to size-dependent trends seen across other terrestrial mammals. Consequently, both giraffes and other large animals must contend with greater sensorimotor delays and lower innervation density in comparison to smaller animals. Because of their unconventional leg length, giraffes may experience even longer delays compared with other animals of the same mass when sensing distal stimuli. While there are certainly advantages to being tall, there appear to be challenges as well - our results suggest that giraffes are less able to precisely and accurately sense and respond to stimuli using feedback alone, particularly when moving quickly.

A semi-automated method for identifying and measuring myelinated nerve fibers in scanning electron microscope images.

Diagnosing illnesses, developing and comparing treatment methods, and conducting research on the organization of the peripheral nervous system often require the analysis of peripheral nerve images to quantify the number, myelination, and size of axons in a nerve. Current methods that require manually labeling each axon can be extremely time-consuming as a single nerve can contain thousands of axons. To improve efficiency, we developed a computer-assisted axon identification and analysis method that is capable of analyzing and measuring sub-images covering the nerve cross-section, acquired using a scanning electron microscope. This algorithm performs three main procedures - it first uses cross-correlation to combine the acquired sub-images into a large image showing the entire nerve cross-section, then identifies and individually labels axons using a series of image intensity and shape criteria, and finally identifies and labels the myelin sheath of each axon using a region growing algorithm with the geometric centers of axons as seeds. To ensure accurate analysis of the image, we incorporated manual supervision to remove mislabeled axons and add missed axons. The typical user-assisted processing time for a two-megapixel image containing over 2000 axons was less than 1h. This speed was almost eight times faster than the time required to manually process the same image. Our method has proven to be well suited for identifying axons and their characteristics, and represents a significant time savings over traditional manual methods.

Scaling of sensorimotor control in terrestrial mammals.

Sensorimotor control is greatly affected by two factors--the time it takes for an animal to sense and respond to stimuli (responsiveness), and the ability of an animal to distinguish between sensory stimuli and generate graded muscle forces (resolution). Here, we demonstrate that anatomical limitations force a necessary trade-off between responsiveness and resolution with increases in animal size. To determine whether responsiveness is prioritized over resolution, or resolution over responsiveness, we studied how size influences the physiological mechanisms underlying sensorimotor control. Using both new electrophysiological experiments and existing data, we determined the maximum axonal conduction velocity (CV) in animals ranging in size from shrews to elephants. Over the 100-fold increase in leg length, CV was nearly constant, increasing proportionally with mass to the 0.04 power. As a consequence, larger animals are burdened with relatively long physiological delays, which may have broad implications for their behaviour, ecology and evolution, including constraining agility and requiring prediction to help control movements.