NEWS IN PHYSIOLOGICAL SCIENCES The Missing Error Signal-

Homeostatic negative feedback fails to explain the essentially error-free regulation of bodily functions such as cardiorespiratory response, water intake, or temperature control. It seems likely that the performance is guided by past experience, which means that autonomic responses are learned at an early age. Time was when it seemed easy to ex-plain to our students the adjustment of the circulation to exercise. We taught that working muscles released vasodi-later metabolites, speeding local blood flow. Assisted by the contracting muscle (“muscle pump”), venous return in-creased, raising pressure in the vena cava and hence diastolic volume of the cardiac chambers. By the dual action of the Bainbridge reflex and Starling’s law of the heart, heart rate and stroke vol-ume increased. Simple, straightforward, logical. But then Rushmer and Smith (12) have shown that venous return is not what drives the heart during muscular exer-cise. What is more, arterial pH, oxygen and CO2 tension cannot be the driving stimuli either, as all remain within nor-mal resting limits (7, 15), except in ex-treme effort by those trained for compe-tition (10). Respiration, cardiac output, and arterial blood pressure increase without hesitation at the very moment when muscular exertion begins (5, 15) and then continue to keep abreast of demand. In the years since these major discov-eries, increasingly refined techniques have defined more precisely the afferent signals originating from exercising mus-cles that stimulate the central controllers of respiration and circulation (16). Yet the most fundamental questions have not been answered: How does the brai