DOI: 10.25549/usctheses-c3-216127
title: A novel neuronal mechanism for temporal order discrimination

description: Natural signals often flow systematically across an array of biological sensors (e.g. the pattern of optic flow on the retina), leading to ordered stimulation of neighboring sensors within small fractions of a second. As such, the need to distinguish the temporal order in which two neighboring sensors, A and B, have been stimulated is often critical for interpreting the stimulus (e.g. detecting whether motion of an object is toward or away from the animal). A variety of neural mechanisms have been proposed for this task, nearly all involving (1) some form of temporal asymmetry between the A and B input pathways, and (2) a nonlinearity that detects or rejects temporal coincidence (Jeffress 1948; Rall 1964; Borg-Gram and Gryzwacz, 1992; Hassenstein and Reichardt 1956, Borst and Egelhaaf 1989). ❧ In this work we explore a novel biophysical mechanism for temporal order-sensitivity (TOS) based on the distinct properties of AMPA and NMDA conductances in glutamatergic synapses. This mechanism establishes a preference for the stimulus sequence A→B compared to B→A when the A pathway is dominated by a slow NMDA conductance while the B pathway is dominated by a fast AMPA conductance. Using a mathematical approach we identify several key properties of this TOS mechanism: (1) we show why the typical sigmoidal input-output curve due to NMDA channel activation allows the summation nonlinearity and temporal asymmetry between the A and B pathways to be simultaneously maximized; (2) we show that there are two thresholds for NMDA spike activation: A threshold amount of NMDA conductance must be activated, and a threshold membrane voltage must be reached in order to trigger an NMDA spike; (3) we give theoretical expressions for the start and end of the superlinear TOS summation window in time, and show why this window is surprisingly short compared to the typical time course of NMDA channel activation; (4) we show that this TOS mechanism depends on the fast temporal responses of AMPA channels activated in dendrites, and would not work in a lumped cell model; (5) we predict that interactions between AMPA, NMDA, and voltage-dependent Na+ channels in the membrane should increase the robustness of TOS responses; (6) we predict the best absolute and relative dendritic locations for two synaptic pathways to achieve temporal order selectivity; and (7) we predict that feed-forward GABAA-mediated inhibition narrows the time window for superlinear summation without significantly weakening the response nonlinearity. Using compartmental simulations, we verified these effects and predictions by identifying conditions that produce “strong” TOS responses, defined as responses that are (1) superlinear to the preferred ordering A→B, i.e. significantly larger than the sum of the individual responses to A and B; (2) temporally asymmetric, i.e. not responding superlinearly to the non-preferred ordering B→A; and (3) robust, i.e. insensitive to small perturbations in the AMPA and NMDA conductances. Our results give a theoretical basis for understanding temporal order-sensitive summation between two pathways when the priming or “modulatory” pathway (activated first) is dominated by NMDA channels, the trigger or “driver” pathway (activated second) has a strong AMPA component, feed-forward inhibition quickly follows the driver input, the two synaptic pathways are physically commingled on the dendrites relatively close to the soma, and the dendritic membrane contains voltage-dependent Na+ channels. ❧ We explored a possible functional application of this TOS scheme in a model of the retinogeniculate projection onto LGN relay cells, that could allow relay cells to respond more quickly, powerfully, and reliably to visual features that move in and out of their receptive fields within a few milliseconds.