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When a social sound category initially gains behavioral significance to an animal, plasticity events presumably enhance the ability to recognize that sound category in the future. In the context of learning natural social stimuli, neuromodulators such as norepinephrine and estrogen have been associated with experience-dependent plasticity and processing of newly salient social cues, yet continued plasticity once stimuli are familiar could disrupt the stability of sensorineural representations. Here we employed a maternal mouse model of natural sensory cortical plasticity for infant vocalizations to ask whether the engagement of the noradrenergic locus coeruleus (LC) by the playback of pup-calls is affected by either prior experience with the sounds or estrogen availability, using a well-studied cellular activity and plasticity marker, the immediate early gene c-Fos. We counted call-induced c-Fos immunoreactive (c-Fos-IR) cells in both LC and physiologically validated fields within the auditory cortex (AC) of estradiol or blank-implanted virgin female mice with either 0 or 5-days prior experience caring for vocalizing pups. Estradiol and pup experience interacted both in the induction of c-Fos-IR in the LC, as well as in behavioral measures of locomotion during playback, consistent with the neuromodulatory center's activity being an online reflection of both hormonal and experience-dependent influences on arousal. Throughout core AC, as well as in a high frequency sub-region of AC and in secondary AC, a main effect of pup experience was to reduce call-induced c-Fos-IR, irrespective of estradiol availability. This is consistent with the hypothesis that sound familiarity leads to less c-Fos-mediated plasticity, and less disrupted sensory representations of a meaningful call category. Taken together, our data support the view that any coupling between these sensory and neuromodulatory areas is situationally dependent, and their engagement depends differentially on both internal state factors like hormones and external state factors like prior experience.Hormonal state and past experience affects how individuals process the same sound.Estrodiol and social experience interact to drive LC response to infant call playback.Prior infant experience decreases c-Fos in core AC and A2 to familiar call playback.At best, estradiol only weakly modulates AC c-Fos response to infant call playback.