Maturational Changes in Prefrontal and Amygdala Circuits in Adolescence: Implications for Understanding Fear Inhibition during a Vulnerable Period of Development

Abstract

Anxiety disorders that develop in adolescence represent a significant burden and are particularly challenging to treat, due in no small part to the high occurrence of relapse in this age group following exposure therapy. This pattern of persistent fear is preserved across species; relative to those younger and older, adolescents consistently show poorer extinction, a key process underpinning exposure therapy. This suggests that the neural processes underlying fear extinction are temporarily but profoundly compromised during adolescence. The formation, retrieval, and modification of fear- and extinction-associated memories are regulated by a forebrain network consisting of the prefrontal cortex (PFC), the amygdala, and the hippocampus. These regions undergo robust maturational changes in early life, with unique alterations in structure and function occurring throughout adolescence. In this review, we focus primarily on two of these regions—the PFC and the amygdala—and discuss how changes in plasticity, synaptic transmission, inhibition/excitation, and connectivity (including modulation by hippocampal afferents to the PFC) may contribute to transient deficits in extinction retention. We end with a brief consideration of how exposure to stress during this adolescent window of vulnerability can permanently disrupt neurodevelopment, leading to lasting impairments in pathways of emotional regulation.

Too much, too young? Altered corticolimbic axonal innervation and resting state functional connectivity suggests sex-dependent outcomes in a rat model of early life adversity

“…The present findings support previous work indicating the distinct functional relationship between the BLA and PL and IL regions of mPFC (Calhoon and Tye, 2015), with PL connectivity related to anxiogenic effects (Felix-Ortiz et al, 2016) and IL connectivity promoting anxiolytic effects (Maroun et al, 2012). Furthermore, these findings are in line with the idea that altered neuroanatomy and functionality of PL and IL, along with BLA, likely have reciprocal effects on one another, further contributing to the exacerbation of ELS-induced anxiety-like phenotypes in adolescence and early adulthood (Likhtik and Paz, 2015;Zimmermann et al, 2019).…”

Adolescent maturation of the prefrontal cortex: Role of stress and sex in shaping adult risk for compromise

“…The adult brain is shaped in part by an increase in pruning and decrease in overall synaptic number that is initiated with the transition from juvenile development to the beginning of the adolescent timeframe (Figure ). From birth through adolescence, gray matter of the brain decreases in a process known as cortical thinning . The decrease in cortical gray matter is due to the pruning of synapses, encompassing a normal decrease in axo‐dendritic, axo‐axonal and axo‐somatic connections that are maintained through experience and activity.…”

“…The rate of change differs within the PFC, with layer V cells showing more hormone‐insensitive pruning than cells that reside in layer II/III . An in‐depth review of these differences in the dynamic nature of changes in the synaptic connections in the PFC has been recently published by Delevich et al and Zimmermann et al…”

“…From birth through adolescence, gray matter of the brain decreases in a process known as cortical thinning. [68][69][70][71] The decrease in cortical gray matter is due to the pruning of synapses, encompassing a normal decrease in axo-dendritic, axo-axonal and axo-somatic connections that are maintained through experience and activity. The rate of change differs within the PFC, with layer V cells F I G U R E 1 Development within the prefrontal cortex (PFC), in a process that is conserved in mammals, continues throughout adolescence.…”

“…67) showing more hormone-insensitive pruning than cells that reside in layer II/III. 68 An in-depth review of these differences in the dynamic nature of changes in the synaptic connections in the PFC has been recently published by Delevich et al 68 and Zimmermann et al 71 Recent studies have suggested a sex difference in synaptic pruning of the PFC during adolescence. Female rats appear to have an earlier peak in synapses than males which could alter the window of sensitivity to exposures between the sexes.…”