Functional Contribution of the Medial Prefrontal Circuitry in Major Depressive Disorder and Stress-Induced Depressive-Like Behaviors

Abstract

Despite decades of research on the neurobiology of major depressive disorder (MDD), the mechanisms underlying its expression remain unknown. The medial prefrontal cortex (mPFC), a hub region involved in emotional processing and stress response elaboration, is highly impacted in MDD patients and animal models of chronic stress. Recent advances showed alterations in the morphology and activity of mPFC neurons along with profound changes in their transcriptional programs. Studies at the circuitry level highlighted the relevance of deciphering the contributions of the distinct prefrontal circuits in the elaboration of adapted and maladapted behavioral responses in the context of chronic stress. Interestingly, MDD presents a sexual dimorphism, a feature recognized in the molecular field but understudied on the circuit level. This review examines the recent literature and summarizes the contribution of the mPFC circuitry in the expression of MDD in males and females along with the morphological and functional alterations that change the activity of these neuronal circuits in human MDD and animal models of depressive-like behaviors.

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“…mPFC, a hub region in the integration and consolidation of emotional responses to chronic stress, is highly impacted in depressive patients and animal models of chronic stress [ 4 , 56 ]. This complex process appears to involve a series of morphological and anatomical alterations combined with changes in the strength of mPFC inputs from several brain structures [ 57 ].…”

“…It is particularly true considering the low treatment efficacy despite various types of targeted antidepressant drugs. This persistent incapacity for treating depression efficiently results in part from the heterogeneity of the disorder and the insufficient understanding of the functional and molecular mechanisms underlying its onset [ 4 ]. Hence, this is urgent need for immediate and effective treatments for depression with fewer adverse events, and complementary and alternative medicinal therapies, particularly traditional Chinese medicine (TCM), are widely tested for this purpose [ 5 , 6 ].…”

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“…As a central hub that receives input from cortical, thalamic, and limbic regions and sends outputs to structures that regulate emotion, fear, and stress responses, the PFC has been demonstrated to be highly involved with emotional and cognitive processing, and to play a critical role in mood disorders, such as anxiety, depression, and schizophrenia. Previous studies reveal that the PFC is necessary and sufficient for the actions of ketamine ( Lepack et al, 2014 ; Fuchikami et al, 2015 ; Bittar and Labonte, 2021 ). Inactivation of the medial FPC (mPFC), a subregion of PFC, completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models.…”