The HD Physiology Project is a Japanese research consortium that aimed to develop methods and a computational platform in which physiological and pathological information can be described in high-level definitions across multiple scales of time and size. During the 5 years of this project, an appropriate software platform for multilevel functional simulation was developed and a whole-heart model including pharmacokinetics for the assessment of the proarrhythmic risk of drugs was developed. In this article, we outline the description and scientific strategy of this project and present the achievements and influence on multilevel integrative systems biology and physiome research.

Early afterdepolarization (EAD) is known as a cause of ventricular arrhythmias in long QT syndromes. We theoretically investigated how the rapid ( I_Kr) and slow ( I_Ks) components of delayed-rectifier K⁺ channel currents, L-type Ca²⁺ channel current ( I_CaL), Na⁺/Ca²⁺ exchanger current ( I_NCX), Na⁺-K⁺ pump current ( I_NaK), intracellular Ca²⁺ (Ca_i) handling via sarcoplasmic reticulum (SR), and intracellular Na⁺ concentration (Na_i) contribute to initiation, termination, and modulation of phase-2 EADs, using two human ventricular myocyte models. Bifurcation structures of dynamical behaviors in model cells were explored by calculating equilibrium points, limit cycles (LCs), and bifurcation points as functions of parameters. EADs were reproduced by numerical simulations. The results are summarized as follows: 1) decreasing I_Ks and/or I_Kr or increasing I_CaL led to EAD generation, to which mid-myocardial cell models were especially susceptible; the parameter regions of EADs overlapped the regions of stable LCs. 2) Two types of EADs (termination mechanisms), I_Ks activation–dependent and I_CaL inactivation–dependent EADs, were detected; I_Ks was not necessarily required for EAD formation. 3) Inhibiting I_NCX suppressed EADs via facilitating Ca²⁺-dependent I_CaL inactivation. 4) Ca_i dynamics (SR Ca²⁺ handling) and Na_i strongly affected bifurcations and EAD generation in model cells via modulating I_CaL, I_NCX, and I_NaK. Parameter regions of EADs, often overlapping those of stable LCs, shifted depending on Ca_i and Na_i in stationary and dynamic states. 5) Bradycardia-related induction of EADs was mainly due to decreases in Na_i at lower pacing rates. This study demonstrates that bifurcation analysis allows us to understand the dynamical mechanisms of EAD formation more profoundly. NEW & NOTEWORTHY We investigated mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of human ventricular myocyte (HVM) models. EAD formation in paced HVMs basically depended on bifurcation phenomena in non-paced HVMs, but was strongly affected by intracellular ion concentrations in stationary and dynamic states. EAD generation did not necessarily require I_Ks.

Fast-spiking (FS) cells in the neocortex are interconnected both by inhibitory chemical synapses and by electrical synapses, or gap-junctions. Synchronized firing of FS neurons is important in the generation of gamma oscillations, at frequencies between 30 and 80 Hz. To understand how these synaptic interactions control synchronization, artificial synaptic conductances were injected in FS cells, and the synaptic phase-resetting function (SPRF), describing how the compound synaptic input perturbs the phase of gamma-frequency spiking as a function of the phase at which it is applied, was measured. GABAergic and gap junctional conductances made distinct contributions to the SPRF, which had a surprisingly simple piecewise linear form, with a sharp midcycle break between phase delay and advance. Analysis of the SPRF showed how the intrinsic biophysical properties of FS neurons and their interconnections allow entrainment of firing over a wide gamma frequency band, whose upper and lower frequency limits are controlled by electrical synapses and GABAergic inhibition respectively. Oscillations of the electrical field in the brain at 30–80 Hz (gamma oscillations) reflect coordinated firing of neurons during cognitive, sensory, and motor activity, and are thought to be a key phenomenon in the organization of neural processing in the cortex. Synchronous firing of a particular type of neuron, the inhibitory fast-spiking (FS) cell, imposes the gamma rhythm on other cells in the network. FS cells are highly interconnected by both gap junctions and chemical inhibition. In this study, we probed FS cells with a synthetic conductance stimulus which mimics the electrical effect of these complex connections in a controlled way, and directly measured how the timing of their firing should be affected by nearby FS neighbours. We were able to fit a mathematically simple but accurate model to these measurements, the “synaptic phase-resetting function”, which predicts how FS neurons synchronize at different frequencies, noise levels, and synaptic connection strengths. This model gives us deeper insight into how the FS cells synchronize so effectively at gamma oscillations, and will be a building-block in large-scale simulations of the FS cell network aimed at understanding the onset and stability of patterns of gamma oscillation in the cortex.