A Theoretical Aside
So in this post I am going to talk about a couple of invited chapters I have recently written. The general point of these two chapters is that it takes very careful task selection to appropriately model the cognitive sequelae associated with human genetic disease in rat and mouse models. If this sounds familiar, it is because I have written about this general theme before Link1, Link2, Link3.
So the two chapters I am going to speak about are now posted on my reprint websites in HTML format Here, and Here. Both of these chapters are intended as helpful guides to task selection and behavioral analysis, but I am going to focus this post on one I wrote in honor of my old advisor, Ray Kesner’s, Festschrift since these chapters are my attempt of extending his legacy into the future.
The main précis of these chapters is that there is a great need for cognitive neuroscience to get into the business of evaluating the consequences of disease in numerous patient populations.
I say this because although we have made dramatic leaps in our understanding of the brain, we still limit ourselves to IQ tests and basic standardized neuropsychological tests when looking at patient populations. We then over interpret the results of these assessment tools to the point they become meaningless. Then we try to use these contrived outcome measures as endpoints in treatment studies and clinical trials, leading to an almost guaranteed failure.
Now in a large degree to fix this problem, the NIH called upon researchers to develop a set of core toolboxes to evaluate cognitive function. They have collected these in the NIH Toolbox. I’m not going to go into the specific strengths and weaknesses of the NIH toolbox-based approach, other than to say it casts a relatively wide net to test cognitive function using more up to date tasks that have been shown to be sensitive to brain dysfunction. This has been sorely lacking in studies into patient populations so I applaud the effort.
This is great for humans, but for mice we are still sitting around using the Water maze and fear conditioning, all while calling the study “innovative research” because it’s a new mouse being evaluated. I propose, what I consider a modest solution to this.
My proposed solution is simply to develop a core set of tasks that can be selected from to test rats and mice, based on hypotheses the researchers gleans from the literature into patients being modeled. In short, a sort of NIH Toolbox for mice and rats.
After an introduction to the way I view research into the brain (The Attribute Specificity model for those keeping tabs), I propose a series of tasks that are chosen specifically to be analogous to the tests in the NIH Toolbox. Or, if that is too bold an assertion, at least testing similar cognitive domains as those tested by the NIH Toolbox.
I hope that these chapters can serve as sort of references for behavioral scientists trying to design studies using a new disease model. I hope people can glean my experience and avoid the wasted time and false alleyways of designing behavioral paradigms from scratch to test a model that we do not yet understand.
My TL;DR of this post is that I have proposed a rodent/murine analog of the NIH Toolbox. I believe that applying the NIH toolbox to humans patient populations and selecting analogous tests for the rat/mouse models will greatly facilitate cross-species comparisons and perhaps even make the mouse models useful for evaluating cognitive endpoints drug testing, something they really aren’t any good for at present.
My second, and perhaps more honest TL;DR Is Please go and read my chapters! I worked hard on them and hope they can be useful for others.