Conneconomics: The Economics of Dense, Large-Scale, High-Resolution Neural Connectomics

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We analyze the scaling and cost-performance characteristics of current and projected connectomics approaches, with reference to the potential implications of recent advances in diverse contributing fields. Three generalized strategies for dense connectivity mapping at the scale of whole mammalian brains are considered: electron microscopic axon tracing, optical imaging of combinatorial molecular markers at synapses, and bulk DNA sequencing of trans-synaptically exchanged nucleic acid barcode pairs. Due to advances in parallel-beam instrumentation, whole mouse brain electron microscopic image acquisition could cost less than $100 million, with total costs presently limited by image analysis to trace axons through large image stacks. Optical microscopy at 50 to 100 nm isotropic resolution could potentially read combinatorially multiplexed molecular information from individual synapses, which could indicate the identifies of the pre-synaptic and post-synaptic cells without relying on axon tracing. An optical approach to whole mouse brain connectomics may be achievable for less than $10 million and could be enabled by emerging technologies to sequence nucleic acids in-situ in fixed tissue via fluorescent microscopy. Novel strategies relying on bulk DNA sequencing, which would extract the connectome without direct imaging of the tissue, could produce a whole mouse brain connectome for $100k to $1 million or a mouse cortical connectome for $10k to $100k. Anticipated further reductions in the cost of DNA sequencing could lead to a $1000 mouse cortical connectome.

A novel paradigm for auditory discrimination training with social reinforcement in songbirds

Zebra finches are a highly social, gregarious, species and eagerly engage in vocal communication. We have developed a training apparatus that allows training zebra finches to discriminate socially reinforced and aversive vocal stimuli. In our experiments, juvenile male zebra finches were trained to discriminate a song that was followed by a brief air puff (aversive) and a song that allowed them to stay in visual contact with another bird, ‘audience’ (social song). During training, the birds learned quickly to avoid air puffs by escaping the aversive song within 2 sec. They escaped significantly more aversive songs than socially reinforced ones, and this effect grew stronger with the number of training sessions. Therefore, we propose this training procedure as an effective method to teach zebra finches to discriminate between different auditory stimuli, which may also be used as a broader paradigm for addressing social reinforcement learning. The apparatus can be built from commercially available parts, and we are sharing the software on our website.

The micron-scale structural organization of hippocampal area CA1 neuropil

Various structures in the brain contain many important clues to the brain’s development and function. Among these, the organization of neuropil tissue at micron scales is of particular importance since such organization has a direct potential to affect the formation of synaptic connectivity between nearby axons and dendrites, thus, serving as an important factor contributing to the brain’s development and disorders. While the organization of the brain at large and intermediate scales had been well studied, the microscopic organization of neuropil tissue remains largely unknown. In particular, presently it is not known what specific structures exist in neuropil at micron scales, what effect such structures have on synaptic connectivity, and what processes shape the neuropil’s organization at micron scales. The present work performs an analysis of recent complete electron microscopy reconstructions of blocks of hippocampal CA1 neuropil tissue in rat to produce answers to these questions. We use a novel statistical approach to analyze the small-scale organization of neuropil systematically and to show that such organization can be well understood in terms of disordered, random arrangement of axonal and dendritic processes without significant local order. We also discuss several deviations from this simple picture observed in the distributions of glia and dendritic spines. Finally, we examine the question of the relationships between local neuropil’s organization and synaptic connectivity.

Simultaneous optogenetic manipulation and calcium imaging in freely moving C. elegans

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A fundamental goal of systems neuroscience is to probe the dynamics of neural activity that drive behavior. Here we present an instrument to simultaneously manipulate neural activity via Channelrhodopsin, monitor neural response via GCaMP3, and observes behavior in freely moving C. elegans. We use the instrument to directly observe the relation between sensory stimuli, interneuron activity and locomotion in the mechanosensory circuit. Now published as: Front Neural Circuits 8:28, doi:10.3389/fncir.2014.00028