The roles of dopamine and the sodium pump in the spinal control of locomotion

Rhythmically active, locomotor networks of the spinal cord are subject to both neuromodulation and activity-dependent homeostatic regulation. I first show that the neuromodulator dopamine exerts potent inhibitory effects on the central pattern generator (CPG) circuit controlling locomotory swimming in post-embryonic Xenopus tadpoles. Dopamine, acting endogenously on spinal D2-like receptors, reduces spontaneous fictive swimming occurrence and shortens, slows and weakens swimming. The mechanism involves a TTX-resistant hyperpolarisation of rhythmically active CPG neurons, mediated by the direct opening of a K+ channel with GIRK-like pharmacology. This increases rheobase and reduces spike probability. I next explore how sodium pumps contribute to the activity-dependent regulation of the Xenopus swim circuit, and possible interactions of the pumps with modulators, temperature and ionic conductances. I characterise the pump-mediated ultra-slow afterhyperpolarisation (usAHP), and show that monensin, a sodium ionophore, enhances pump activity, converting the usAHP into a tonic hyperpolarisation; this decreases swim episode duration and cycle frequency. I also characterise a ZD7288-sensitive Ih current, which is active in excitatory dIN interneurons and contributes to spiking. Blocking Ih with ZD7288 decreases swim episode duration and destabilises swim bursts. Both Ih and the usAHP increase with temperature, which depolarises CPG neurons, decreases input resistance, and increases spike probability; this increases cycle frequency, but the enhanced usAHP shortens swimming. I also show that the usAHP is diminished by nitric oxide, but enhanced by dopaminergic signalling. Finally, I explore sodium pumps in the neonatal mouse. The sodium pump blocker ouabain increases the duration and frequency of drug- and sensory-induced locomotion, whilst monensin has opposite effects. Decreasing inter-episode interval also shortens and slows activity, a relationship abolished by ouabain, implicating sodium pumps in a feedforward motor memory mechanism. Finally, I show that the effects of ouabain on locomotion are dependent on dopamine, which enhances a TTX- and ouabain-sensitive usAHP in spinal neurons

Contributory studies to the development, validation and field use of a telemetry system to monitor ventilation and trophic activity in wild Brown Trout

This work was performed as part of a major research project into the evaluation of the ecology of lake dwelling Brown Trout, Salmo trutta L. using ultrasonic biotelemetry techniques. The supplementary research results. leading up to and after the execution of a program of experiments involving the telemetry of feeding and ventilatory rhythms are described: 1. The presence of red (slow) fibres in the adductor mandibulae muscle of Brown Trout was confirmed to be as previously described in the Rainbow Trout, Sälmo gairdneri Richardson and other salmonids. 2. By electromyographic (EMG) and pharmacological means, the red fibres in the a. mandibulae were shown to be active during ventilation and the mosaic fibres comprising the bulk of the muscle were recruited during more dynamic events such as feeding and coughing. Observations were made on the innervation of the red fibres. 3. Comparative investigations made at sea on large deep sea Squaloid and Galeoid sharks (which have a simple adductor muscle like the Trout) showed an identical functional differentiation as obtained in the Trout. 4. The presence of a migratory 'pace setter potential' was found for the first time in Fish. Its use as an indicator of feeding activity by telemetry was rejected on practical grounds. ýýY NO 5. An ultrasonic transmitter was developed to telemeter an analogue of the adductor mandibulae EMG from wild Brown Trout, using a novel electrode design. Four fish were so equipped and released into Airthrey Loch, University of Stirling and tracked for up to 24 hours (following a 24 hr allowance for post-anaesthetic recovery). Feeding and ventilatory periodicity, linear and angular movement patterns and photoperiod were intercorrelated. Angle of turn and subsequent step length were positively correlated and feeding activity was marked by a preference for dextral turning. 'Area restricted searching' and 'area avoided searching' were the probable causes of the movement patterns seen in this and previous investigations at Airthrey Loch. A depth preference and orientation of the fish to topography was demonstrated. Following analysis of the angle of turn and step length data, it was concluded that the larger transmitter package and more severe surgery materially affected the fishes' behaviour relative to data previously obtained at Airthrey Loch using smaller transmitters. 6. Due to difficulties experienced in 5 above due to an unsuspected effect on the a. mandibulae EMG detectable up to 24 hrs post-anaesthesia, a frequency analysis was made of the a. mandibulae EMG of the Brown Trout and several other species. This disclosed that the EMG from red fibres has a frequency spectrum considerably lower than that of 'standard' mammalian muscle. The progressive failure of the EMG transmitter with time was due to a combination of the anaesthetic effect and the frequency spectrum relative to certain design features. (vii, In the light of these observations, subsequent designs of the EMG transmitter were able to take this into account

On the mechanism of response latencies in auditory nerve fibers

Despite the structural differences of the middle and inner ears, the latency pattern in auditory nerve fibers to an identical sound has been found similar across numerous species. Studies have shown the similarity in remarkable species with distinct cochleae or even without a basilar membrane. This stimulus-, neuron-, and species- independent similarity of latency cannot be simply explained by the concept of cochlear traveling waves that is generally accepted as the main cause of the neural latency pattern. An original concept of Fourier pattern is defined, intended to characterize a feature of temporal processing—specifically phase encoding—that is not readily apparent in more conventional analyses. The pattern is created by marking the first amplitude maximum for each sinusoid component of the stimulus, to encode phase information. The hypothesis is that the hearing organ serves as a running analyzer whose output reflects synchronization of auditory neural activity consistent with the Fourier pattern. A combined research of experimental, correlational and meta-analysis approaches is used to test the hypothesis. Manipulations included phase encoding and stimuli to test their effects on the predicted latency pattern. Animal studies in the literature using the same stimulus were then compared to determine the degree of relationship. The results show that each marking accounts for a large percentage of a corresponding peak latency in the peristimulus-time histogram. For each of the stimuli considered, the latency predicted by the Fourier pattern is highly correlated with the observed latency in the auditory nerve fiber of representative species. The results suggest that the hearing organ analyzes not only amplitude spectrum but also phase information in Fourier analysis, to distribute the specific spikes among auditory nerve fibers and within a single unit. This phase-encoding mechanism in Fourier analysis is proposed to be the common mechanism that, in the face of species differences in peripheral auditory hardware, accounts for the considerable similarities across species in their latency-by-frequency functions, in turn assuring optimal phase encoding across species. Also, the mechanism has the potential to improve phase encoding of cochlear implants

Studies on the pharmacology of carotid body chemoreceptors

SIGLEAvailable from British Library Document Supply Centre- DSC:D66393/86 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The mode of action of some drugs and chemicals used to treat hypertension or as muscle relaxants

The thesis is divided into two parts as follows:- Part I - Studies on the effect of certain drugs upon the flux of calcium, potassium and sodium ions in skeletal muscle. Part II - Studies on the pharmacology of petaline chloride, a convulsant alkaloid from Leontice leontopetalum Linn. Part I - Studies on the effect of certain drugs upon the flux of calcium, potassium and sodium ions in skeletal muscle. In the isolated frog sartorius muscle, depolarising and contracture producing drugs including suxamethonium, decamethonium, nicotine, neostigmine and ryanodine significantly increased the uptake of calcium-47 and sodium-24 hut depressed the uptake of potassium-42, Suxamethonium, nicotine, neostigmine and ryanodine also caused an increased release of calcium-47 and potassium-42 from the sartorius muscle. Decamethonium increased the release of potassium-42. Edrophonium depressed the uptake of calcium-47 and potassium- 42 and increased the release of calcium-47. Carbachol increased the release of potassium-42, Protoveratrine A and protoveratrine B depressed the uptake of calcium-47. Non-depolarising drugs - tubocurarine and gallamine - did not cause any significant change in the uptake of calcium-47, potassium-42 or sodium-24 or in the release of calcium-47 and potassium-42. It is concluded that when depolarising or contracture producing drugs are used, calcium ions may become more mobile being dissociated from combination with a carrier or displaced from a site on the cell membrane. This may result in the breakdown of barriers which retain potassium ions within the cell and sodium ions outside. Part II - Studies on the pharmacology of petaline chloride, a convulsant alkaloid from Leontice leontopetalum Linn. The alkaloidal salt petaline chloride, obtained from the tubers of Leontice leontopetalum Linn is a potent convulsant and is apparently 5 to 7 times as potent as leptazol and one-third as active as picrotoxin. At lower dose levels it appears to reduce the convulsant activity of leptazol and apparently gives some protection from electrically induced seizures. It has tubocurarine-like muscle relaxant properties and depresses both patellar tendon and crossed extension reflexes. It causes a fall in the blood pressure in anaesthetised animals and increases the rate, force and amplitude of the beat of isolated cardiac muscle depressed in a low calcium medium. It also antagonises the effect of different spasmogens on isolated smooth muscle preparation. It is concluded that because of its powerful convulsant action the use of petaline chloride is of dubious value in the treatment of epilepsy, but its pharmacological properties which includes muscle relaxant activity give some apparent basis for its use in folk medicine

Deep Brain Stimulation (DBS) Applications

The issue is dedicated to applications of Deep Brain Stimulation and, in this issue, we would like to highlight the new developments that are taking place in the field. These include the application of new technology to existing indications, as well as ‘new’ indications. We would also like to highlight the most recent clinical evidence from international multicentre trials. The issue will include articles relating to movement disorders, pain, psychiatric indications, as well as emerging indications that are not yet accompanied by clinical evidence. We look forward to your expert contribution to this exciting issue