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Abstract: We evaluated the effect of plasma hyperosmolality on behavioral thermoregulation in mice, using a new experimental system. The system consisted of Plexiglas box (dimensions: 50×12×19cm) with five computer-controlled Peltier boards (dimensions: 10×10cm) at the bottom. Experiments were conducted in two different settings of the system. An operant behavior setting: each board was first set to 39°C, and the right-end board was changed to 20°C for 1min when a mouse moved to a specific position. A temperature mosaic setting: each board was randomly set to 15°C, 22°C, 28°C, 35°C, or 39°C with a 6-min interval, but each board temperature was different from the others at a given time point. Mice were injected subcutaneous (s.c.) isotonic or hypertonic saline (154mM (IS group) or 2,500mM (HS group), 10ml/kg body wt), and exposed to either setting for 90min. In the operant setting, the HS group showed fewer operant behavior counts than the IS group (11±5 and 25±4 counts, respectively; P<0.05) with greater increase in body temperature (1.6±0.4°C vs. 0.0±0.2°C, respectively; P<0.05). In the mosaic setting, the HS group selected the board temperature of 35°C more frequently than the other temperatures (P<0.05) with the same increase in body temperature. These results may suggest that plasma hyperosmolality modulates behavioral thermoregulatory response to heat and induce regulated hyperthermia. [Copyright &y& Elsevier]