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Direction selectivity is computed by active dendritic integration in retinal ganglion cells

Nature Neuroscience volume 16, pages 1848–1856 (2013)Cite this article

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Abstract

Active dendritic integration is thought to enrich the computational power of central neurons. However, a direct role of active dendritic processing in the execution of defined neuronal computations in intact neural networks has not been established. Here we used multi-site electrophysiological recording techniques to demonstrate that active dendritic integration underlies the computation of direction selectivity in rabbit retinal ganglion cells. Direction-selective retinal ganglion cells fire action potentials in response to visual image movement in a preferred direction. Dendritic recordings revealed that preferred-direction moving-light stimuli led to dendritic spike generation in terminal dendrites, which were further integrated and amplified as they spread through the dendritic arbor to the axon to drive action potential output. In contrast, when light bars moved in a null direction, synaptic inhibition vetoed neuronal output by directly inhibiting terminal dendritic spike initiation. Active dendritic integration therefore underlies a physiologically engaged circuit-based computation in the retina.

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Figure 1: Dendritic spikes are evoked by visual stimuli.
Figure 2: Forward propagation of dendritic spikes.
Figure 3: Dendritic spikes amplify sensory input.
Figure 4: Properties of dendritic spikes in DSGCs.
Figure 5: Cascade of active dendritic integration compartments in DSGCs.
Figure 6: Null-direction light-evoked inhibitory synaptic control of dendritic integration.
Figure 7: Inhibitory synaptic control of terminal dendritic integration underlies direction selectivity.

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Acknowledgements

We are grateful to D. Vaney, W. Taylor, W. Levick, M. Harnett, R. Tweedale and G. Murphy for critically reading the manuscript. This work was supported by grants from the Australian Research Council (FT100100502 and DP130101630) and National Health and Medical Research Council (APP1004575) to S.R.W. and a University of Queensland Early Career Researcher Award (2012003384) to B.S.

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Authors and Affiliations

  1. Queensland Brain Institute, The University of Queensland, Brisbane, Australia

    Benjamin Sivyer & Stephen R Williams

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  1. Benjamin Sivyer
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B.S. and S.R.W. conceived the project, designed the experiments and wrote the paper. B.S. conducted the experiments.

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Correspondence to Stephen R Williams.

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Integrated supplementary information

Supplementary Figure 1 Asymmetrical distance-dependent attenuation of sub-threshold voltage responses in DSGCs.

(a) Distance-dependent increase in the local amplitude of dendritic voltage responses, but decrease in the amplitude of somatic voltage responses, when sub-threshold voltage responses were evoked by steps of negative current (–0.2 nA) delivered to the dendritic recording electrode (open symbols). The lines are exponential fits to the data. (b) Asymmetric distance-dependent attenuation of sub-threshold voltage responses, generated at dendritic (D-S) or somatic (S-D) sites (–0.2 nA). The lines are exponential fits to the data.

Supplementary Figure 2 Axo-somatic blockade of sodium channels does not disturb dendritic spike generation.

(a) Fluorescence micrograph of an ON-DSGC showing the placement of recording electrodes. Scale bar = 100 μm. (b) Local axo-somatic application of tetrodotoxin (TTX, 1 μM) attenuates somatically recorded action potentials (black traces) but not dendritic regenerative activity (red traces) evoked by a preferred-direction moving light bar. (c) In TTX, small-amplitude spikelets are recorded from the soma (black traces), but large-amplitude spikes are dendritically recorded (red trace). Section of the trace expanded from panel b. (d) Overlain spikes recorded from the soma (black) and dendrite (red) under control and following local axo-somatic TTX application. Under control, spikes were aligned at the peak of somatically recorded action potentials, and show dendritic spikes that precede the somatically recorded action potentials and back-propagating dendritically recorded action potentials evoked as the light bar sweeps across the receptive field. In TTX, spikes have been aligned at the peak of the somatically recorded spikelets, showing the generation of dendritic spikes as the light bar passes over the recorded dendritic subfield, but the absence of dendritically recorded activity as the light bar excites the contralateral dendritic subfield. In this example, the number of spiekelets generated by light-stimuli following axo-somatic TTX was 83 % of the number of action potentials generated under control, indicating that a large fraction of action potentials are driven by dendritic spikes. Using this criterion, analysis of pooled data indicated that 81 ± 12 % of somatically recorded action potentials were driven by dendritic spikes (n = 6, light responses).

Supplementary Figure 3 Dendro-somatic attenuation of small-amplitude terminal dendritic spikes.

The graph shows the amplitude distribution of isolated small-amplitude dendritic spikes recorded from parent dendritic and somatic sites. The line represents equality. The inset shows the cumulative probability distribution of the dendro-somatic voltage attenuation of small-amplitude dendritic spikes.

Supplementary Figure 4 Simulation of the dual-component rising phase of light-evoked large-amplitude dendritic spikes.

(a) Experimentally recorded light-evoked small-amplitude (terminal dendritic) spikes (upper offset traces), current-evoked parent dendritic spikes (middle traces) and the addition of these components (complex spikes). Dendritic recording was made 147 ÎĽm from the soma. (b) Time course of the positive phase of the first derivative measured at the base (5% of peak) of computed complex spikes as a function of the temporal delay between terminal and parent dendritic spikes. (c) Representative first derivative of the rising phase of complex spikes computed with 0.05 ms (red), 0.2 ms (blue) and 0.35 ms (black) temporal delay between components.

Supplementary Figure 5 Null-direction light-evoked inhibitory postsynaptic potentials are dendritically generated.

(a) Simultaneous dendritic (red trace, 245 μm from the soma) and somatic (black trace) recording of inhibitory postsynaptic potentials (IPSPs) evoked during the movement of null-direction light bars. (b) Overlain records show the large amplitude and fast kinetics of individual (thin traces) and averaged IPSPs (thick traces) at the dendritic recording site (red traces), and the attenuation and filtering of IPSPs as they spread to the soma (black traces). (c) The amplitude distribution of IPSPs at dendritic and somatic recording sites. The inset shows a cumulative probability distribution of the attenuation of dendritic IPSPs as they spread to the soma. Data have been pooled from n = 6 neurons, 427 events, dendritic recordings = 226 ± 20 μm from the soma.

Supplementary Figure 6 Dendritic spikes and action potentials are generated at high frequency in DSGCs.

(a) Somato-dendritic recording of repetitive high-frequency initiation of dendritic spikes evoked by an incremental series of positive current steps delivered to the dendritic recording electrode (245 μm from the soma). (b) Pooled current-discharge relationship generated in response to dendritic (red symbols) or somatic current (black symbols) (n = 10 cells, dendritic recordings 247 ± 12 μm from the soma). Lines represent the average frequency. (c) Cumulative probability distribution of preferred-direction light stimuli-evoked instantaneous action potential firing frequency (data pooled from n = 18 cells). (d) Axonal action potentials inactivate dendritic spike generation only at short inter-spike intervals. Representative example of the impact of axonal action potential firing evoked by short (2 ms) somatic current steps (black traces) on the initiation of dendritic spikes evoked by dendritic current steps (700 pA; 198 μm from the soma). Note that at 2 ms interval dendritic spike generation is blocked. (e) Impact of axonal action potentials evoked at decreasing time-delays on the normalized (to dendritic spike evoked in isolation) peak amplitude of dendritic activity evoked by the indicated amplitude current steps.

Supplementary Figure 7 Multi-layered active dendritic integration scheme for the computation of direction selectivity.

(a) Diagram of a proposed multi-compartmental active dendritic integration scheme, highlighting the presence of three integration areas; terminal dendrites (red), parent dendrites (blue), and axo-somatic (black). (b) Excitatory drive (bipolar cells) of terminal dendritic spike generation in DSGCs in response to light stimuli moving in the preferred-direction ignites the integration cascade. (c) Postsynaptic inhibition of terminal dendritic spike generation by starburst amacrine cells (SBACs) vetoes the integration cascade when light stimuli move in a null-direction.

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Sivyer, B., Williams, S. Direction selectivity is computed by active dendritic integration in retinal ganglion cells. Nat Neurosci 16, 1848–1856 (2013). https://doi.org/10.1038/nn.3565

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