Abstract
Inhibitory neurons in mammalian cortex exhibit diverse physiological, morphological, molecular, and connectivity signatures. While considerable work has measured the average connectivity of several interneuron classes, there remains a fundamental lack of understanding of the connectivity distribution of distinct inhibitory cell types with synaptic resolution, how it relates to properties of target cells, and how it affects function. Here, we used large-scale electron microscopy and functional imaging to address these questions for chandelier cells in layer 2/3 of the mouse visual cortex. With dense reconstructions from electron microscopy, we mapped the complete chandelier input onto 153 pyramidal neurons. We found that synapse number is highly variable across the population and is correlated with several structural features of the target neuron. This variability in the number of axo-axonic ChC synapses is higher than the variability seen in perisomatic inhibition. Biophysical simulations show that the observed pattern of axo-axonic inhibition is particularly effective in controlling excitatory output when excitation and inhibition are co-active. Finally, we measured chandelier cell activity in awake animals using a cell-type-specific calcium imaging approach and saw highly correlated activity across chandelier cells. In the same experiments, in vivo chandelier population activity correlated with pupil dilation, a proxy for arousal. Together, these results suggest that chandelier cells provide a circuit-wide signal whose strength is adjusted relative to the properties of target neurons.
Highlights
The diversity of inhibitory cell types in mammalian neocortex, each with distinctive projection patterns and physiology, implies a rich role in cortical computation (Ascoli et al, 2008; Fino et al., 2013; Freund and Buzsáki, 1996; Jiang et al, 2015; Kepecs and Fishell, 2014; Kubota, 2014)
We conclude that we established a high-throughput electron microscopy (EM) pipeline that, combined with novel image-processing computational tools, allows the ability to reconstruct entire cortical circuits at unprecedented spatial detail. 135 A complete map of synaptic input to the axon initial segments of an excitatory network We manually identified all cell bodies in the volume (n=547) and manually classified each as excitatory PyCs (n=416), inhibitory (n=34), or glia (n=97) based on morphology and ultrastructural features such as dendritic spines
We observed a remarkable diversity of total inputs, ranging 155 from 1 to 32 synapses per axon initial segment (AIS) (Figure 1F), pointing to differing magnitudes of AIS innervation across the PyC population. 158 PyC AIS input is a mix of Chandelier and non-Chandelier synapses While Chandelier cell (ChC) are the only cell type to target the AIS, other cell types can form synapses on the AIS (Gonchar et al, 2002; Gour et al, 2021; Kisvárday et al, 1985; Somogyi, 1977)
Summary
The diversity of inhibitory cell types in mammalian neocortex, each with distinctive projection patterns and physiology, implies a rich role in cortical computation (Ascoli et al, 2008; Fino et al., 2013; Freund and Buzsáki, 1996; Jiang et al, 2015; Kepecs and Fishell, 2014; Kubota, 2014). PyC populations in different brain regions and layers are contacted by diverse numbers of AIS-targeting boutons (DeFelipe et al, 1985; Veres et al, 2014; Wang and Sun, 2012) Consistent with this observation, activation of the ChC population in vivo has diverse effects on nearby PyCs, ranging from strong inhibition to a lack of response (Lu et al, 2017) despite apparently dense ChC connectivity (Inan et al, 2013). We use a novel genetic approach to selectively measure ChC activity in the visual cortex of awake behaving mice being presented with visual stimuli
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