Extremely mild hypothermia to 36.0 °C is not thought to appreciably differ clinically from 37.0 °C. However, it is possible that 36.0 °C stimulates highly sensitive hypothermic signaling mechanism(s) and alters biochemistry. To the best of our knowledge, no such ultra-sensitive pathway/mechanisms have been described. Here we show that cold stress protein RNA binding motif 3 (RBM3) increases in neuron and astrocyte cultures maintained at 33 °C or 36 °C for 24 or 48 h, compared to 37 °C controls. Neurons cultured at 36 °C also had increased global protein synthesis (GPS). Finally, we found that melatonin or fibroblast growth factor 21 (FGF21) augmented RBM3 upregulation in young neurons cooled to 36 °C. Our results show that a 1 °C reduction in temperature can induce pleiotropic biochemical changes by upregulating GPS in neurons which may be mediated by RBM3 and that this process can be pharmacologically mimicked and enhanced with melatonin or FGF21.