StdpC: a modern dynamic clamp

With the advancement of computer technology many novel uses of dynamic clamp have become possible. We have added new features to our dynamic clamp software StdpC (“Spike timing-dependent plasticity Clamp”) allowing such new applications while conserving the ease of use and installation of the popular earlier Dynclamp 2/4 package. Here, we introduce the new features of a waveform generator, freely programmable Hodgkin–Huxley conductances, learning synapses, graphic data displays, and a powerful scripting mechanism and discuss examples of experiments using these features. In the first example we built and ‘voltage clamped’ a conductance based model cell from a passive resistor–capacitor (RC) circuit using the dynamic clamp software to generate the voltage-dependent currents. In the second example we coupled our new spike generator through a burst detection/burst generation mechanism in a phase-dependent way to a neuron in a central pattern generator and dissected the subtle interaction between neurons, which seems to implement an information transfer through intraburst spike patterns. In the third example, making use of the new plasticity mechanism for simulated synapses, we analyzed the effect of spike timing-dependent plasticity (STDP) on synchronization revealing considerable enhancement of the entrainment of a post-synaptic neuron by a periodic spike train. These examples illustrate that with modern dynamic clamp software like StdpC, the dynamic clamp has developed beyond the mere introduction of artificial synapses or ionic conductances into neurons to a universal research tool, which might well become a standard instrument of modern electrophysiology

A biophysical model explains the spontaneous bursting behavior in the developing retina

During early development, waves of activity propagate across the retina and play a key role in the proper wiring of the early visual system. During the stage II these waves are triggered by a transient network of neurons, called Starburst Amacrine Cells (SACs), showing a bursting activity which disappears upon further maturation. While several models have attempted to reproduce retinal waves, none of them is able to mimic the rhythmic autonomous bursting of individual SACs and reveal how these cells change their intrinsic properties during development. Here, we introduce a mathematical model, grounded on biophysics, which enables us to reproduce the bursting activity of SACs and to propose a plausible, generic and robust, mechanism that generates it. The core parameters controlling repetitive firing are fast depolarizing $V$-gated calcium channels and hyperpolarizing $V$-gated potassium channels. The quiescent phase of bursting is controlled by a slow after hyperpolarization (sAHP), mediated by calcium-dependent potassium channels. Based on a bifurcation analysis we show how biophysical parameters, regulating calcium and potassium activity, control the spontaneously occurring fast oscillatory activity followed by long refractory periods in individual SACs. We make a testable experimental prediction on the role of voltage-dependent potassium channels on the excitability properties of SACs and on the evolution of this excitability along development. We also propose an explanation on how SACs can exhibit a large variability in their bursting periods, as observed experimentally within a SACs network as well as across different species, yet based on a simple, unique, mechanism. As we discuss, these observations at the cellular level have a deep impact on the retinal waves description.Comment: 25 pages, 13 figures, submitte

Neural Dynamics Underlying Impaired Autonomic and Conditioned Responses Following Amygdala and Orbitofrontal Lesions

A neural model is presented that explains how outcome-specific learning modulates affect, decision-making and Pavlovian conditioned approach responses. The model addresses how brain regions responsible for affective learning and habit learning interact, and answers a central question: What are the relative contributions of the amygdala and orbitofrontal cortex to emotion and behavior? In the model, the amygdala calculates outcome value while the orbitofrontal cortex influences attention and conditioned responding by assigning value information to stimuli. Model simulations replicate autonomic, electrophysiological, and behavioral data associated with three tasks commonly used to assay these phenomena: Food consumption, Pavlovian conditioning, and visual discrimination. Interactions of the basal ganglia and amygdala with sensory and orbitofrontal cortices enable the model to replicate the complex pattern of spared and impaired behavioral and emotional capacities seen following lesions of the amygdala and orbitofrontal cortex.National Science Foundation (SBE-0354378; IIS-97-20333); Office of Naval Research (N00014-01-1-0624); Defense Advanced Research Projects Agency and the Office of Naval Research (N00014-95-1-0409); National Institutes of Health (R29-DC02952

Dynamics from seconds to hours in Hodgkin-Huxley model with time-dependent ion concentrations and buffer reservoirs

The classical Hodgkin--Huxley (HH) model neglects the time-dependence of ion concentrations in spiking dynamics. The dynamics is therefore limited to a time scale of milliseconds, which is determined by the membrane capacitance multiplied by the resistance of the ion channels, and by the gating time constants. We study slow dynamics in an extended HH framework that includes time-dependent ion concentrations, pumps, and buffers. Fluxes across the neuronal membrane change intra- and extracellular ion concentrations, whereby the latter can also change through contact to reservoirs in the surroundings. Ion gain and loss of the system is identified as a bifurcation parameter whose essential importance was not realized in earlier studies. Our systematic study of the bifurcation structure and thus the phase space structure helps to understand activation and inhibition of a new excitability in ion homeostasis which emerges in such extended models. Also modulatory mechanisms that regulate the spiking rate can be explained by bifurcations. The dynamics on three distinct slow times scales is determined by the cell volume-to-surface-area ratio and the membrane permeability (seconds), the buffer time constants (tens of seconds), and the slower backward buffering (minutes to hours). The modulatory dynamics and the newly emerging excitable dynamics corresponds to pathological conditions observed in epileptiform burst activity, and spreading depression in migraine aura and stroke, respectively.Comment: 18 pages, 11 figure

Phasic Firing in Vasopressin Cells: Understanding Its Functional Significance through Computational Models

Vasopressin neurons, responding to input generated by osmotic pressure, use an intrinsic mechanism to shift from slow irregular firing to a distinct phasic pattern, consisting of long bursts and silences lasting tens of seconds. With increased input, bursts lengthen, eventually shifting to continuous firing. The phasic activity remains asynchronous across the cells and is not reflected in the population output signal. Here we have used a computational vasopressin neuron model to investigate the functional significance of the phasic firing pattern. We generated a concise model of the synaptic input driven spike firing mechanism that gives a close quantitative match to vasopressin neuron spike activity recorded in vivo, tested against endogenous activity and experimental interventions. The integrate-and-fire based model provides a simple physiological explanation of the phasic firing mechanism involving an activity-dependent slow depolarising afterpotential (DAP) generated by a calcium-inactivated potassium leak current. This is modulated by the slower, opposing, action of activity-dependent dendritic dynorphin release, which inactivates the DAP, the opposing effects generating successive periods of bursting and silence. Model cells are not spontaneously active, but fire when perturbed by random perturbations mimicking synaptic input. We constructed one population of such phasic neurons, and another population of similar cells but which lacked the ability to fire phasically. We then studied how these two populations differed in the way that they encoded changes in afferent inputs. By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input. Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response. These findings show large differences in information coding between the populations, and apparent functional advantages of asynchronous phasic firing

Locomotor Network Dynamics Governed By Feedback Control In Crayfish Posture And Walking

Sensorimotor circuits integrate biomechanical feedback with ongoing motor activity to produce behaviors that adapt to unpredictable environments. Reflexes are critical in modulating motor output by facilitating rapid responses. During posture, resistance reflexes generate negative feedback that opposes perturbations to stabilize a body. During walking, assistance reflexes produce positive feedback that facilitates fast transitions between swing and stance of each step cycle. Until recently, sensorimotor networks have been studied using biomechanical feedback based on external perturbations in the presence or absence of intrinsic motor activity. Experiments in which biomechanical feedback driven by intrinsic motor activity is studied in the absence of perturbation have been limited. Thus, it is unclear whether feedback plays a role in facilitating transitions between behavioral states or mediating different features of network activity independent of perturbation. These properties are important to understand because they can elucidate how a circuit coordinates with other neural networks or contributes to adaptable motor output. Computational simulations and mathematical models have been used extensively to characterize interactions of negative and positive feedback with nonlinear oscillators. For example, neuronal action potentials are generated by positive and negative feedback of ionic currents via a membrane potential. While simulations enable manipulation of system parameters that are inaccessible through biological experiments, mathematical models ascertain mechanisms that help to generate biological hypotheses and can be translated across different systems. Here, a three-tiered approach was employed to determine the role of sensory feedback in a crayfish locomotor circuit involved in posture and walking. In vitro experiments using a brain-machine interface illustrated that unperturbed motor output of the circuit was changed by closing the sensory feedback loop. Then, neuromechanical simulations of the in vitro experiments reproduced a similar range of network activity and showed that the balance of sensory feedback determined how the network behaved. Finally, a reduced mathematical model was designed to generate waveforms that emulated simulation results and demonstrated how sensory feedback can control the output of a sensorimotor circuit. Together, these results showed how the strengths of different approaches can complement each other to facilitate an understanding of the mechanisms that mediate sensorimotor integration

Pattern generating role for motoneurons in a rythmically active neuronal network

The role of motoneurons in central motor pattern generation was investigated in the feeding system of the pond snail Lymnaea stagnalis, an important invertebrate model of behavioral rhythm generation. The neuronal network responsible for the three-phase feeding motor program (fictive feeding) has been characterized extensively and divided into populations of central pattern generator (CPG) interneurons, modulatory interneurons, and motoneurons. A previous model of the feeding system considered that the motoneurons were passive followers of CPG interneuronal activity. Here we present new, detailed physiological evidence that motoneurons that innervate the musculature of the feeding apparatus have significant electrotonic motoneuron¿interneuron connections, mainly confined to cells active in the same phase of the feeding cycle (protraction, rasp, or swallow). This suggested that the motoneurons participate in rhythm generation. This was assessed by manipulating firing activity in the motoneurons during maintained fictive feeding rhythms. Experiments showed that motoneurons contribute to the maintenance and phase setting of the feeding rhythm and provide an efficient system for phase-locking muscle activity with central neural activity. These data indicate that the distinction between motoneurons and interneurons in a complex CNS network like that involved in snail feeding is no longer justified and that both cell types are important in motor pattern generation. This is a distributed type of organization likely to be a general characteristic of CNS circuitries that produce rhythmic motor behavior