A Critical Period for Prefrontal Network Configurations Underlying Psychiatric Disorders and Addiction

Abstract

The medial prefrontal cortex (mPFC) has been classically defined as the brain region responsible for higher cognitive functions, including the decision-making process. Ample information has been gathered during the last 40 years in an attempt to understand how it works. We now know extensively about the connectivity of this region and its relationship with neuromodulatory ascending projection areas, such as the dorsal raphe nucleus (DRN) or the ventral tegmental area (VTA). Both areas are well-known regulators of the reward-based decision-making process and hence likely to be involved in processes like evidence integration, impulsivity or addiction biology, but also in helping us to predict the valence of our future actions: i.e., what is "good" and what is "bad." Here we propose a hypothesis of a critical period, during which the inputs of the mPFC compete for target innervation, establishing specific prefrontal network configurations in the adult brain. We discuss how these different prefrontal configurations are linked to brain diseases such as addiction or neuropsychiatric disorders, and especially how drug abuse and other events during early life stages might lead to the formation of more vulnerable prefrontal network configurations. Finally, we show different promising pharmacological approaches that, when combined with the appropriate stimuli, will be able to re-establish these functional prefrontocortical configurations during adulthood.

Keywords: basolateral amygdala; critical period; decision-making; prefrontal networks; ventral hippocampus.

Figure 1

(A) Diagram of a sagittal section of the rodent brain illustrating how the integration of information in the medial prefrontal cortex (mPFC) affects both directly (in blue) and indirectly (in red) monoaminergic nuclei in the brain, as an example for the top-down control of the mPFC. The rest of the connections are colored in gray. (B) Diagram illustrating some of the main inputs to the mPFC. We have colored in red the projection from the BLA and in blue the projection from the vHC: two regions we hypothesize to compete for target innervation in the mPFC. The rest of the connections are colored in gray.

Figure 2

Diagram showing two different neurodevelopmental trajectories according to its prefrontocortical inputs: (1) an amygdaloid-dominant scenario, with strong projections from the basolateral amygdala to the mPFC, with increased volume in the amygdala which, as discussed in the main text, is related to increased fear expression and neuropsychiatric disorders; and (2) a hippocampal-dominated network, associated to antidepressant action and increased neuroplasticity. We also indicate the possibility of new treatments able to revert the network configuration as explained in the main text.