A structure-distribution-relationship approach leading to the development of Tc-99m mebrofenin: an improved cholescintigraphic agent.

Thirty-three HIDA (hepatobiliary IDA) derivatives were tested and correlations drawn between physicochemical parameters, structural effects, and in vivo characteristics. Capacity factors of the ligands on reverse-phase HPLC were used as a measure of lipophilicity, and to predict protein binding and in vivo distribution of the complexes. Fragmentary pi values were used to derive theoretical lipophilicities, which showed that ortho substituents have reduced lipophilic activity, probably because of self-shielding. Ortho substitution was found to affect hepatocellular transit times. Various combinations of substituents with the desired overall lipophilicity were tested. The best compound, Tc-3-bromo-2,4,6-trimethyl HIDA, possessed high hepatic specificity, and rapid hepatocellular transit; it was also resistant to competition for hepatobiliary excretion from bilirubin.

The cerebellar dorsal granular ridge in an elasmobranch has proprioceptive and electroreceptive representations and projects homotopically to the medullary electrosensory nucleus.

1. Response properties of neurons in the dorsal granular ridge (DGR) of the little skate, Raja erinacea, were studied in decerebrate, curarized fish. Sensory responses included proprioceptive (426 of 952; 45%) and electroreceptive units (526 of 952; 55%). Electroreceptive units responded to weak electric fields with a higher threshold than lower-order units and had large ipsilateral receptive fields, whose exact boundaries were often unclear but contained smaller, identifiable best areas. Proprioceptive units responded to displacement of the ipsilateral fin and were either position- or movement-sensitive. 2. Both proprioceptive and electroreceptive units showed a progression of receptive fields from anterior to posterior body in the rostral to caudal direction along the length of DGR. Sensory maps in DGR projected homotopically to the electrosensory somatotopy in the dorsal nucleus. Peak evoked potentials and units responding to local DGR stimulation occurred only in areas of the dorsal nucleus with receptive fields located within the composite receptive field at the DGR stimulation site. 3. Single shocks to DGR produced a short spike train followed by a prolonged suppression period in the medullary dorsal nucleus. These results have implications for the role of the parallel fiber system in medullary electrosensory processing.

Dipole source localization by mottled sculpin. I. Approach strategies.

Lake Michigan mottled sculpin respond to a chemically-inert vibrating sphere (a dipole source) with an initial orientation towards the source followed by a step-wise progression towards and final strike at the source. An analysis of videotape recordings of this behavior indicate that although pathways to the source varied, they tended to be influenced by the fish's position at signal onset. Fish heading toward the source at signal onset approached the source in an indirect fashion by either (a) keeping the source to one side in a smoothly arching path to the source or (b) alternating between keeping the source to the left and to the right. When the source was to the side of the fish at the time of stimulus onset, fish tended to approach the source in a more direct path. Most (79%) initial orienting responses placed the fish within 45 degrees of the source, but response angles were not strongly correlated with initial source angle. Most (83%) unsuccessful strikes (misses) occurred when the source was directly in front of the fish (+/- 20 degrees) and source angles associated with misses were significantly smaller than source angles associated with successful strikes. Approach strategies used by mottled sculpin in finding dipole sources appear to include (1) moving in a direction that increases the pressure difference along the head while keeping it consistently low (between 1 and 10 Pa) across the head, (2) narrowing the fish-to-source gap with each successive step in the pathway, (3) keeping the source lateralized (on average, 30 degrees to one or the other side of the head) and (4) avoiding approach positions that are perpendicular to the flow line or that place the fish in the pressure null area of the dipole field. These results are consistent with the hypothesis that spatial excitation patterns along the lateral line system play a major role in encoding both source direction and distance.

Dipole source localization by the mottled sculpin. II. The role of lateral line excitation patterns.

Extracellular, single unit recording techniques were used to measure the responses of posterior lateral line nerve fibers to a 50-Hz dipole source that slowly changed its location along the length of the fish. The flow-field equations for a dipole source were used to model the pressure gradient pattern and thus, the expected excitation pattern along a linear array of lateral line receptor organs for different source locations. Finally, excitation patterns were similarly modeled along the left and right side of the fish's head for actual steps taken by sculpin in approach pathways to the 50-Hz dipole source. Spatial histograms of posterior lateral line nerve fiber responses to different locations of the dipole source could be predicted from pressure gradient patterns modeled from the flow-field equations, confirming that the modeling approach applied to behavioral results was a good predictor of excitation patterns likely to be encoded by the lateral line periphery. An examination of how modeled excitation patterns changed from one position to the next in typical approach pathways and how patterns differed between positions from which successful and unsuccessful strikes were launched suggests that approach and strike strategies can indeed be explained by the information available in excitation patterns. In particular, changes in the spatial distribution of pressure gradient directions (polarities), available only when the source is lateral (as opposed to directly in front of the fish), appear to enhance the ability of sculpin to determine source distance. Without such information, misses are more likely to occur and successful strikes are more likely to be launched from short distances only.

Rate representation and discriminability of second formant frequencies for /epsilon/-like steady-state vowels in cat auditory nerve.

Alternate forms of the steady-state vowel /epsilon/ with second formant peaks located at 1400, 1500, 1700, and 2000 Hz were used to study the representation and discrimination of second formant frequencies at the level of the auditory nerve. Recordings from large populations of auditory nerve fibers in response to these stimuli were used to create rate-place plots, which show second formant peaks that resembled the stimulus spectra. Measures of the peak amplitude decreased as sound level was increased and as second formant frequency was lowered. Representation of the spectra was degraded at the higher sound level because of saturation and two-tone suppressive effects. However, formant peaks were clearly represented in plots of rate differences between two vowels. Such plots resemble the ratio of the magnitudes of the two vowel spectra. The results suggest that information concerning the position of formant peaks is present in the average discharge rate of the auditory nerve. A measure of discriminability, d', between vowel pairs was also calculated. Second formants differing by 125-240 hz can be discriminated using the rate responses of individual fibers that are optimally placed on the basilar membrane; the estimated second formant jnd for the whole auditory nerve is approximately 1 Hz.

Dipole source localization by mottled sculpin. III. Orientation after site-specific, unilateral denervation of the lateral line system.

To test the hypothesis that spatial excitation patterns along the lateral-line system underlie source localization, we videotaped the orientation behavior of blinded mottled sculpin in response to a small dipole source (50-Hz vibrating sphere) before and after unilateral denervation of the lateral line system on different body regions (head, trunk and head + trunk). Approach pathways were qualitatively similar to those followed by normal intact animals. Abnormal behavior (turning in circles) was not observed. However, the frequency with which fish placed their intact side facing the source increased by 12-89%, depending on the denervation site. The angular accuracy of orientation decreased by 20 degrees to 60 degrees (100% to 370% change) depending on source location and region of lateral line denervated. Deficits tended to be site-specific. For example, unilaterally denervating lateral-line organs on the head resulted in less accurate orienting responses when the source was located on the denervated side of the head, but not on the opposite side of the head or on either side of the trunk. Site-specific deficits and the absence of abnormal approach pathways argue that animals are relying on a point-by-point spatial representation of source location along the sensory surface rather than computations based on bilateral comparisons.

Hydrodynamic image formation by the peripheral lateral line system of the Lake Michigan mottled sculpin, Cottus bairdi.

Lake Michigan mottled sculpin (Cottus bairdi) have a lateral-line-mediated prey-capture behaviour that consists of an initial orientation towards the prey, a sequence of approach movements, and a final strike at the prey. This unconditioned behaviour can be elicited from blinded sculpin in the laboratory by both real and artificial (vibrating sphere) prey. In order to visualize what Lake Michigan mottled sculpin might perceive through their lateral line when approaching prey, we have combined anatomical, neurophysiological, behavioural and computational modelling techniques to produce three-dimensional maps of how excitation patterns along the lateral line sensory surface change as sculpin approach a vibrating sphere. Changes in the excitation patterns and the information they contain about source location are consistent with behavioural performance, including the approach pathways taken by sculpin to the sphere, the maximum distances at which approaches can be elicited, distances from which strikes are launched, and strike success. Information content is generally higher for laterally located sources than for frontally located sources and this may explain exceptional performance (e.g. successful strikes from unusually long distances) in response to lateral sources and poor performance (e.g. unsuccessful strikes) to frontal sources.

Somatosensory effects on neurons in dorsal cochlear nucleus.

1. Single units and evoked potentials were recorded in dorsal cochlear nucleus (DCN) in response to electrical stimulation of the somatosensory dorsal column and spinal trigeminal nuclei (together called MSN for medullary somatosensory nuclei) and for tactile somatosensory stimuli. Recordings were from paralyzed decerebrate cats. 2. DCN principal cells (type IV units) were strongly inhibited by electrical stimulation (single 50-microA bipolar pulse) in MSN or by somatosensory stimulation. Units recorded in the fusiform cell and deep layers of DCN were inhibited, suggesting that the inhibition affects both types of principal cells (i.e., both fusiform and giant cells). 3. Interneurons (type II units) that inhibit principal cells were only weakly inhibited by electrical stimulation and were never excited, demonstrating that the inhibitory effect on principal cells does not pass through the type II circuit. In the vicinity of the DCN/PVCN (posteroventral cochlear nucleus) boundary, units were encountered that were excited by electrical stimulation in MSN; some of these neurons responded to sound, and some did not. Their response properties are consistent with the hypothesis that they are deep-layer inhibitory interneurons conveying somatosensory information to the DCN. 4. Analysis of the evoked potentials produced by electrical stimulation in MSN suggests that the somatosensory inputs activate the granule cell system of the DCN molecular layer. A model based on previous work by Klee and Rall was used to show that the distribution of evoked potentials in DCN can be explained as resulting from radial currents produced in the DCN molecular and fusiform-cell layers by synchronous activation of granule cells inputs to fusiform and cartwheel cells. Current-source density analysis of the evoked potentials is consistent with this model. Thus molecular layer interneurons (cartwheel and stellate cells) are a second possible source of inhibition to principal cells. 5. With lower stimulus levels (20 microA) and pulse-pair stimuli (50- to 100-ms interstimulus interval), three components of the inhibitory response can be recognized in both fusiform cell layer and deep layer type IV units: a short-latency inhibition that begins before the start of the evoked potential; a longer-latency inhibition whose timing corresponds to the evoked potential; and an excitatory component that occurs on the rising phase of the evoked potential. The excitatory component is usually overwhelmed by the inhibitory components and could be derived from granule cell inputs; the long-latency inhibitory component could be derived from cartwheel cells or the hypothesized deep-layer inhibitory interneurons.(ABSTRACT TRUNCATED AT 400 WORDS)