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.

Non-cell autonomous OTX2 transcription factor regulates anxiety-related behavior in the mouse

“…It has been hypothesized that critical periods impact the development of mood disorders such as anxiety and schizophrenia (21)(22)(23). Supporting the above-mentioned maternal separation results, we recently found that the Otx2 +/AA mice display prolonged acquisition of acoustic preference in adulthood linked to anxiolysis (20).…”

Critical periods shaping the social brain: A perspective from Drosophila

“…[6,7] Being able to use this knowledge and manipulate the course and duration of a CP might have an enormous therapeutic poten-tial for a variety of developmental cognitive disabilities, as well as recovery from brain injuries and stroke. [1,8,9] There is a special need to develop new models that specifically address these topics and that provide the ability to control plasticity in the adult brain.…”

“…[ 6,7 ] Being able to use this knowledge and manipulate the course and duration of a CP might have an enormous therapeutic potential for a variety of developmental cognitive disabilities, as well as recovery from brain injuries and stroke. [ 1,8,9 ] There is a special need to develop new models that specifically address these topics and that provide the ability to control plasticity in the adult brain. In this review we consider the most recent studies focusing on CPs in fruit fly Drosophila melanogaster (Figure 1) that provide new insights into regulatory mechanisms, opportunities for in vivo CP manipulations and linking them with maturation of social behaviors.…”

Optical activation of TrkB neurotrophin receptor in mouse ventral hippocampus promotes plasticity and facilitates fear extinction

“…The CA1 region of the vHP in particular sends strong projections to other regions, such as the BA, hypothalamus, nucleus accumbens, and the mPFC (47)(48)(49)(50), and there is evidence that these projections process emotional behavior (51)(52)(53). In addition, impaired function in Hippocampal-prefrontal circuit has been observed in psychiatric patients including PTSD and schizophrenic subjects (54), and configurational changes in prefrontocortical inputs from Amygdala and Hippocampus have been suggested as a possible mechanism underlying psychiatric disorders (55). Furthermore, it has been reported that BDNF infusion into the PFC and HP erases fear memory (56), and engram cells of projection neurons in CA1 of vHC play a necessary and sufficient role in social memory (57).…”

“…CC-BY-NC-ND 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted February 14, 2021. ; https://doi.org/10.1101/2021.02.14.431126 doi: bioRxiv preprint inputs from Amygdala and Hippocampus have been suggested as a possible mechanism underlying psychiatric disorders (55). Furthermore, it has been reported that BDNF infusion into the PFC and HP erases fear memory (56), and engram cells of projection neurons in CA1 of vHC play a necessary and sufficient role in social memory (57).…”