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This research involves several different collaborations within the Branch and with other research groups, both at the NIH and elsewhere. This report describes recent work in the areas of cellular and network neurobiology, oscillatory activity of secretory cells, microcirculation, and renal physiology. During the past year, international collaborative projects have involved foreign investigators at Hebrew University, Jerusalem (Department of Neurobiology), and at the University of Alicante, Alicante, Spain.
Invited presentations were given at distinguished symosia by A Sherman (Pancreatic Islet Study Group of the European Association for the Study of Diabetes, Alicante, Spain), J Rinzel (International Hebb Symposium, Toronto; International Neural Network Society Satellite Symposium to Annual Meeting, Society for Neuroscience, Washington DC), Y-X Li (Gordon Research Conference on Theoretical Biology and Biomathematics, Tilton NH; Workshop on Calcium Waves and Dynamics, Marconi Center CA), D Golomb (Neural Networks for Physicists, Minneapolis MN). Wilfrid Rall's development of the theoretical framework of dendritic function was honored by the dedication to Rall of the inaugural issue, Journal of Computational Neuroscience, and by the publication by MIT Press of several selected Rall papers with commentaries (eds., I Segev, J Rinzel, G M Shepherd).
MRB staff were involved with organizing various symposia and meetings. A Sherman was program co-chair of the 1994 Gordon Conference on Theoretical Biology and Biomathematics. R Mejia organized a session on Mathematical Physiology at the First World Congress on Computational Medicine, Public Health and Biotechnology, Austin, TX, April, 1994. J Rinzel served on the program committee for the Computation and Neural Systems meetings: CNS*93, Washington DC; CNS*94, Monterey CA. MRB staff were involved also with teaching activities. J Rinzel and A Sherman were invited to teach in the course, Methods in Computational Neuroscience, Woods Hole, MA. M Rush and P Pinsky received their Ph D degrees (Univ Maryland, College Park, Applied Mathematics) for thesis research carried out at the NIH and directed by J Rinzel.
During FY 94, two senior staff retired: Drs. Josˇ Gonzalez-Fernandez and Wilfrid Rall, after 32 and 37 years in MRB, respectively. Also of significance, the Branch has relocated to the BSA Bldg (corner of Cedar Ln and Wisconsin Ave) after many years in Bldg 31. Design and organization of the new space were carried out by the team of Rall, Rinzel, and Sherman.
Epileptiform activity in hippocampal networks. We continue to explore simplified models of hippocampal neurons and neural networks. Simulation studies of excitatory hippocampal networks with NMDA and AMPA synapses show that synchronized population bursting (as seen in in vitro seizure models) persists in the face of considerable cell heterogeneity. Desynchronization upon removal of AMPA was shown to depend on both the level of heterogeneity and the intrinsic dynamics of the neurons (i.e., periodic versus chaotic). We have developed various measures which quantify the level of synchrony of network solutions. We analyze and compare the analytic properties of these measures and assess their performance when applied to hippocampal networks. We have now added inhibitory cells to our hippocampal network model and are exploring various phenomena including partially synchronized bursting. (P Pinsky and J Rinzel)
Experimentally-based model of sub-threshold oscillations in the inferior olive nucleus. The inferior olivary neurons are involved in motor tasks such as coordination and learning by generating rhythmic activity at the cerebellar level. This rhythmic activity is expressed, in vitro, as a sub-threshold oscillation (STO) of the membrane potential. Indirect evidence suggests that the STOs are due to both the biophysical properties of the neurons and the electrotonic coupling between these neurons. This work has two parts. In the experimental part, the properties of the currents that participate in the generation of the STO were characterized using the voltage clamp technique in the whole cell patch clamp configuration. In the theoretical part, these data are incorporated into a network of electrically coupled neurons. Starting with a model of two neurons, we show that quiescent neurons can generate STOs when they are electrically coupled, provided that they differ in their ion channel densities. In a large network of such neurons, we show that several different mechanisms could underly STO generation as observed in the olivary nucleus. The model suggests experimental ways to distinguish between these possible mechanisms. Furthermore, the model provides important insights regarding the relations between the non-linear dynamics of the single neurons and the emergent behavior of a population of these neurons. (J Rinzel, and Y Manor, I Segev, Y Yarom: Hebrew U, Jerusalem)
The lamprey central pattern generator (CPG) for swimming. The isolated spinal cord of the lamprey can produce periodic rostral-to-caudal waves of neural activity. This activity can be characterized by measuring the times at which bursts of action potentials occur at different motor nerves along the cord. We are developing a time series model which relates the burst times on one wave to burst times on the previous wave. There are two sources of noise in the model: intrinsic noise, which can be attributed to fluctuations in the CPG's rhythm, and output noise. The model contains a matrix describing the interaction between segments. We are presently fitting the model's parameters to experimental data. (T Kiemel, A Cohen: Univ MD and N Mellon: UCLA)
Dendritic origin of bistability of motoneuron firing patterns. Under certain conditions, bistable oscillatory behavior has been observed in vertebrate motoneurons, such as cat lumbar and turtle motoneurons. The two stable oscillatory states can differ in frequency by as much as 10Hz. This bistability is present in intact animals and can be induced in reduced preparations by application of pharmacological agents such as serotonin, noradrenaline, or the potassium channel blocker TEA. When action potentials are depressed by TTX, a plateau potential that provides the cell with two stable states is observed. We hypothesize that the bistability observed in the soma of these cells is due to bistable kinetics in the dendrites. In particular, the higher frequency oscillations, or the depolarized plateau under TTX, occur because the dendrites are in a depolarized stable state. To investigate this hypothesis, we constructed an idealized model of a motoneuron that consists of two compartments. The soma is represented by one compartment containing repetitive spiking kinetics. The dendrites are lumped into the second compartment and display two stable steady solutions. The compartments are coupled electrotonically. For nonzero coupling conductance, bistable periodic solutions exist in the soma compartment. We are exploring this idealized model to determine the dependence of the existence of bistable behavior on coupling parameters and kinetics of the compartments and the necessity for spatial differentiation of soma and dendritic properties. We are also developing a more biophysically accurate motoneuron model with the aim of elucidating the specific membrane properties responsible for the bistable behavior. Our effort involves consultative interaction with various experimentalist neuroscientists: O Kiehn: Panum Inst, Copenhagen and P Schwindt: U Washington). (V Booth and J Rinzel)
NMDA-induced bursting in dopamine neurons. Burst firing of dopamine neurons in vitro is induced by the glutamate agonist N-methyl-D aspartate (NMDA). The hyperpolarization between bursts is believed due to Na extrusion by a ouabain-sensitive pump. We formulate and explore a theoretical model for this novel mechanism of burst generation. We show that interaction between the regenerative, inward NMDA-mediated current and the outward Na-pump current is sufficient to generate the slow oscillation (0.5 Hz) underlying the burst. The region of negative slope in the I-V relation of the NMDA channel in the presence of Mg is indispensable for the occurrence of this slow rhythm. We find that at least 2 spatial compartments are required: a soma where action potentials (APs) are produced and a dendrite where the slow rhythm is generated. The time scale of Na- handling in the dendrite determines the burst period. In the absence of NMDA, the model shows tonic spiking (2 Hz) which is insensitive to Na pump inhibitors. When NMDA is present, tonic spiking is replaced by repetitive bursting. Tetrodotoxin blocks the APs but leaves the slow rhythm unchanged. Na pump inhibitors tranform bursting back into tonic firing. When the soma is voltage-clamped, slow oscillations in current, which are generated in the dendritic compartment, are still present. These results are in good agreement with experimental observations. nsights obtained with our model may apply to other neuron types where bursting appears to involve NMDA channel activity (Y-X Li, R Bertram, and J Rinzel)
Electrophysiological patch-clamp protocol. We have completed work begun several years ago on voltage-clamping single beta-cells within an intact pancreatic islet. This challenging approach is motivated by the desire to circumvent problems inherent in deducing islet behavior from patch clamp measurements taken from isolated cells at lower temperatures in a less physiological milieu. Although artifactual coupling currents from unclamped neighbors of the impaled cell are introduced, our computer simulations show that this can be overcome by a standard leak-subtraction protocol: the coupling currents behave approximately linearly when the neighbors are in their silent phases. These simulations have also suggested a method for estimating coupling conductance in situ by measuring the magnitude of invading burst currents. Mears is presently applying this method experimentally. (A Sherman, and from U Houston: C Stokes and L Xu, and from LCBG, NIDDK: I Atwater, D Mears, and E Rojas)
Slow Ca++ oscillations in pancreatic beta-cells. We continue to examine slow oscillations (period 2 - 20 min) of Ca++ and insulin secretion in pancreatic beta-cells. These may supplant or coexist with faster oscillations driven by bursting electrical activity (BEA). More than one mechanism may be involved, as one group has reported that the mitochondrial fuel alpha-ketoisocaproate induces oscillations whereas others propose that such oscillations are glycolytic in origin. We have developed and explored a detailed model of oscillating glycolysis based on allosteric interactions of phosphofructokinase with substrate, product, AMP, and ATP. We have also coupled this model to models for BEA through glycolytic modulation of ATP concentration and hence of the ATP-sensitive K+ conductance. This modulates Ca++ influx and causes oscillations of Ca++ in-phase with ATP, in agreement with data of Corkey et al. Uptake and release of Ca++ from the ER are also required to give observed Ca++ time courses. (P Smolen and A Sherman)
Agonist-induced and membrane potential-generated calcium oscillations in pituitary gonadotrophs. Based on the Hodgkin-Huxley (HH)-like formalism of agonist-induced calcium oscillations, we have already developed a model for the calcium (Ca) responses in gonadotrophs when stimulated with increasing doses of hormonal signal. We further analyzed the spontaneous fluctuations in Ca resulting from the plasma membrane (PM) voltage oscillations. Based on patch-clamp experimental data for the ionic currents, we have developed a quantitative model describing the PM electrical activity and its link to the accompanying oscillations in Ca. We conclude that each Ca fluctuation is produced by the Ca-entry during a single action potential (AP). This calcium concentrates mostly within a thin shell-layer neighboring the PM. We show that, due to the influence of Ca-entry on the Ca-activated K channels, the frequency and the temporal profile of the APs are not only determined by the PM channels, but also by the spatial distribution of the intracellular Ca (Y-X Li and J Rinzel). The dynamic coupling of the agonist-induced Ca oscillations in the cytoplasm and the PM potential oscillations are also studied. We show that the PM Ca pump activity is crucial in determining the steady AP firing frequency. The model reproduces experimental observations at different levels of agonist stimulation with striking agreement. It also shows that, in agreement with experiments, the Ca-entry during each AP gives a stronger phase shift of the cytoplasmic oscillator when the content of intracellular Ca pool is reduced. (Y-X Li, J Rinzel, S Stojilkovic:ERRB/NICHD, J Keizer:UC Davis)
Concentrating mechanism. Oxytocin has been shown to increase water permeability in perfused rat terminal inner medullary collecting duct at low concentration (0.1 nM) and to inhibit at higher concentration (10 nM). We have used a multinephron model with five populations to study the composition of urine as a function of water permeability of the collecting duct. The model shows urine osmolality to be near maximal for 0.1 nM oxytocin, and total solute mass excretion to peak at basal values and decrease as the water permeability increases. The inhibitory effect on water permeability of higher concentrations of oxytocin (and vasopressin, not studied here) is associated with binding to an oxytocin receptor, to a novel vasopressin receptor, or both. (R Mejia, C-L Chou and M Knepper:NHLBI)
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