L1 function is necessary for the guidance of corticospinal axons across the pyramidal decussation in mice. Some of the defects in the corticospinal tract of humans with mutations in L1 could be due to errors in axon guidance at the pyramidal decussation.

Because of the coatings needed to solubilize and passivate quantum dots for biological applications, their use in fluorescent resonance energy transfer (FRET) has been limited. However, hydrophobic particles without polymer coatings may be embedded into lipid membranes, as demonstrated here with biomimetic vesicles. FRET is seen to a lipid-soluble dye (DiD) and a water-soluble dye (Cy3.5) in which the vesicles are suspended. The degree of energy transfer to each dye suggests that most of the QDs are located deep within the lipid, as confirmed by electron microscopy of whole mounts and thin sections of vesicles. Energy transfer is also seen to a voltage-sensitive, lipid-soluble dye (di-4-ANEPPS) only when the potassium ionophore valinomycin is present in the membrane. The effect is dependent upon potassium ion concentration rather than absolute membrane potential.

Detailed knowledge of both synaptic connectivity and the spatial proximity of neurons is crucial for understanding wiring specificity in the nervous system. Here, we volumetrically reconstructed the C. elegans nerve ring from legacy serial-sectioned electron micrographs at two distinct time points: the L4 and young adult. The new volumetric reconstructions provide detailed spatial and morphological information of neural processes in the nerve ring. Our analysis suggests that the nerve ring exhibits three levels of wiring specificity: spatial, synaptic and subcellular. Neuron classes innervate well defined neighborhoods and aggregate functionally similar synapses to support distinct computational pathways. Connectivity fractions vary based on neuron class and synapse type. We find that the variability in process placement accounts for less than 20% of the variability in synaptic connectivity and models based only on spatial information cannot account for the reproducibility of synaptic connections among homologous neurons. This suggests that additional, non-spatial factors also contribute to synaptic and subcellular specificity. With this in mind, we conjecture that a spatially constrained, genetic model could provide sufficient synaptic specificity. Using a model of cell-specific combinatorial genetic expression, we show that additional specificity, such as sub-cellular domains or alternative splicing, would be required to reproduce the wiring specificity in the nerve ring.

Animal nervous system organization is crucial for all body functions and its disruption can manifest in severe cognitive and behavioral impairment. This organization relies on features across scales, from nano-level localization of synapses, through multiplicities of neuronal morphologies and their contribution to circuit organization, to the high level stereotyped connections between different regions of the brain. The sheer complexity of this organ means that to date, we have yet to reconstruct and model the structure of a complete nervous system that is integrated across all these scales. Here, we present a complete structure-function model of the nematode C. elegans main neuropil, the nerve ring, which we derive by integrating the volumetric reconstruction from two animals with corresponding synaptic and gap junctional connectomes. Whereas previously the nerve ring was considered a densely packed tract of axons, we uncover internal organization into 5 functional bundles and show how they spatially constrain and support the synaptic connectome. We find that the C. elegans connectome is not invariant, but that a precisely wired core circuit is embedded in a background of variable connectivity, and propose a corresponding reference connectome for the core circuit. Using this reference, we show that the architecture of the C. elegans brain can be viewed as a modular Residual Network that supports sensory computation and integration, sensory-motor convergence, and brain-wide coordination. These findings point to scalable and robust features of brain organization that are likely universal across phyla. 2 Since the discovery of neurons and their connections through synapses and gap junctions, a major effort has focused on 3 characterizing these units and the micro-and macro-circuits that they comprise, culminating in a growing body of high 4 resolution nano-connectomic data across species 1-10 . Naturally, data, however rich, cannot, on their own provide explanatory 5 power to address the computation within circuits or to determine how these circuits communicate and coordinate information 6 flow to generate behavior. Indeed, constructing a comprehensive brain map will require a meaningful strategy for integrating 7 structure and function across scales. Achieving this feat in even a small animal can provide a useful model for postulating 8 principles of organization across scales 11 . 9The free-living nematode C. elegans has a small, compact nervous system 2 while exhibiting a range of complex, individual-10 ized behaviors, making it an ideal model system for studies of whole brain organization 11 . All 302 C. elegans neurons have been 11 anatomically characterized based on serial sectioned electron micrographs (EM) 2 to produce a whole animal connectome 2,5,12 . 12This animal's invariant cell-lineage 13 and anatomy 2 might suggest that its connectome too is invariant 14 . Unfortunately, the 13 small sample size of available reconstructions has precluded a reliable estimate of reproducibility and variability of th...