Lateral hypothalamic orexin/hypocretin (OH) circuits enhance exploratory behaviour and cortical gamma power, key physiological variables affecting neuronal responses in the primary visual cortex (V1). In order to elucidate the functional significance of OH signals for V1 experience-dependent plasticity, we tested orexin KO-mice in the classic ocular dominance plasticity (ODP) paradigm using intrinsic signal optical imaging (OI). Since ODP depends on age and housing conditions, we tested ODP during the critical period (CP) for ODP (P21-P35) and in adults (>P110) with standard cage (SC) housing or running wheel (RW) enrichment during monocular deprivation (MD).During early (P21-P23) and mid-CP (P24-27), both SC orexin WT/KO-mice showed ODP after 4 days of MD. In contrast, during late CP (P28-P35), ODP in orexin KO was compromised: unlike WT, KO-mice needed 7 days of MD to display ODP. Moreover, RW enrichment failed to boost ODP in KO-mice. In adult SC WT-mice (>P110), ODP is absent after 7 days of MD, but can be rescued after RW-enrichment (Kalogeraki et al 2014, JNS34:15476). In contrast, and as in juvenile KO-mice, RW enrichment did not boost ODP in adult orexin KO-mice: V1-activity remained dominated by the deprived (contralateral) eye, notably even when KO-mice ran similar distances as WT-mice (WT/KO: 3.9±1.2/4.1±1.4 km/d, n=3/3). Together with our accompanying poster (Schöne et al), our study suggests that OH promotes experience-dependent plasticity and propagates the plasticity-boosting effects of RW-enrichment in mouse V1.