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so I just realized I forgot to #skeetprint my Contactomes paper... (is that what we're calling it?) www.biorxiv.org/content/10.6... @kordinglab.bsky.social @dacolon.bsky.social smithneurallab.weebly.com @jhuapl.bsky.social #academicsky #preprint #neuroscience

TLDR: We know neurons communicate at synapses. But they also talk in a bunch of other ways! diffusion, glial interactions, ephaptic coupling, neuropeptides (cc @lidia-ripolls.bsky.social!) The list is long. probably longer than we know :) So let's make a map of all physical contact between neurons!

I first got excited about this ~8y ago when I started seeing a pattern in #microns and other datasets at bossdb.org @alleninstitute.org @bcmhouston.bsky.social @princeton.edu @mit.edu Usually neuron cell bodies are spread out... But every so often, you get what I call "cuddle buddies". wtf?

More generally, if you knew every cell a neuron touches, would you know something new beyond its synaptic #contactome? How many other cells does a neuron touch, anyway? Here was our first exploration: a single pyramidal cell (cyan), followed by all its synaptic partners, and then all its contacts:

Our first result was super obvious: in mice, CONTACT networks (the #contactome) are 5-10 times as dense as the synaptic connectome.

(That also presents the engineering challenge and the reason these analyses aren't commonplace: the resulting network is 100s of GB, before you even _think_ about the ~petabytes of underlying data to generate that.)

It also turns out that different cell types have different "fingerprints" of their volume to surface-area relationships. Unsurprisingly, you can immediately tell who's a neuron and who's glia (green = glia, blue = neuron), and in fact different cell types even have their own "sub-fingerprint"!

SECOND: One of the weaknesses of connectomics today is we only get a single snapshot in time. If we instead watched the neurons form and kill synapses, how many new partners might be available? One way to learn this is to look at a "halo" around each cell: how many un-contacted neurons are nearby?

ok cool so let's take each neuron (blue), and draw increasing radii around it: 0.5µm (green), 1µm (yellow), 2µm... all the way up to 10µm. That's actually quite a lot of distance! ~1000x more volume than the neuron itself. So how many new partners are there in that HUGE halo we don't already touch?

The answer, INCREDIBLY, is... basically ZERO! *A neuron already touches virtually every neuron that comes within ~10µm of its cell membrane.* omg!

I mean... that's crazy. That means that synaptogenesis needs to move MANY microns away to even see a new potential partner. That has some pretty big implications for biological learning algorithms, which, like, I hear that's a big deal bsky.app/profile/sean... #neuroai

When we look at contactomes instead of connectomes, we also get an obvious bonus: GLIA!! Glia aren't commonly involved in synapses, but they are EVERYWHERE. Lots of chatter recently about astrocytes: www.thetransmitter.org/astrocytes/t... @thetransmitter.bsky.social #astrocytes #glia

So let's see if we can find any evidence of an astrocytic long-range network (a "syncytium," which is totally award-winning spelling for a word)... Let's look at our contactomes and get the network of astrocytes-contacting-astrocytes. Can we see that long-range network?

The answer is... holy crap YES. Here, I've shaded in red the astrocytes that participate in this network. Yep. It's literally EVERYWHERE. If we look at the nuclei of these astrocytes, they're perfectly uniformly distributed in the mouse visual cortex too!

Seeing that astrocytic network was a jaw-drop moment for me. Thank you to Cody Smith at Notre Dame for driving this science: This changed the way I think about neuroscience entirely!! smithneurallab.weebly.com

For our next trick: Does that glial network touch synapses specifically? Another resounding YES: PRACTICALLY EVERY SYNAPSE has a glial cell within 1µm, and near the synaptic site, almost ALL of the surrounding tissue is glial. Glam-shot: a synapse's microenvironent is dominated by an astrocyte :)

Here's a beautiful shot of a single dendritic spine (black). It has ~3 synaptic partners (blue). But it has nearly TWENTY contact partners (red), which could be electrically or chemically influencing it! (thank you @blender.org for making it so easy to create videos like this ❤️)

Contact is a totally new way to think about how nervous systems are organized. As part of this science, we're releasing all of our code and data #opensource (happening presently), and if you have a dataset that could benefit from a contactome, get in touch please :) github.com/aplbrain/

Finally, I want to return to those cuddle buddies that inspired me ages ago. Here's what it looks like to sneak "inside" a soma of a TRIPLE(!!) cuddle buddy. When you look "up" at the surface of the cell, it's dominated by contact with other neurons. Clearly important! But why?