High-resolution volumetric imaging constrains compartmental models to explore synaptic integration and temporal processing by cochlear nucleus globular bushy cells

Abstract

Bushy neurons of the cochlear nucleus encode temporal fine structure and modulation of sound with high fidelity. However, the synaptic maps and electrotonic structures that underlie these properties are not specified in meaningful explanatory detail. We employed modern volume electron microscopy techniques to provide exact data on the numbers of synaptic inputs and their weights determined by the number of contained active zones, and the surface areas of all postsynaptic cellular compartments. Leveraging these high-resolution images, we discovered cabling of dendrite branches and new structures within dendrites, and identified non-innervated dendrites. We extend current nanoscale connectomic studies with methods to export cellular reconstructions into morphologically-constrained, biophysically-based predictive computational models. We reveal both coincidence detection and mixed supra/subthreshold modes of input convergence across the bushy cell population and show subthreshold inputs contribute to enhanced temporal encoding even in the presence of suprathreshold inputs. We demonstrate the variation of dendritic load and axon parameters and their importance in controlling excitability as potential homeostatic mechanisms, thereby defining heterogeneity in stimulus-evoked responses across the BC population.

Dendritic degeneration and altered synaptic innervation of a central auditory neuron during age-related hearing loss

“…Bushy neurons are known for their unique bush-like cellular morphology (Brawer et al, 1974; Cant and Morest, 1979; Tolbert et al, 1982; Rouiller and Ryugo, 1984). Despite decades of research, studies that characterize both bushy cell morphology and the comprehensive innervation pattern of connecting AN synapses are rare (Spirou et al, 2022), especially regarding to AN synapses on dendrites, the subtype-specificity of AN synapses, and changes of these features during ARHL. Combining electrophysiology and immunohistochemistry, we developed the technique to investigate both the physiology and morphology of individual bushy neurons and their AN synapses in young and aged mice (Wang et al, 2021; Zhang et al, 2022).…”

“…Dendrites are generally viewed as the main site of a neuron to receive incoming synaptic inputs, which is unlikely the case in bushy neurons. Gomez-Nieto and Rubio (2009, 2011) and Spirou et al (2022) reported that bushy neurons receive small AN synapses on the dendrites, which presumably help transmit sound information from the cochlea. Our measurement showed that the total volume of dendritic synapses is only 26% of the somatic synapses on average in bushy neurons from normal hearing young mice (Fig.…”

“…These dendritic synapses are probably not a major source of excitatory drive to elicit spikes in bushy neurons, especially after considering the fact that dendritic signals are substantially attenuated due to the cable property of the dendrites (White et al, 1994; Sumner et al, 2009; Koert and Kuenzel, 2021). Besides the excitatory AN synapses, inhibitory synapses were also found on the dendrites (Gomez-Nieto and Rubio, 2009, 2011; Spirou et al, 2022), which help provide modulatory inhibition to regulate discharge rate and temporal precision of bushy neurons (Caspary et al, 1994; Kopp-Scheinpflug et al, 2002; Gai and Carney, 2008; Xie and Manis, 2013; Kuenzel et al, 2015). However, the low synaptic density on dendrites (Fig.…”

“…However, the low synaptic density on dendrites (Fig. 1, 5A) (Gomez-Nieto and Rubio, 2011) and complete lack of any synapse on some branches (Spirou et al, 2022) suggest that bushy cell dendrites also contribute to other functions.…”

“…Such process increases the overall leakiness of the neuron and contributes to their unique biophysical properties. Indeed, computer model simulation showed that without altering synaptic inputs, reducing surface area by pruning dendrites is sufficient to increase membrane input resistance and time constant, and lead to enhanced neuronal excitability and reduced temporal precision (Spirou et al, 2022). Our previous study showed that bushy neurons from aged mice exhibit increased excitability and compromised temporal precision (Xie, 2016).…”