Age-dependent changes in prefrontal intrinsic connectivity

The prefrontal cortex continues to mature after puberty and into early adulthood, mirroring the time course of maturation of cognitive abilities. However, the way in which prefrontal activity changes during peri- and postpubertal cortical maturation is largely unknown. To address this question, we evaluated the developmental stage of peripubertal rhesus monkeys with a series of morphometric, hormonal, and radiographic measures, and conducted behavioral and neurophysiological tests as the monkeys performed working memory tasks. We compared firing rate and the strength of intrinsic functional connectivity between neurons in peripubertal vs. adult monkeys. Notably, analyses of spike train cross-correlations demonstrated that the average magnitude of functional connections measured between neurons was lower overall in the prefrontal cortex of peripubertal monkeys compared with adults. The difference resulted because negative functional connections (indicative of inhibitory interactions) were stronger and more prevalent in peripubertal compared with adult monkeys, whereas the positive connections showed similar distributions in the two groups. Our results identify changes in the intrinsic connectivity of prefrontal neurons, particularly that mediated by inhibition, as a possible substrate for peri- and postpubertal advances in cognitive capacity.The prefrontal cortex, the brain area associated with the highest-level cognitive operations, is known to undergo a protracted period of development (1–3). A virtually linear increase in performance with age has been observed in tasks that assess visuospatial working memory, executive control, and resistance to distraction, a process that continues well after puberty and into early adulthood (4, 5). The accrual of cognitive capacities during this period parallels structural changes of the prefrontal cortex in humans and nonhuman primates (6–10). Imaging studies in humans suggest that patterns of brain activation associated with working memory tasks undergo distinct changes between childhood and adulthood, supporting the idea of prolonged prefrontal maturation (11–14). However, how the patterns of prefrontal activation change during cortical maturation remains unclear. A possible mechanism that could account for variations in prefrontal responses—and which could have a significant functional impact (15)—is an overall change in the distribution of intrinsic functional connections, i.e., those between neurons within the prefrontal cortex. The intrinsic connectivity of a network is directly related to the correlation structure of neuronal responses, and this determines in a fundamental way the information-coding properties of the network and its ability to sustain activity on its own (16–18). In this study, we sought to determine if the strengths of functional connections inferred from multisite neurophysiological recordings differ between peripubertal and adult monkeys.