Systems and circuit neuroscience need an evolutionary perspective

“Nothing in biology makes sense except in the light of evolution.” It’s a common refrain across many areas of biological research, yet evolutionary perspectives are often overlooked in systems and circuit neuroscience. This omission stems in part from the rise of powerful genetics tools in the early 2000s that pushed the field to focus on a small number of model organisms, primarily mice, fruit flies and Caenorhabditis elegans. Research on those model organisms drove the rapid expansion of experimental tools for labeling, manipulating and measuring specific neural systems.

By continuing to focus on such a limited set of species, though, researchers risk conflating species-specific adaptations with universal principles of brain function. Integrating evolutionary thinking into systems and circuit neuroscience is essential for identifying mechanisms that generalize across species.

Fortunately, new tools, including viral vectors, genome editing, functional imaging and large-scale electrophysiology techniques, now enable comparative cross-species analysis at the level of systems and circuits. When framed in an evolutionary context, such studies can reveal which features of circuit design and function generalize and which reflect ecological or phylogenetic adaptations.

Of course, studying a range of species isn’t new to neuroscience; the field has a strong tradition of diversity, a practice that has seen a resurgence. As more neuroscientists turn to non-model organisms, their work highlights the diversity of neural-circuit architectures and computations that can give rise to similar cognitive capabilities and behaviors. For instance, studies in corvids (crows, ravens and magpies) reveal high-level cognition despite a relatively compact brain. Cephalopods (octopuses, squids and cuttlefish) instead achieve complex functions through a partially decentralized nervous system that can regulate localized motor control.

But neither the insights from non-model organisms nor the in-depth dissection of model organisms alone are sufficient to fully determine the general principles by which neural systems are organized. An emerging and promising strategy is to perform targeted comparisons across sets of species selected to juxtapose each species’ ecological niche and evolutionary history. Such comparative studies can reveal conserved circuit functions while also identifying genetic and neural differences that underlie species-specific behaviors.

W

e think the field needs to take two key steps to adopt a comparative and evolutionary approach.

The first step consists of genetically identifying and characterizing homologous cell types, circuits and structures across species. The retina is exceptionally suited for these types of analyses because we can link genetic, morphological and functional properties of many of its cell types. For instance, transcriptomic analysis of 17 animal species shows that differences in retinal cell type composition become more pronounced as one moves along the visual processing pathway from photoreceptors (simple light detectors) to retinal ganglion cells (complex feature encoders). These evolutionary changes arise predominantly through adjustments in the relative proportions of cell types, rather than the addition or removal of specific types.

The second step is to perform targeted comparisons of closely related species with well-defined ecological differences. This approach provides a tractable framework for linking circuit function to evolutionary change. For instance, pioneering work by Hopi Hoekstra, Janet Crossland and their colleagues provided insights into the genetic basis of complex mammalian behavior by comparing different species of deer mice. In collaborative work with the Hoekstra Lab, we found species-specific differences in dorsal periaqueductal gray function that align with habitat and defensive strategy. In Peromyscus maniculatus, a species of deer mouse that lives in highly vegetated areas, this circuit regulates escape behavior in response to a threatening stimulus. In another mouse species, Peromyscus polionotus, which lives in open sand dunes, it does not—fitting with this species’ tendency to freeze, a response that may be better in exposed environments.

Beyond mammals, neuroscientists are increasingly using evolutionary frameworks to clarify how neural circuit structure and function adapt across different species, including fish, insects and crustaceans. For example, crabs in low-predation environments show slower responses to looming threats, not only behaviorally but also at the neuronal level. Among cichlids, a diverse group of fish occupying distinct but adjacent microhabitats, interspecies differences in behavior and morphology are linked to differences in brain anatomy and neural activity; species that build more elaborate mating nests show increased neural activity in the hindbrain, and those from visually complex environments or with polygamous mating systems tend to have sharper vision. Collectively, these types of studies reveal how evolution implements alternative solutions to similar ecological challenges, determining which features of neural circuits and neuron function remain conserved versus which are evolutionarily flexible. 

The traditional model organisms we use in research remain invaluable. But focusing too narrowly risks reinforcing assumptions that may not hold across species. A striking example is the study of the Gr28b.d receptor in fruit flies. When first studied exclusively in Drosophila melanogaster, its downstream neural targets appeared to exclusively regulate a dedicated high-temperature avoidance circuit. Yet comparative work done later across multiple Drosophila species revealed that this circuitry is highly flexible, shifting its response range and circuit structure to match each species’ preferred temperature range, reflecting an adaptation to their distinct ecological niches. Such findings highlight the value of comparative approaches not only for identifying species-specific differences but also for refining our understanding of the broader rules that govern brain function.

Adopting a comparative and evolutionary perspective does have its challenges. Maintaining multiple species in a lab requires special permits, expertise and adjustments to housing and protocols. And studying multiple vertebrate species in the lab is more difficult than studying an array of invertebrates.  Still, we believe neuroscientists can address these hurdles through coordinated, collaborative efforts across institutions and among labs that work on different animal models. Beyond practical considerations, it is not obvious which and how many species need to be studied to confidently identify a certain circuit function as a general feature. This is a matter for ongoing scientific debate, relevant not only to model organisms but to biology more broadly.