Dendritic Excitability and Gain Control in Recurrent Cortical Microcircuits

Abstract

Layer 5 thick tufted pyramidal cells (TTCs) in the neocortex are particularly electrically complex, owing to their highly excitable dendrites. The interplay between dendritic nonlinearities and recurrent cortical microcircuit activity in shaping network response is largely unknown. We simulated detailed conductance-based models of TTCs forming recurrent microcircuits that were interconnected as found experimentally; the network was embedded in a realistic background synaptic activity. TTCs microcircuits significantly amplified brief thalamocortical inputs; this cortical gain was mediated by back-propagation activated N-methyl-D-aspartate depolarizations and dendritic back-propagation-activated Ca(2+) spike firing, ignited by the coincidence of thalamic-activated somatic spike and local dendritic synaptic inputs, originating from the cortical microcircuit. Surprisingly, dendritic nonlinearities in TTCs microcircuits linearly multiplied thalamic inputs--amplifying them while maintaining input selectivity. Our findings indicate that dendritic nonlinearities are pivotal in controlling the gain and the computational functions of TTCs microcircuits, which serve as a dominant output source for the neocortex.

Keywords: active dendrites; cortical microcircuit; multiscale modeling; network simulation.

Figure 1.

Simulated TTCs microcircuits. (A) An exemplar microcircuit of 50 cells. Connection probabilities between cells were 0.13 for unidirectional connections (black edges), and 0.06 for reciprocal connections (red edges). Reciprocal excitatory synaptic connections were 1.5 times stronger than unidirectional connections. (B) An example of a modeled TTC, with its detailed morphology, receiving a background Poisson input from 10 000 excitatory synapses (red) and 2500 inhibitory (blue) synapses (see Materials and Methods). On top of this background input, all cells in the microcircuit were simultaneously stimulated by a brief somatic current input of 1.4 nA and 5 ms duration (black electrode), mimicking a brief perisomatic thalamic input. In addition to firing somatic Na⁺ APs, the TTC model was capable of generating dendritic Ca²⁺ spikes at the apical “hot zone” (shaded red ellipse). (C) Spontaneous firing of an exemplar single (isolated) TTC in response to the background synaptic input. (D) Voltage traces of another example cell, from a microcircuit of 150 cells, firing spontaneously (2 spikes, left) and in response to simultaneous somatic input to all network cells (4 spikes, right). Stimulus is indicated by black bar below the voltage trace.

Figure 2.

Modulation of response rate by recurrent activity and dendritic excitability. (A) An example raster plot (top) and PSTH (bottom) of the firing of single (unconnected) cells in response to brief suprathreshold somatic/thalamic input at t = 0 (stimulus as in Fig. 1B). (B) Example raster plot (top) and PSTH (bottom) for the response to somatic input in microcircuits of N = 150 cells, all receiving brief suprathreshold somatic input at t = 0. (C) Same as in (B), except that apical dendritic Na⁺ channels in modeled cells were removed (denoted: −a.Na). (D) Response rate of cells in microcircuits of size N = 1–150 cells, in control condition as in (B) (black curve) and when removing particular apical dendritic channels (high-voltage-gated Ca²⁺ channels, green curve; both high- and low-voltage-gated Ca²⁺ channels, red curve; Na⁺ channels, purple curve) or NMDA receptors on both basal and apical dendrites (blue curve). The instantaneous rate was measured in a time window of 50 ms following stimulus onset.

Figure 3.

Microcircuit response involves strong dendritic nonlinearities. (A) Voltage traces at the soma (black) and at the apical main bifurcation (650 μm from the soma, red, see scheme in Fig. 1B) of an exemplar cell. The cell was part of a microcircuit of size N = 150 cells, receiving a brief suprathreshold somatic input to all circuit cells in control conditions. Somatic stimulus at t = 0 is indicated by black bar below the trace. The area under the dendritic voltage response, for t = 0–50 ms, is shaded in red. (B–D) Same as (A), but for the cases when the dendritic Ca²⁺ channels were removed (B), or also NMDA receptors were removed (C), or only dendritic Na⁺ channels were removed (D). (E) Distribution of the integral of the membrane depolarization at the apical main bifurcation over the 50 ms time window in all cells from microcircuits of 150 cells from 4 different randomized simulations (n = 600 cells for each curve, see Materials and Methods), receiving simultaneous somatic input, under control conditions (solid black curve), when dendritic Ca²⁺ channels were removed (red curve), when also NMDA channels were removed (blue curve), or when only dendritic Na⁺ channels were removed (purple curve). The distribution for unconnected cells under control conditions is shown by the dashed black curve (n = 400 cells). The bimodal distribution for the solid black curve indicates nonlinear dendritic events.

Figure 4.

Modulation of network response by recurrent activity and dendritic excitability is robust to temporal noise in the thalamic input. (A) Raster plot (top) and PSTH (bottom) for microcircuits of 150 cells, receiving brief suprathreshold somatic input, with a random jitter of 0–10 ms in the onset of the somatic stimulus. (B) Response of cells in microcircuits of size N = 1–150 receiving somatic input with 0–10 ms jitter, in control conditions (black curve) and when dendritic Ca²⁺ or Na⁺ channels were removed (red and purple curves). (C) Distribution of voltage integral at the main apical bifurcation in all cells from microcircuits of 150 cells (n = 600), receiving jittered somatic input, under control conditions (solid black curve) and when dendritic Ca²⁺ or Na⁺ channels were removed (red and purple curves). The distribution of dendritic integral for unconnected cells is given by the dashed black curve (n = 400).

Figure 5.

Microcircuit response to a partial thalamic input. (A) Example raster plot (top) and PSTH (bottom) for the response to somatic/thalamic input given to 60% of the cells in microcircuits consisting of 150 cells. (B) The response rate in microcircuits of 150 cells as a function of the percent of cells stimulated, in control conditions (black curve) and when dendritic Ca²⁺ or Na⁺ channels were removed (red and purple curves).

Figure 6.

Dendritic excitability and recurrent activity amplify response to thalamic input while maintaining selectivity. (A) The average response in microcircuits of 150 cells (solid curves) or in unconnected cells (dashed black curve) to different somatic pulse amplitudes, reflecting different stimulus orientations (see Materials and Methods). Control conditions are depicted by the black curves whereas color curves are for the cases when dendritic Ca²⁺ or Na⁺ channels, or also NMDA receptors were removed. (B) Normalized response curves taken from (A). (C) The probability of large dendritic depolarizations in microcircuits of 150 cells increased with stimulus orientation towards the preferred orientation (90°). Large dendritic depolarization was defined to be the case when the dendritic voltage integral at the main apical bifurcation was >800 mV ms. (D) The predicted response rate in microcircuits of 150 cells based on the probability of obtaining large dendritic depolarization, as a function of orientation (given in C) is shown by the green line. Purple and black curves are as in (A).