Leveraging Preclinical Models to Understand Human Neurobiology and Behavior

Rodent models have become indispensable tools for investigating the neurobiological mechanisms underlying human behavior and disease. Despite the substantial phenotypic differences between rodents and humans, shared evolutionary history, conserved genomic architecture, and analogous neural circuitry allow preclinical findings to meaningfully inform our understanding of human conditions. This chapter reviews the behavioral paradigms most commonly used to evaluate five core domains in rodent models: motor function, stress and anxiety-like behavior, repetitive and restrictive behaviors, social behavior, and learning and memory. For each domain, we describe established assays, discuss the underlying innate behaviors they leverage, and highlight examples in which preclinical data have advanced mechanistic understanding or therapeutic development for human neuropsychiatric and neurodevelopmental disorders. We emphasize that behavioral findings must be interpreted with careful precision, as rodent behaviors are not direct equivalents of humans' intentional, complex behaviors or human emotional states but rather analogous outputs of neural circuits that can be operationally quantified. Throughout this chapter, we highlight critical considerations for rigor and reproducibility, an ongoing issue in the preclinical rodent behavioral space, such as the influence of environment; the appropriate selection of control groups; the importance of litter effects and background strain; and sex as a biological variable. Taken together, this chapter provides both a practical guide to preclinical behavioral neuroscience and a framework for maximizing the translational value of animal model research.