Linking mPFC circuit maturation to the developmental regulation of emotional memory and cognitive flexibility

Abstract

The medial prefrontal cortex (mPFC) and its abundant connections with other brain regions play key roles in memory, cognition, decision making, social behaviors, and mood. Dysfunction in mPFC is implicated in psychiatric disorders in which these behaviors go awry. The prolonged maturation of mPFC likely enables complex behaviors to emerge, but also increases their vulnerability to disruption. Many foundational studies have characterized either mPFC synaptic or behavioral development without establishing connections between them. Here, we review this rich body of literature, aligning major events in mPFC development with the maturation of complex behaviors. We focus on emotional memory and cognitive flexibility, and highlight new work linking mPFC circuit disruption to alterations of these behaviors in disease models. We advance new hypotheses about the causal connections between mPFC synaptic development and behavioral maturation and propose research strategies to establish an integrated understanding of neural architecture and behavioral repertoires.

Long-Term Consequences of Adolescent Exposure to THC-Rich/CBD-Poor and CBD-Rich/THC-Poor Combinations: A Comparison with Pure THC Treatment in Female Rats

“…In addition, brain development continues throughout adolescence, especially in cortical regions, and involves dramatic changes in gross morphology with a loss of gray and a rise in white matter [30,31]. The PFC is known to reach full development late in adolescence, and alterations in its maturation have been implicated in several psychiatric disorders, such as schizophrenia and depression [32]. Indeed, endophenotypes for both these disorders were described in adult female rats exposed to THC during adolescence [14].…”

“…The functioning of the PFC relies on a balance between excitatory and inhibitory neurotransmission. This excitatory/inhibitory (E/I) balance arises from a complex interplay of heterogeneous glutamatergic and GABAergic neurons interacting within a local circuit [32]. In particular, GABAergic interneurons that express the calcium-binding protein parvalbumin (PV) are major regulators of E/I balance and play an important role in prefrontal-dependent emotional and cognitive behaviors [33].…”

Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Development

“…However, after adolescence an excitatory effect of D2 receptor stimulation emerges in PFC GABAergic interneurons, creating the inhibitory tone characteristic of the mature PFC and balancing the enhanced DA-driven excitation of pyramidal neurons (Tseng and O’Donnell, 2007 ; O’Donnell, 2011 ). The adolescent shift of DAergic regulation over excitatory and inhibitory transmission in the PFC is thought to be a critical step in the developmental calibration of cognitive control (Klune et al, 2021 ), and to be dysregulated in psychiatric disorders of adolescent onset (O’Donnell, 2011 ; Caballero et al, 2016 ; Caballero et al, 2021 ).…”

Cannabidiol Exposure During the Mouse Adolescent Period Is Without Harmful Behavioral Effects on Locomotor Activity, Anxiety, and Spatial Memory

“…Notably, we did not assess measures of cognitive flexibility or working memory that rely heavily on prefrontal cortical circuitry (Hamilton and Brigman, 2015) and undergo maturation during this adolescent time period (Klune et al, 2021), which makes them vulnerable to pharmacological perturbation.…”