Figure 1. Threat response regulation behavior and neurobiology across adolescence.

(a) Although memories of threat-associated cues emerge as early as postnatal day 10 (P10), long-term retention of these memories does not emerge until preadolescence. Similarly, the ability to extinguish a memory of a threat-associated cue and retain this extinction memory emerges in pre-adolescence. However, extinction retention is temporarily reduced during adolescence. Dynamic remodeling of the prefrontal cortex (PFC) (including the prelimbic (PL) and infralimbic (IL) subregions) and basolateral amygdala (BLA) parallels these behavioral changes. Key maturational changes discussed in the review are highlighted here. While some changes occur gradually across development (inhibitory system integration in the BLA), others are transiently increased (spine density in the PL) or decreased (extinction-induced plasticity) relative to pre-adolescence and adulthood. It is important to note that this schematic is based on studies done in male mice and rats and may differ for females. (b,c) Theoretical scenarios to consider when designing and interpreting developmental fear studies. (b) Little is known about the impact of adolescent stress on the maturation of circuitry related to threat responding. While accelerated development (i.e., heightened plasticity occurs earlier) may occur (scenario #1), it is important to consider how stress may delay the emergence of (scenario #2) or even truncate (scenario #3) the duration of neural plasticity, and thus the timing of sensitive windows. Misalignment in developmentally-expected experiences (such as increased exploration independent of caregivers and increased interaction with novel conspecifics (14, 25) (gray arrows) and periods of increased neural plasticity may disrupt canonical maturation of these threat response systems. (c) When studying potential sex differences, it is important to consider where a male or female rodent is in their development at the time measurements or manipulations are taking place. While a measurement or manipulation (gray arrows) may occur when both males and females are both in a state of heightened neural plasticity (scenario #1), others may occur when either only males (scenario #2) or only females (scenario #3) are experiencing maximum plasticity. For example, measuring extinction retention at the same chronological age in males and females may result in different behavioral phenotypes not because there is a sex difference but because males and females are at different stages of development.