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

Table 1 Representative evidence supporting hippocampus-amygdala-prefrontal cortex circuit involvement in anxiety and depressive disorders

Ref.	Study type	Main focus	Key finding	Relevance to this review
Hare and Duman[1], 2020	Narrative review	Prefrontal cortex circuits in depression and anxiety	Prefrontal circuits and their target regions contribute to affective symptoms	Supports the circuit-based framework of anxiety and depression
Cha et al[6], 2016	Clinical neuroimaging study	Hippocampal structure and function in clinical anxiety with comorbid depression	Abnormal hippocampal structure and function were observed in clinical anxiety and comorbid depression	Supports hippocampal involvement in anxiety-depression comorbidity
Tang et al[7], 2018	Meta-analysis	Amygdala resting-state functional connectivity in major depressive disorder	Abnormal amygdala connectivity with hippocampal and prefrontal regions was reported	Supports amygdala-centered circuit dysregulation in depression
Robinson et al[9], 2014	Observational imaging study	dmPFC/ACC-amygdala circuit in generalized and social anxiety disorders	A dorsal medial prefrontal anterior cingulate cortex-amygdala aversive amplification circuit was identified	Supports anxiety-specific frontolimbic dysregulation
Padilla-Coreano et al[10], 2016	Animal circuit study	Ventral hippocampal-prefrontal input in anxiety-like behavior	Direct ventral hippocampal-prefrontal input was required for anxiety-related neural activity and behavior	Provides mechanistic support for hippocampus-prefrontal involvement in anxiety
Kim and Whalen[23], 2009	Diffusion imaging study	Structural integrity of an amygdala-prefrontal pathway and trait anxiety	Amygdala-prefrontal pathway integrity predicted individual differences in trait anxiety	Supports a structural connectivity basis for frontolimbic regulation
Kaiser et al[28], 2015	Meta-analysis	Large-scale resting-state networks in major depressive disorder	Major depressive disorder was associated with large-scale network dysfunction	Places the hippocampus-amygdala-prefrontal cortex circuit in a broader network context
Gray et al[29], 2020	Multimodal meta-analysis	Structural and functional abnormalities in major depressive disorder	Convergent abnormalities involved limbic and prefrontal regions	Supports multimodal evidence for limbic-prefrontal involvement in depression
Espinoza Oyarce et al[31], 2020	Systematic review and meta-analysis	Brain volume differences in clinical depression with anxiety	Anxiety comorbidity was relevant to structural brain differences in depression	Supports the importance of considering comorbid anxiety in depressive disorders
Xu et al[32], 2021	Comparative connectivity study	Intrinsic connectivity differences between major depressive disorder and generalized anxiety disorder	Different connectivity patterns helped distinguish major depressive disorder from generalized anxiety disorder	Supports both shared and disorder-specific circuit mechanisms

dmPFC: Dorsomedial prefrontal cortex; ACC: Aanterior cingulate cortex.

Table 2 Functional roles and proposed alterations of the hippocampus, amygdala, and prefrontal cortex in anxiety and depressive disorders

Brain region	Main functional role	Proposed alteration in anxiety disorders	Proposed alteration in depressive disorders	Clinical relevance
Hippocampus	Contextual memory, stress-related adaptation, and safety-threat discrimination	Impaired contextual discrimination and fear generalization	Negative memory bias and impaired contextual updating	Excessive worry, avoidance, rumination, and difficulty updating emotional meaning
Amygdala	Emotional salience, threat detection, and fear learning	Increased threat sensitivity and hypervigilance	Heightened response to negative emotional information	Fear, negative affect, emotional persistence, and increased salience of adverse experiences
Prefrontal cortex	Top-down regulation, cognitive control, and emotional appraisal	Insufficient or maladaptive control of threat responses	Impaired regulation of negative affect and repetitive thinking	Emotional dysregulation, cognitive inflexibility, rumination, and impaired reappraisal