Comparative Neuroanatomy in Health and Disease: One Size Does Not Fit All
Authors: Zeiss Caroline 
Published: June 2021

Comparative studies of the central nervous system typically serve one of two purposes: to illuminate fundamental aspects of neurologic design, particularly those that contribute to our uniquely human brain, and to develop approaches mitigating its demise from age, injury or disease. The former approach relies upon inferences based on observed similarities and differences across species and brain region. The latter utilizes similar methodology, but confronts the added burden of identifying and exploiting those mechanisms that translate across species to achieve therapeutic benefit in humans.

In general, ascending and descending systems segregate into functionally and topologically organized structures that are, in principle, comparable across a very broad range of species, from insects to mammals. Similarly, aminergic systems are highly conserved from fish through mammals. The major organizational differences across mammalian evolution involve expansion of the association cortex, relative reduction of the limbic system, and altered relations of cortical and subcortical structures resulting from bipedal posture. Additional numerous differences occur within each system that may impact experimental design. For example, rodents have a combined caudate‐putamen (Cpu) that is not bisected by the internal capsule as is that of higher mammals. Motor function in rodents is less reliant upon an intact corticospinal tract because of greater contributions of rubrospinal system, and descending corticospinal tracts in rodents occupy dorsal rather than ventral funicular locations.

Region‐specific genes at sub‐gross levels are largely conserved across mammalian brains at both the sequence and gene expression level. However, here again, the devil is in the details, and this principle cannot be applied to all genes. Expression patterns for some genes vary by tissue, but have highly similar patterns of expression across species. For these, extrapolating results from mice to humans may hold true. However, for other genes, there is greater variation across species within the same tissue. For these, assuming that function is conserved across species is a riskier proposition.

Despite tremendous investment and preclinical success for common neurologic disorders, effective disease‐altering treatments for patients have remained elusive. One highly cited reason for this discrepancy is flawed animal study design, in which the intended goal of the intervention is mismatched with model choice, timing of the intervention, statistical flaws, and failure to integrate biomarker data with functional outcome measures that are clinically relevant to humans. It is generally understood that most models are only able to interrogate individual aspects of complex phenomena. For example, mouse models of Alzheimer's disease replicate individual aspects (such as amyloidopathy) of the disease quite well, but cannot replicate the neuropathologic and mechanistic complexity of the disease. One approach is to consider animals as models of individual molecular targets rather than as models of individual diseases and to migrate the concept of predictive validity from the individual model, to the body of experiments that demonstrate translatability of a given target.

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This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.