Cue-reward spatial association to palatable food is impaired in ErbB4 KO mice. To evaluate for spatial-cue associations to rewards, a five-test design (days 2, 4, 6, 8, and 10) was used to allow assessment of the development of a CPP to palatable food rewards. Food-restricted mice were conditioned to receive palatable food rewards (14-mg dustless pellets, BioServ) in a previously assigned LPS of the apparatus versus no food at the PS in two consecutive training sessions at days 1, 3, 5, 7, and 9. The left panel is a representative heat map of ErbB4 KO (KO) and control (Ctrl) mice exploring the PS, center (C), and LPS of the apparatus across test sessions and the right panel shows the preference ratio of mice to develop CPP. Control mice (n = 15) progressively conditioned across sessions to spent more time in the LPS, yet ErbB4 KO mice (n = 16) did not develop spatial-cue associations to palatable food rewards (two-way ANVOA genotype effect: F(1,29) = 32.78, p < 0.0001, two-way ANVOA time effect: F(4,116) = 8.619, p < 0.0001). Data represents the mean ± SEM; ***p < 0.005.