The really big picture
Over the course of development, agglomerations of amoeboid neurons and glial cells organize themselves circuits that process experience and direct behavior in a useful way. Understanding the strategies that evolution came up with for building information processing circuits out of cells is fundamental to biological science, regenerative medicine, and artificial intelligence.
Vision is integral to daily life and human evolution. Luckily, the visual system lends itself to experimental manipulation because complex visual stimuli can readily be repeated, neural circuit motifs are repeated for most regions of visual space, and visual computations are often laid out in the geometry of neuronal connections. These advantages have made circuit mapping the retina one of the most productive systems for explaining system function in terms of synaptic organization. Immediately downstream of the retina is the dorsal lateral geniculate nucleus of the thalamus (dLGN), a visual nucleus that parallels the retina’s topographic mapping of visual space, layering of channels and local inhibition. The dLGN diverges from the retina in that the development of its synaptic relationships are heavily dependent on the firing patterns of neurons. The mix of geometric encoding of computation and developmental plasticity makes the dLGN an ideal system for studying experience-dependent circuit formation.
Circuit scale electron microscopy (3DEM) reveals the synaptic organization of neural tissue
A core approach of the lab is using 3DEM to map the synaptic organization of neuronal circuits. Serial section electron microscopy reveals every synapse and cell in a fixed piece of tissue by revealing nanometer-scale ultrastructure in three dimensions. By automating tissue collection, image acquisition, and image analysis, it is possible to perform nanometer-scale 3D reconstructions of hundreds of microns worth of neuronal circuits. Circuit scale 3DEM reconstructions provide the first direct (as opposed to composite) observation of the synaptic organization of neuronal networks.
Dorsal lateral geniculate nucleus of the thalamus (dLGN) as a model system for vision and circuit formation
In mammals and other amniotes, the links between the eye and primary visual cortex are the thalamocortical cells of the dLGN. These cells constitute a gateway through which the circuitry of the dLGN reconstructs, processes, modulates and filters visual experience.
What does the dLGN synaptic glomerulus do? The feedforward synaptic connectivity of the dLGN is organized into clusters of synapses call glomeruli that are much smaller than the arborizations of the participating neurons. The microcircuitry of these glomeruli range from simple retinogeniculate relay connections to complex convergences of retinal and inhibitory synaptic connections. We are working on characterizing and classifying these local synaptic motifs and mapping them onto their visual function.
How does retinal activity shape the microcircuitry of the dLGN? During development, spontaneous and light evoked activity in the retina helps determine which retinal ganglion cells innervate which dLGN thalamocortical cell neurons. We are investigating the development of the dLGN glomerulus with emphasis on whether retinal activity can shape the subcellular patterning of microcircuitry.
What happens to the microstructure of the dLGN when retinal inputs are lost or regained? All retinal pathologies result in some functional disruption of retinal ganglion cell activity and some pathologies, such as glaucoma, progress to the structural loss of retinal inputs to the dLGN. We are investigating how the dLGN respond to loss and return of retinal input.
Synaptic organization of retinal processing
Retinal amacrine neurons shape the temporal and spatial response properties of retinal ganglion cells and, in some cases, generate novel feature-specific-responses such as motion detection. Most amacrine cell computation is occurs in neurites that are both pre and post synaptic so that multiple subcellular pathways of information flow pass through a single neuron. We are combining 3DEM circuit reconstruction with functional imaging to identify these subcellular pathways and determine the rules of synaptic organization that shape them.
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