Analysis of Voluntary Behavior to Interrogate Neural Function

Abstract

Mice and rats are critical to our understanding of human biology. They share most of our genome, are susceptible to most of the same diseases and usually benefit from clinical therapeutics, if only at very high doses. Equally important has been the development of new rodent research tools that allow us to manipulate their genome, to induce new likenesses and illuminate our similarities. However, there remain substantial obstacles to modeling clinically relevant human somatosensory experiences, such as chronic pain, in rodents. Conventional rodent pain assays require robust stimuli to generate brief behavioral readouts and they are able to detect the effects of analgesics only at levels well beyond clinically effective human doses. New technologies are needed that are sensitive to low intensity nociceptive stimuli and are able to detect the effects of analgesic drugs at clinically relevant doses. It is possible to tell when someone is in pain simply by his or her body language; but rodents and other prey animals do not as readily show behaviors that betray the presence of pain or injury. We propose that ancestral selection pressures have favored propagation of prey that mask outward signs of injury or disease from the predator, and that behavioral indicators of ongoing pain or itch in rodents should therefore be most evident when the appearance of predation risk is minimized and/or from a viewpoint not naturally seen by predators. Based on this hypothesis, we developed new devices and techniques for observation and analysis of voluntary rodent behavior, with careful consideration of their ecological position as nocturnal prey animals. Here, we demonstrate the capability of one of these new technologies to detect the prolonged effects of low intensity nociceptive stimuli in freely behaving mice and rats and to show that clinically relevant analgesic doses can extinguish pain related behaviors in rodents. Applying the same hypothesis to the study of pruriception (itch), we built another device that optimizes quantification of rodent scratching behavior. We demonstrate its utility by using it to reveal new insights into the cellular basis of pain and itch sensation and advance novel therapeutics for human injury and disease.