Neuronal phase shifts differ for excitation vs. inhibition: a computer modeling study

Abstract

Rhythmic activity is ubiquitous in neural systems, and impedance analysis has been widely used to examine frequency-dependent responses of neuronal membranes to rhythmic inputs. Impedance analysis assumes the neuronal membrane is a linear system, requiring the use of small signals to stay in a near-linear regime. However, postsynaptic potentials are often large and trigger nonlinear mechanisms. We therefore augmented impedance analysis to evaluate membrane responses in this nonlinear domain, analyzing responses to injected current for subthreshold membrane voltage (Vmemb), suprathreshold spike-blocked Vmemb, and spiking in a validated neocortical pyramidal neuron computer model. Responses in these output regimes were asymmetrical, with different phase shifts during hyperpolarizing and depolarizing half-cycles. Suprathreshold chirp stimulation gave equivocal results due to nonstationarity of response, requiring us to use fixed-frequency sinusoids. Sinusoidal inputs produced phase retreat: action potentials occurred progressively later in cycles of the input stimulus, resulting from adaptation. Conversely, sinusoidal current with increasing amplitude over cycles produced a pattern of phase advance: action potentials occurred progressively earlier. Phase retreat was dependent on Ih and IAHP currents; phase advance was modulated by these currents. Our results suggest differential responses of cortical neurons depending on the frequency of oscillatory input in the delta - beta range, which will play a role in neuronal responses to shifts in network state. We hypothesize that intrinsic cellular properties complement network properties and contribute to in vivo phase-shift phenomena such as phase precession, seen in place and grid cells, and phase roll, observed in hippocampal CA1 neurons. New & NoteworthyWe augmented electrical impedance analysis to characterize phase shifts between large amplitude current stimuli and nonlinear, asymmetric membrane potential responses. We predict different frequency-dependent phase shifts in response excitation versus inhibition, as well as shifts in spike timing over multiple input cycles, in resonant pyramidal neurons. We hypothesize that these effects contribute to navigation-related phenomena like phase precession and phase roll. Our neuron-level hypothesis complements, rather than falsifies, prior network-level explanations of these phenomena.