V for Ventral
This post’s title alludes to the graphic novel and movie, V for Vendetta, which recounts a bottom-up revolution against a totalitarian regime. At the movie’s onset, the charismatic titular character, V, rescues a woman from the secret police and, as a flourish, recites a monologue filled by words starting with the letter V. Our first few posts have also focused on a V-word (er, phrase): the vagus nerve, along which the body’s signals rise up to the brain. Current medicine has reduced this famous autonomic nervous pathway to a simple binary: “rest and digest” or “fight or flight”; but today’s neuroscience is showing that the hundreds of thousands of fibers within “the” vagus nerve can each contain highly specific information associated with its own specific logic, sometimes more binary (to faint/cough/sneeze or not) and sometimes more like a dial (just how much inflammation to allow for bloodborne bacteria).
In societies, bottom-up pluralism is the antidote for top-down totalitarianism. So far, the lower nervous system seems to have a pluralistic constitution, with identifiable vagus nerve populations mapping to specific functions. In other words: with distinct components versus cloned ones (like the arrayed transistors of a solid state hard drive or a GPU core). Does this pluralism extend into the lower parts of the brain? Current neuroscience again says yes, and recently introduced me to another V-phrase: the “ventral brain.” This phrase stuck in my head after seeing a late 2023 social media post from the Allen Institute, which has led the way in disseminating advanced neuroscience technologies and reference datasets.
Source: Twitter/X, December, 2023
This post was part of a social media explainer thread (once upon a time a “tweetorial”) announcing the Institute’s major part in a flagship achievement from the first decade of the US BRAIN Initiative: a striking ten-paper collection in the journal Nature entitled the “Brain Initiative Cell Census Network (BICCN) 2.0”. Of these ten, four were “whole brain cell-type atlases”, including the Allen Institute’s publication, two from Harvard, and one from its neighbor the Broad Institute. A summary of the BICCN 2.0 results explained that such atlases combine two technologies which advanced greatly during the prior decade: spatial transcriptomics and single cell RNA sequencing.
Spatial transcriptomics makes brain atlases “4-dimensional” by considering the expression of genes 🧬in brain cells (i.e., presence of mRNA), in addition to the three-dimensions of their spatial location📍. Hence the colorful images comprising the public Allen Brain Cell (ABC) atlas.
While spatial transcriptomics can explore hundreds of marker genes, single cell RNA sequencing (aka scRNA-seq) can probe much deeper into the “molecular identity” of an individual cell, in some cases sequencing for activity of all known genes (“whole transcriptome”). To produce these milestone atlases, data of both types were computationally combined at large scale (1-10 million cells). Given the high spatial and molecular resolution, the largest atlases are conveyed with statistical representations, such as UMAP plots, to concisely represent the categories of cells, alternately called “cell types” or “transcriptional clusters” across the papers.
The BICCN 2.0 landmark achievement was the scope and scale of these cell atlases, for the first time covering a whole mammalian (mouse) brain. This is not only impressive as a technical achievement, but important scientifically: it enabled unbiased comparison between brain areas for the first time, which revealed a large number of cell categories in the lower “ventral” brain regions. This finding was also a win for reproducible science, with these same top-level scientific results being found by different teams using differing methodologies, from the “gold standard” MERFISH (Allen team) to the more recent and scalable (cost-effective) Slide-Seq (Broad team). Moreover, and separately from this paper series, these discoveries have been corroborated by a more preliminary atlas of human brain cell categories.
The authoring teams were clearly surprised by these results, using phrases such as “astonishing diversity” and “remarkably high” while describing the number of distinguishable brain cell categories in the ventral brain. The two studies with the broadest category coverage both found over 5000 distinctive brain cell categories by space and gene expression profile. Nearly all categories were neuronal, with relatively fewer non-neuronal and immune brain cell categories (even if widely spatially distributed), and with the majority (over 3000) of distinctive categories falling in the hypothalamus, midbrain, or hindbrain.
Extent of the lower “ventral brain” as implied by the discussion and Figure 6 (regional cell type counts) from “A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain” in Nature. Since ventral means “belly side”, the cerebellum is included, although fewer cell types were found there.
Ventral is an anatomical term for the “belly” side of an organism, making the term neatly universal across vertebrate brains, from fish to quadrupeds (like mice) to upright bipeds like us. As humans, we can refer to it more colloquially as the “lower brain”, whereas rodent and fish scientists would likely refer to it as the “rear brain”.
The vagus nerve packs information into hundreds of thousands of fibers that can group into molecularly-identifiable “wires” running in parallel to the base of the ventral brain. Our first few posts have also given some insights into function within that ventral brain, showing anatomical nuclei decomposed into functional sub-nuclei. We can start to imagine these thousands of brain cell categories as independent “command centers” packed tightly together, like the multi-chip modules powering recent mobile computers. Not long ago, many of these cells looked indistinguishable and behaved (in isolation) nearly identically, so it’s not surprising that autonomic nervous system functions–and dysfunctions–remain largely uncharted.
The second C in BICCN stands for “census” and these recent publications give us a first-pass count of what may be individual nameable functions carried out by specialized brain cells, the majority of which live in the ventral brain. The research stories highlighted by Ansyme are teaching us that cell-type specific functions can be determined and may directly relate to medical states and symptoms. Moreover the ventral brain is more “ancient” and less “divergent” than the dorsal part, meaning it's largely the same across species from mice to humans. This implies greater translatability of findings from research animal models. The two scientists tapped to summarize the atlas studies chose the phrases “buried treasure” and early maps of “uncharted territories”.
Like the ileocecal valve that demarcates the small and large intestines, something must delineate the boundary of the ventral brain. The Allen Institute’s atlas bounded the lower brain by the hypothalamus, a small anatomical structure with the highest density of molecular cell types: nearly 1000 cell types in about a cubic millimeter. Medicine is historically famous for its mnemonics, and we can now imagine a day where medical students might remember the ventral brain as spanning “from hypothalamus to hindbrain,” with good knowledge of its components, their importance for human health dysfunctions, and even treatment modalities. Ansyme aims to co-author that story. Given the ventral brain’s connection to bodily physiology, the known numerosity of its uncharted pathways, the stronger relevance of its animal data, and the early replication in human samples, perhaps we could title it, H for Hope.