[Opinion]

Neural cell types, like other many cell types, come in a constellation of different morphologies and connectivity amongst other cell-types. For the past century, neurobiologists (and anatomists alike) have pursued the descriptions of neural cell types at the level of gene expression, morphology and connectivity across many diverse animal systems. This could allow one to explore questions such as; What do neural cells look like? How diverse are the ensembles of neural cell-types in a given animal? How are neural cell types organized to allow for ‘information’ flow in the nervous system? Accessing cell-types that make up the so-called nervous system (as well as other animal systems), offers several challenges e.g. How does one ’see’ cells encased in an animal? Is it feasible to visualize every single-cell in a nervous system? What of comparisons across many different animal species? What of the ethics associated with animal research? What are the costs? (i.e. equipment/technology, human labor, computational power). Beyond simply accessing cell-types in the nervous system, an interesting question to pose also includes: What is a neural cell-type? And can any such ‘definition’ help scientists explain the origin of neural cell-types throughout the course of evolution, as well as the diversity in ’types’ observed in nature.

Neural atlases: From an organic to cellular to systems perspective

The nervous system has not always accessible at the single-cell level. Many a neuroanatomist prior to the 19th century described the physical aspects of nervous systems at the level of gross structure (e.g. hippocampus, cortex, cerebellum) or many collections of neural cells e.g. fibers/bundles (see Milestones in Neuroscience Research; The Cytoskeleton of Nerve Cells in Historic Perspective ). This view was further refined by work primarily credited to Santiago Ramon y Cajal and Camillo Golgi (see Essay, NYTimes Report), who provided insights into the nervous system being a composition of morphologically identifiable cells. This extensive body of research utilized a staining method to label relatively few cells in a mosaic fashion. Later efforts took the approach of filling cells with dyes which could be further coupled with measuring electrophysiology, allowing the probing of the relationship between morphology and function. Cells could also be filled with viral-coupled dyes which infect cells that are synaptically linked, allowing mapping of ‘circuits’ – multiple synaptically linked cells. The age of genetics and molecular biology allowed labelling of cells according to the genes they express; adding yet another layer of information in the attempt to understand the relationship between a cell’s genetic code (i.e. genes expressed) and it’s wiring diagram (see Focus on Mapping the Brain).

Each of the aforementioned techniques offers unique perspectives of the nervous system and its’ organization, depending on one’s question and/or interest. What is thought to be the more comprehensive means of unveiling cell-type morphology and overall nervous system structural organization involves electron microscopic reconstruction of neural tissue. This technique offers a high resolution of neural processes and their synaptic connectivity, in a relatively unbiased fashion. Some limitations however include, image acquisition time, the data size, sample sizes and, fast-and-reliable analysis methods for neural reconstruction. It is not surprising then that only few animal models have had major components of their nervous system mapped and reconstructed. This however is changing with scientists utilizing the power of many by crowdsourcing – “the practice of obtaining information or input into a task or project by enlisting the services of a large number of people, either paid or unpaid, typically via the Internet” – thereby dramatically increasing the human-power required for analyzing large amounts of data sets (see eyewire.org/explore; crowdsourcing-fly-connectome; 3d-map-of-a-mouse-retina; brainflight.org). Furthermore, such efforts may be an interesting way for science to interact and engage with the wider public.

While reconstructing an entire nervous system can reveal anatomical organization and morphological ‘types’ (see NBLAST), given our working model of cellular molecules (i.e. DNA, RNA, protein and more) being essential for life, the marriage between a cell’s molecular profile and its morphological and/or organizational features, is an interesting scientific field to explore further. Many efforts are currently underway to profile a cell’s entire molecular profile and explore the relationships -if any- between genotype and phenotype (see The BRAIN Initiative Cell Census Consortium ; CeNGEN ). Armed with such an atlas, it is felt that one would be able to describe cell-types comprising the nervous system to an unprecedented detail. Furthermore, if such atlases were available for multiple different animals, sampled evenly across the tree of life, it is only imagined how fascinating such a perspective could be, if one was interested in the evolution of neural cell-types. Moreover, if and/or how this differs or is similar across the diverse animal forms on earth offers an intriguing challenge, scientifically and socially; especially considering our awareness of animal welfare and our impacts on biodiversity (positive and/or negative).

Addressing some limitations of studying neural cell-type(s)

Assuming a framework of investigating diverse species so as to explore evolution of cell-types, a major limitation to overcome if one were to aim at understanding neural cell-type(s) – morphology, gene expression and/or function – is the limited diversity of animal specimen thus far studied (Table 1). This limitation is understandable given the cost associated with establishing animal model systems (incl. ethics and laboratory constraints of maintaining stable environments for experimental studies) as well as the expense of assaying the entire nervous system in an unbiased or at least a comprehensive manner. Notwithstanding, if one were to model how nervous system structure and organization could have arisen in nature, would the handful of species currently under investigation be sufficient?

Animal ethics and welfare

While many have discussed the potential scientific rewards of studying many diverse animals across the tree of life (see Hale, 2014 and Yartsev, 2017), it is also felt that re-examining our ethical position(s) on animal studies is equally important. As a disclaimer, it is not suggested that scientists are not considering animal ethics. Neither is it suggested that ethics is not a vital component of scientific research. This is only a reflection considering the effort(s) toward studying more animal species so as to understand life around us. While it is believed that animal research has been instrumental in our interpretation of nature and its’ presumed inner workings, it is also proposed that we – humanity (esp. the scientific community) – encourage a deeper appreciation of the societal demands for transparent animal ethics policies and animal welfare. It is hoped – perhaps naively – that active and constructive discussions with more diverse members of the public (i.e. extending beyond the scientific community e.g. philosophers, animal welfare activists, governmental boards), could yield alternative solutions to perhaps needless animal sacrifices, while allowing even greater sampling of animal species that extend far beyond the handful of model systems that anchor many of our interpretations of basic biology.

Conclusion

Naively speaking, exploring neural cell-types offers a stimulating adventure ahead, both aesthetically (neural cell-type morphology and connectivity are alluring) and intellectually (how did nature manifest these cell-types?). Nevertheless, it is felt that there are challenges that would be intriguing to face. And while the challenges discussed here are by no means comprehensive, the hope is that tackling them would open doors to unforeseen corners of neural cell-type evolution. Who knows, one might just dream of explaining the origins of nervous systems and the diverse manifestations we observe in present day animal species.

Disclaimers

The author wishes to remind the readers that this was written by #hownottobloglikekevin. The author also apologizes if this piece has ignored or neglected important details relevant to the discussion, and requests that people feel free to criticize, clarify and/or comment on any issues one feels passionate about J. It is also noted that there is no reference list, this is because the author attempted to incorporate the links within the text to the actual source.

Table 1. A brief overview of animal models with a significant portion of their nervous system anatomy mapped
Animal Brief description Resource/Links
Ciona intestinalis

(C. intestinalis)

A sea squirt that has been used for developmental and evolutionary biology. The tadpole larval central nervous system (CNS) has been mapped at the EM synapse level. Exhaustive comparative studies are yet to be realized. https://elifesciences.org/articles/16962

 

Caenorhabditis elegans (C. elegans)

 

[Note: Another nematode species Pristionchus pacificus has also had a portion of its nervous system mapped]

A nematode round-worm whose entire anatomical wiring nervous system has been described at the synaptic resolution (for both male and female). Researchers have also extensively described many of the genes expressed in these neural cell-types, identifying markers that specify certain cell fates. This extensive resource coupled with genetic tools have also enabled physiological measurements of individual cells in many behavioral contexts. https://www.wormatlas.org

http://www.wormbook.org

 

 

Drosophila melanogaster (D. melanogaster) A vinegar fly whose larval ventral nerve cord (VNC), components of the central nervous system (CNS), and the adult brain (incl. visual system) have been mapped at the EM synaptic level. Furthermore, comprehensive genetic tools built by the community have allowed mapping of neural cell-types and their projections. (@flyconnectome)

https://flyconnecto.me

https://www.janelia.org/project-team/flyem

http://fruitflybrain.org

 

Danio rerio (D. rerio) A zebrafish whose entire larval brain has been mapped at the synaptic level. Many efforts are aimed at mapping circuits for the entire animal using similar resources available for Drosophila. https://www.neuro.mpg.de/2019-07-Baier-Kunst

https://fishatlas.neuro.mpg.de/zebrafishatlas/main_page#

 

Mus musculus (M. musculus) A mouse model with a comprehensive retina connectome (EM) and a brain-wide mesoscale – neural projections – connectivity map via confocal microscopy. http://portal.brain-map.org

 

 

Platynereis dumerilii (P. dumerilii) A relatively recent animal species thought to be useful for understanding evolution of certain neural characteristics. It’s larval visual system and neurosecretory centers have been mapped at the EM synaptic level. Further efforts to attain the complete wiring diagram so as to compare with the other organisms is ongoing. https://twitter.com/JekelyLab

https://www.evocell-itn.eu/2019/01/25/zooming-in-on-my-favourite-marine-worm/

 

 

 

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