Coordinated dysregulation of the hippocampus-amygdala-prefrontal cortex circuit in anxiety and depressive disorders: A narrative review

Abstract

Anxiety and depressive disorders are frequently encountered in clinical practice and often are comorbid with psychiatric problems. Despite distinct diagnostic characteristics, both disrupt emotional regulation, threat appraisal, negative memory processing, and cognitive control. Recent findings indicate that these symptoms may reflect aberrant interactions between neural systems rather than isolated dysfunction within focal brain regions. This narrative review provides an overview of the current findings regarding the hippocampus-amygdala-prefrontal cortex circuit and discusses how integrated dysregulation of this circuit may underlie anxiety, depression, and comorbidities. The hippocampus is involved in contextual and stress-related memory, the amygdala is involved in emotional salience and threat-related learning, and the prefrontal cortex is involved in the regulation of affective states via top-down control. In anxiety disorders, circuit dysfunction may promote biased emotional processing toward threat hypervigilance, fear generalization, and exaggerated anticipation. In depressive disorders, this may underlie negative memory bias, rumination, and cognitive inflexibility. In comorbid forms, threat anticipation and negatively biased memory processing may reinforce one another and maintain long-term symptomatology. Such a circuit-based approach may provide an avenue through which clinical phenomenology can be linked to the underlying neurobiology and may guide future efforts toward biomarker development and intervention.

Keywords: Anxiety disorders; Depressive disorders; Hippocampus; Amygdala; Prefrontal cortex; Functional connectivity; Emotional regulation; Neural circuit

Core Tip: This review highlights that anxiety and depressive disorders involve dysregulation of the hippocampus-amygdala-prefrontal cortex circuit, rather than isolated regional dysfunction. In anxiety, disruption of this circuit promotes hypervigilance to threats and the generalization of fear; in depression, it underlies negative memory bias and cognitive inflexibility. Comorbidity involves the reciprocal reinforcement of threat anticipation and negative memory. This circuit-based perspective links clinical phenomenology to neurobiology, guiding the development of biomarkers and interventions.