Frontolimbic Functional Connectivity Development from Birth to Emerging Adulthood

Abstract Frontolimbic circuits connecting the frontal cortex with the amygdala and the hippocampus are critical for emotion and learning. These connections undergo major changes throughout childhood and adolescence, yet the principles guiding their maturation remain unclear. Analyzing large developmental cohorts, we show that fronto-hippocampus connectivity develops rapidly in early childhood and stabilizes thereafter. In contrast, fronto-amygdala connectivity becomes progressively differentiated from fronto-hippocampus connectivity, with development most pronounced during adolescence. This entailed hippocampus and amygdala respectively becoming preferentially tethered to association-related regions and sensorimotor-related regions. Greater adversity exposure was associated with more differentiated fronto-amygdala connectivity for a given age. Higher cognitive ability was associated with less differentiated fronto-hippocampus connectivity. These findings suggest that frontolimbic connectivity development follows a principle of differentiation, with circuit-specific timing and sensitivity to stress and learning. This work provides a foundation for understanding typical and atypical frontolimbic circuitry development from birth to emerging adulthood. Significance Statement The frontolimbic circuit, especially the fronto-hippocampus and fronto-amygdala circuitry, is integral for cognitive and affective processes. Yet its maturation has been challenging to characterize due to variable connectivity growth across the frontal cortex. Here, we reveal that this variability follows a principle of differentiation, where the hippocampus and the amygdala acquire respectively unique connectivity profiles with the frontal cortex at disparate developmental stages. Deviations from these normative trajectories were linked to cognitive ability and cumulative adversity, respectively. This approach provides a framework to unify inconsistent findings while serving as a foundation for identifying circuit-specific windows of plasticity and vulnerability.