Biology subjects

Silversmith, W. M.

Publications and source records attributed to Silversmith, W. M..

8 recordsLinked to original sources

bioRxiv2025

Connectomic reconstruction from hippocampal CA3 reveals spatially graded mossy fiber inputs and selective feedforward inhibition to pyramidal cells

The mossy fiber (MF) connections to pyramidal cells in hippocampal CA3 are hypothesized to participate in pattern separation and memory encoding, yet no large-scale neuronal wiring diagram exists for these connections. We assembled a 3D electron microscopy volume ([~]1x1x0.1mm3) from mouse hippocampal CA3. By proofreading and automated segmentation, we reconstructed and classified all soma-containing neurons--including 1,815 pyramidal cells and 229 inhibitory cells--and over 55,000 MFs. Pyramidal cells receive more numerous MF inputs along a proximodistal gradient. Some distal cells show surprisingly high convergence via relatively small terminals with fewer vesicles. Pyramidal cells share significantly more MF inputs than networks randomized by degree-preserving swap, and are better approximated by networks randomized by proximity-preserving swap. We identify a feedforward inhibitory circuit from MFs via perisomatic interneurons that selectively target a pyramidal subtype. We demonstrated large-scale mapping across levels in the hippocampus--from circuits to cell types to vesicles. The dataset is shared through Pyr, an online platform for hippocampal connectomics.

neuroscience↗

bioRxiv2022

Fast imaging of millimeter-scale areas with beam deflection transmission electron microscopy

Serial section transmission electron microscopy (TEM) has proven to be one of the leading methods for millimeter-scale 3D imaging of brain tissues at nanoscale resolution. It is important to further improve imaging efficiency to acquire larger and more brain volumes. We report here a three fold increase in the speed of TEM by using a beam deflecting mechanism to enable highly efficient acquisition of multiple image tiles (nine) for each motion of the mechanical stage. For millimeter-scale areas, the duty cycle of imaging doubles to more than 30%, yielding a net average imaging rate of 0.3 gigapixels per second. If fully utilized, an array of beam deflection TEMs should be capable of imaging a dataset of cubic millimeter scale in several weeks.

neuroscience↗

bioRxiv2022

Special Nuclear Layer Contacts Among Starburst Amacrine Cells in the Mouse Retina

We observed novel classes of cell-cell contacts between retinal starburst amacrine neurons, from finely detailed morphological reconstructions of cells from an electron microscopic image volume of a mouse retina. These contacts have peculiar morphological patterns and traits, different among the respective On and Off starburst amacrine subpopulations, but both occur within the soma layers as opposed to their regular laminae of contact within the inner plexiform layer.

neuroscience↗

bioRxiv2021

Oligodendrocyte precursor cells prune axons in the mouse neocortex

Neurons in the developing brain undergo extensive structural refinement as nascent circuits adopt their mature form1. This transformation is facilitated by the engulfment and degradation of excess axonal branches and inappropriate synapses by surrounding glial cells, including microglia and astrocytes2,3. However, the small size of phagocytic organelles and the complex, highly ramified morphology of glia has made it difficult to determine the contribution of these and other glial cell types to this process. Here, we used large scale, serial electron microscopy (ssEM) with computational volume segmentation to reconstruct the complete 3D morphologies of distinct glial types in the mouse visual cortex. Unexpectedly, we discovered that the fine processes of oligodendrocyte precursor cells (OPCs), a population of abundant, highly dynamic glial progenitors4, frequently surrounded terminal axon branches and included numerous phagolysosomes (PLs) containing fragments of axons and presynaptic terminals. Single- nucleus RNA sequencing indicated that cortical OPCs express key phagocytic genes, as well as neuronal transcripts, consistent with active axonal engulfment. PLs were ten times more abundant in OPCs than in microglia in P36 mice, and declined with age and lineage progression, suggesting that OPCs contribute very substantially to refinement of neuronal circuits during later phases of cortical development.

neuroscience↗

bioRxiv2020

Modularity and neural coding from a brainstem synaptic wiring diagram

How much can connectomes with synaptic resolution help us understand brain function? An optimistic view is that a connectome is a major determinant of brain function and a key substrate for simulating a brain. Here we investigate the explanatory power of connectomics using a wiring diagram reconstructed from a larval zebrafish brainstem. We identify modules of strongly connected neurons that turn out to be specialized for different behavioral functions, the control of eye and body movements. We then build a neural network model using a synaptic weight matrix based on the reconstructed wiring diagram. This leads to predictions that statistically match the neural coding of eye position as observed by calcium imaging. Our work shows the promise of connectome-based brain modeling to yield experimentally testable predictions of neural activity and behavior, as well as mechanistic explanations of low-dimensional neural dynamics, a widely observed phenomenon in nervous systems.

neuroscience↗

bioRxiv2020

Multiscale and multimodal reconstruction of cortical structure and function

We present a semi-automated reconstruction of L2/3 mouse primary visual cortex from 3 million cubic microns of electron microscopic images, including pyramidal and inhibitory neurons, astrocytes, microglia, oligodendrocytes and precursors, pericytes, vasculature, mitochondria, and synapses. Visual responses of a subset of pyramidal cells are included. The data are being made publicly available, along with tools for programmatic and 3D interactive access. The density of synaptic inputs onto inhibitory neurons varies across cell classes and compartments. We uncover a compartment-specific correlation between mitochondrial coverage and synapse density. Frequencies of connectivity motifs in the graph of pyramidal cells are predicted quite accurately from node degrees using the configuration model of random graphs. Cells receiving more connections from nearby cells exhibit stronger and more reliable visual responses. These example findings illustrate the resources utility for relating structure and function of cortical circuits as well as for neuronal cell biology.

neuroscience↗

bioRxiv2019

Binary and analog variation of synapses between cortical pyramidal neurons

Learning from experience depends at least in part on changes in neuronal connections. We present the largest map of connectivity to date between cortical neurons of a defined type (L2/3 pyramidal cells), which was enabled by automated analysis of serial section electron microscopy images with improved handling of image defects. We used the map to identify constraints on the learning algorithms employed by the cortex. Previous cortical studies modeled a continuum of synapse sizes (Arellano et al. 2007) by a log-normal distribution (Loewenstein, Kuras, and Rumpel 2011; de Vivo et al. 2017; Santuy et al. 2018). A continuum is consistent with most neural network models of learning, in which synaptic strength is a continuously graded analog variable. Here we show that synapse size, when restricted to synapses between L2/3 pyramidal cells, is well-modeled by the sum of a binary variable and an analog variable drawn from a log-normal distribution. Two synapses sharing the same presynaptic and postsynaptic cells are known to be correlated in size (Sorra and Harris 1993; Koester and Johnston 2005; Bartol et al. 2015; Kasthuri et al. 2015; Dvorkin and Ziv 2016; Bloss et al. 2018; Motta et al. 2019). We show that the binary variables of the two synapses are highly correlated, while the analog variables are not. Binary variation could be the outcome of a Hebbian or other synaptic plasticity rule depending on activity signals that are relatively uniform across neuronal arbors, while analog variation may be dominated by other influences. We discuss the implications for the stability-plasticity dilemma.

neuroscience↗

bioRxiv2017

Structural and functional diversity of a dense sample of retinal ganglion cells

To aid understanding of retinal structure and function, we present as an online resource the dendritic arbors and visual responses of ganglion cells in a single patch of mouse retina. We divide the inner plexiform layer, which contains the dendritic arbors of ganglion cells, into four sublaminae defined by a purely anatomical principle of arbor segregation. The sublaminae serve as the starting point for a hierarchical clustering of our ganglion cells. We propose and apply a quantitative criterion for validating a cluster as a ganglion cell type: the aggregate neurite density of a type should be approximately uniform (\"density conservation\"). Finally, we find that ganglion cells arborizing in the inner marginal sublamina of the inner plexi-form layer exhibit significantly more sustained visual responses on average.

neuroscience↗