The MICrONS program was a hugely ambitious effort to map the connectivity patterns of 1 mm3 of mouse cortex and their relationships to brain function. I know that it led to some tremendous technical advances in automated electron microscopy and processing of that data. It also led to a connectivity map for 200K neurons and 500 million synapses.

https://www.technologyreview.com/2017/10/12/148291/inside-the-moonshot-effort-to-finally-figure-out-the-brain/

What I understand less about is whether the new concepts and findings that emerged from the project.
@neurobongo, @xaq, (anyone): What is the status there? (Note this Q is not a criticism - if it's all still tech and maps thus far, that's still a really important step).

@NicoleCRust @neurobongo @xaq

A good question for @csdashm ! What were the conceptual advances from the MICrONs project?

@albertcardona @NicoleCRust @neurobongo @xaq

It’s a very fair critique, and some of the PR does us more harm than good. For example, we don’t have a map of 100,000 cells that tells us little, we have an EM volume spanning 100,000 cells that was at the edge of what was possible at the time that still requires a lot of (manual or automated) proofreading to turn into analyzable data.

The full set of initial science papers from the mm3 volume is almost ready to submit, but our existing work has started to reveal details about the nature of connectivity in a cell-type-specific manner. For example, a 2022 eLife paper (Dorkenwald et al.) shows that you see a bimodal distribution of synapse sizes on layer 2/3 cells, but _only_ if you restrict analysis to synapses from other layer 2/3 cells. Similarly, we found a variety of factors that could predict how much chandelier input a pyramidal cell would receive. These data suggest that neurons have type-specific rules for connectivity and plasticity that are hard to see if you can’t separate connections out this way.

More recently (as in Monday), I posted a manuscript to the biorxiv describing inhibitory connectivity across a column of visual cortex that shows that inhibitory selectivity (at least at the cell type level) is the norm, not the exception. In particular, we find selective inhibition not only for each excitatory projection class (IT, NP, ET, and CT) as well as sublaminar groups of IT neurons. This suggests a network of precise inhibition across cortex. We also find a new class of disinhibitory specialist interneuronal that targets basket cells, unlike the well-described VIP->SST circuit. This opens up a host of follow up questions, and we hope that using patch-seq data to link EM data to transcriptomics will help make this experimentally possible.

Ultimately, I think we’re still in the early days of getting the data out and finding the science in it. This is very much like in Drosophila, where the first studies at the whole-brain scale were highly focused. But I believe it will go the same way, becoming a way to study large scale structure at single cell resolution, complementing single lab studies, and helping answer unexpected questions. For example, one of my colleagues noticed that oligodendrocyte precursor cells in the EM looked like they were doing phagocytosis, which wasn’t a known function for them, and she just published a nice PNAS paper (Buchanan et al) about it.

@csdashm @albertcardona @NicoleCRust @neurobongo @xaq
Convenience link to their new paper in case anyone else also wants to look it up:

https://www.biorxiv.org/content/10.1101/2023.01.23.525290v1

@jason_ritt @csdashm @albertcardona @NicoleCRust @neurobongo @xaq

Jumping on the opportunity of asking someone knowledgeable about the topic: is there any ongoing large scale (hundreds of microns?) connectomic project in mouse subcortical areas (midbrain-hindbrain)? I have always had the impression those would be way more suitable to distill physiological principles from purely local structure, as opposed to cortex where everything is more "second order"

@vigji @jason_ritt @csdashm @NicoleCRust @neurobongo @xaq

The midbrain-hindbrain in a mouse is presently too big for #connectomics with #vEM #volumeEM.

Instead, try a small frog or lizard. That's what we aim for.

@albertcardona @jason_ritt @csdashm @NicoleCRust @neurobongo @xaq

The whole of it for sure, but maybe even just small portions could be revelatory - more than equivalent volume in the cortex maybe...
But I definitively agree on aiming for smaller, looking forward to seeing reptiles! (in my case, huge fan of zebrafish larve, there #vEM it has already produced structure-to-function hypotheses - self promotion link: https://www.biorxiv.org/content/10.1101/2022.04.27.489672v1.full)

@vigji @jason_ritt @csdashm @NicoleCRust @neurobongo @xaq

Cool work, nice neural architecture convergence with the #Drosophila central complex!

By the way, which #volumeEM is this–it is not the Hildebrand et al. 2017. The methods say the volume will be released with a paper by Sbara et al. soon; is this then the new whole zebrafish brain volume that the Licthamnn/Engert groups are on, or a different one? Extracellular staining sounds unfortunate: no synapses.

#neuroscience

@albertcardona @jason_ritt @csdashm @NicoleCRust @neurobongo @xaq

The dataset has been subsequently published https://www.nature.com/articles/s41592-022-01621-0 and it is available online! It has been and awesome resource, now it is public and maybe it will keep improving over time (atm there is an automatic segmentation but still requires significant manual curation to get useful morphologies). #vEM #neuroscience #connectomics