Disrupted synapses: prefrontal cortex-reward circuit dysfunction in stress-induced depression-like behaviors

Major depressive disorder (MDD) is a multifactorial, circuit-level disorder often triggered by chronic stress, which fundamentally disrupts the neural networks governing reward processing. Central to this pathology is the prefrontal cortex (PFC), an integration hub exerting top-down executive control over subcortical regions. Here, we synthesize translational and preclinical evidence detailing how chronic stress induces structural, functional, and molecular maladaptations within the PFC and its reward-related downstream projections. By dissecting specific neural pathways-including the PFC's connections to the nucleus accumbens (NAc), ventral tegmental area (VTA), ventral hippocampus (vHIPP), and lateral habenula (LHb)- we map how projection-specific dysregulation drives distinct depressive phenotypes. Furthermore, we examine the cellular mechanisms underlying these circuit alterations, emphasizing the roles of disrupted neuromodulation (dopamine, glutamate, and serotonin), impaired synaptic plasticity, and robust neuroinflammatory cascades. We highlight notable sex-dependent findings where relevant, illustrating how specific transcriptomic, morphological, and circuit-level responses can diverge between males and females. Finally, we discuss the necessity of moving beyond simplistic behavioral dichotomies and integrating multimodal neurobiological approaches. Ultimately, delineating these precise, circuit-specific vulnerabilities provides a critical framework for developing targeted therapeutics for stress-induced affective disorders.