Early adversities that are caregiving-related (crEAs) are associated with a significantly increased risk for mental health problems. Recent neuroscientific advances have revealed alterations in medial prefrontal cortex (mPFC)-subcortical circuitry following crEAs. While this work has identified alterations in affective operations (e.g., perceiving, reacting, controlling, learning) associated with mPFC–subcortical circuitry, this circuitry has a much broader function extending beyond operations. It plays a primary role in affective meaning making, involving conceptual-level, schematized knowledge to generate predictions about the current environment. This function of mPFC–subcortical circuitry motivates asking whether mPFC–subcortical phenotypes following crEAs support semanticized knowledge content (or the concept-level knowledge) and generate predictive models. I present a hypothesis motivated by research findings across four different lines of work that converge on mPFC–subcortical neuroanatomy, including (a) the neurobiology supporting emotion regulation processes in adulthood, (b) the neurobiology that is activated by caregiving cues during development, (c) the neurobiology that is altered by crEAs, and (d) the neurobiology of semantic-based meaning making. I hypothesize that the affective behaviors following crEAs result in part from affective semantic memory processes supported by mPFC–subcortical circuitry that over the course of development, construct affective schemas that generate meaning making and guide predictions. I use this opportunity to review some of the literature on mPFC–subcortical circuit development following crEAs to illustrate the motivation behind this hypothesis. Long recognized by clinical science and cognitive neuroscience, studying schema-based processes may be particularly helpful for understanding how affective meaning making arises from developmental trajectories of mPFC–subcortical circuitry.