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.

Key Words: 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.

INTRODUCTION

Anxiety and depression are widely comorbid and prevalent mental disorders encountered in current clinical practice. Although they differ in diagnostic features and clinical presentations, the shared features of chronic negative affect and dysregulated emotional states suggest that the same or similar brain regions may be involved in the pathophysiology of these disorders. Anxiety and depressive disorders may reflect dysfunctional interactions between the neural circuits that mediate contextual memory and emotional salience[1,2]. However, previous studies have focused on monoaminergic abnormalities, endocrine stress responses, and limbic hyperactivity. Although useful, these modes do not fully explain symptom heterogeneity, high comorbidity, or variable treatment responses. Over the past decades, there has been an increasing focus on circuit-level mechanisms in neuroimaging and experimental neuroscience. From this perspective, psychiatric symptoms are not simply interpreted as the result of localized dysfunction in a single brain region. Instead, they may reflect disrupted neural processing across distributed circuits. Over time, persistent symptoms may further influence neural function and lead to a reciprocal relationship between clinical symptoms and circuit dysfunction[1,3].

The hippocampus-amygdala-prefrontal cortex circuit is particularly relevant to anxiety and depression, in which the hippocampus contributes to contextual memory and stress-related adaptation, the amygdala supports emotional salience and threat-related learning, and the prefrontal cortex exerts cognitive control over limbic responses. The influential learning of emotional salience is supported by the amygdala. The prefrontal cortex exerts cognitive control and modulates limbic activity based on immediate goals and the situational environment[4,5]. Under adaptive conditions, these regions cooperate to distinguish danger from safety, update emotional memories, and regulate affective responses. When this circuit is dysregulated, emotional responses may become excessive, negative memories may persist, and prefrontal regulatory control may become insufficient.

Evidence from clinical neuroimaging, meta-analytical studies, and experimental circuit research supports the relevance of these regions and their interactions, although direct evidence supporting a unified three-node model remains incomplete. Human neuroimaging studies have indicated aberrant hippocampal morphology and function in patients with clinical anxiety and comorbid depression[6]. Meta-analyses of major depressive disorder(s) have shown altered resting-state functional connectivity between the amygdala and the hippocampal and prefrontal areas[7]. Research investigating anxiety disorders has also implicated the disruption of amygdala-prefrontal connectivity in threat processing and fear regulation[8,9]. Moreover, animal experiments offer a mechanistic rationale that the direct ventral hippocampal projections to the medial prefrontal cortex mediate anxiety-like neuronal and behavioral outputs[10].

The present review provides an overview of the dysregulated coordination among the hippocampus, amygdala, and prefrontal cortex in anxiety and depressive disorders through a series of related studies. The key message is that anxiety and depression may be conceptualized - at least in part - as sequentially related but separable clinical manifestations of dysregulated interactions among contextual memory, emotional salience, and prefrontal emotional modulation. Representative clinical and experimental evidence supporting the participation of this circuit in anxiety and depressive disorders is summarized in Table 1.

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.

In this review, coordinated dysregulation refers to a state in which deviations in contextual memory, emotional salience, and prefrontal regulatory control interact, as opposed to independent regional abnormalities. However, this does not exclude the importance of local abnormalities in individual brain regions. Instead, it emphasizes that local alterations in the hippocampus, amygdala, and prefrontal cortex may have greater clinical significance when they disrupt communication across broader circuits. For example, heightened amygdala reactivity, impaired hippocampal contextual processing, or inefficient prefrontal control may contribute to symptoms, but their interaction may better explain persistent negative affect, fear generalization, rumination, and comorbidity. Thus, coordinated dysregulation should be understood as a circuit-level extension of local dysfunction, rather than as an alternative.

LITERATURE SEARCH AND STUDY SELECTION

PubMed, Google Scholar, and Web of Science were searched for English-language articles published between database inception and May 2026. The search terms included combinations of “hippocampus”, “amygdala”, “prefrontal cortex”, “anxiety”, “depression”, “major depressive disorder”, “generalized anxiety disorder”, “functional connectivity”, “fear extinction”, and “emotional memory”. The search was designed to identify studies directly addressing hippocampal, amygdala, or prefrontal mechanisms in anxiety or depressive disorders.

The preferred types of studies were meta-analyses, systematic reviews, representative neuroimaging studies, and experimental circuit studies. Studies were considered eligible if they addressed at least one of the following topics: Structural or functional abnormalities of the hippocampus, amygdala, or prefrontal cortex; connectivity among these regions; symptom-related circuit mechanisms in anxiety or depression; comorbidity between anxiety and depressive disorders; or treatment-related modulation of prefrontal-limbic circuits. Studies were excluded if they were unrelated to anxiety or depressive disorders, focused only on non-affective neurological conditions, lacked direct relevance to hippocampal, amygdala, or prefrontal mechanisms, or were not published in English.

Two authors independently screened titles, abstracts, and full texts for relevance. Disagreements were resolved through discussions with a third author. Additional references were identified by manually screening the reference lists of the relevant articles. Because this was a narrative review, no quantitative synthesis or formal risk-of-bias assessment was performed. A total of 37 references were included in the final narrative synthesis.

FUNCTIONAL ARCHITECTURE OF THE HIPPOCAMPUS-AMYGDALA-PREFRONTAL CORTEX CIRCUIT

The hippocampus, amygdala, and prefrontal cortex are functionally interconnected and collectively mediate emotional adaptations. Each area plays a unique role; however, their importance in anxiety and depression is primarily derived from their interactions. Contextual information and memory are obtained from the hippocampus. The amygdala tags for external and internal events with emotional relevance. The prefrontal cortex assesses emotional input and controls behavioral execution[4,5]. However, this is not a straightforward linear pathway. The flow of information is bidirectional, and the effect in each region varies as a function of emotional state, environmental context, developmental stage, and previous stress exposure. In anxiety and depression, dysfunctional connectivity among these areas can lead to chronic negative effects, even in the absence of immediate external threats. This may explain why symptoms sometimes persist following the resolution of the initial stressor.

The hippocampus and contextual-emotional memory

The hippocampus is known for its role in learning and memory. However, its involvement in mood and emotional disorders is not limited to declarative memory. This is essential for contextual, time-, and stress-responsive adaptation[11,12]. In anxiety disorders, impaired hippocampal function may interfere with the ability to discriminate between threatening and non-threatening situations. This may result in the spread of fear and long-term threat expectations. In depressive disorders, hippocampal impairment may underlie negative memory bias, difficulty in updating emotional meaning, and inflexible thinking[13,14].

Recent studies have identified the hippocampus as a circuit hub for anxiety-related behaviors. A review of the molecular, cellular, and circuit properties of the hippocampus in anxiety highlighted that the hippocampal subregions are reciprocally interconnected with the medial prefrontal cortex and basolateral amygdala, which are key nodes of emotional regulation[15]. This is consistent with the concept that the hippocampus mediates anxiety via distributed circuit interactions rather than mnemonic functions alone.

Clinical data have indicated that hippocampal abnormalities are associated with anxiety and depressive comorbidities. Cha et al[6] found aberrant hippocampal structure and function in patients with clinical anxiety and comorbid depression. Their results indicated that microstructural abnormalities in the hippocampus, combined with altered threat learning, can be a neural pathway linking anxiety and depression. This finding is significant given that it implicates the hippocampus in both threat processing and affective comorbidities.

The amygdala and emotional salience

The amygdala is critical for emotional salience, threat detection, and learning fear[4,16]. It facilitates fast processing of emotionally meaningful stimuli and contributes to the organization of behavioral and physiological reactions. Activation of the amygdala is widely regarded as an index of increased threat sensitivity in anxiety disorders; however, it should not be treated as a fear center. It is involved in salience detection and serves as an interface between memory and regulatory processes.

Amygdalar dysfunction is fundamentally important for negative emotional bias in depressive illnesses. Patients with depression also tend to exhibit biased processing toward negative stimuli and have trouble disengaging from negative information[13,17]. Such processes could be reinforced if amygdala activity is strongly coupled with memory systems or weakly governed by the prefrontal regions.

A recent meta-analysis comparing amygdala resting-state functional connectivity in adults and adolescents with major depressive disorder found aberrant amygdala connectivity in the hippocampal and prefrontal regions[7]. This demonstrates that amygdala-focused dysregulation in depression is not regionally limited to emotional reactivity. In addition, there is a disrupted interaction between the memory and regulatory systems.

The prefrontal cortex and top-down regulation

The prefrontal cortex is also involved in cognitive control, emotional evaluation, behavioral inhibition, and the modulation of limbic activity. It has functionally distinct subareas. The medial prefrontal cortex is intimately involved in emotional appraisal and fear extinction. Executive control is supported by the dorsolateral prefrontal cortex, while the anterior region is involved in conflict monitoring and affective regulation[1,18].

In anxiety and depression, prefrontal dysfunction may manifest as inadequate suppression of emotional responses, reduced cognitive flexibility, and excessive persistence of negative rumination. However, this deficit may not indicate an exaggeration of all prefrontal functions. For example, maladaptive monitoring may be associated with increased activity in some prefrontal areas and a lack of top-down control over limbic responses[1,19]. Thus, the problem is not a simple diminution of prefrontal function, but of region-specific regulation of the limbic and memory systems.

A circuit-based review of prefrontal contributions to depression and anxiety has revealed the significance of distinct neuronal populations and target areas[1]. This view is significant because it transcends the general assertion that the prefrontal cortex needs to be “fixed” or is not working properly. Instead, it supports the concept that specific projections from the prefrontal cortex are involved in emotional symptoms and responses to treatment. Collectively, these 3 areas comprise the basic circuitry of contextual memory, emotional salience, and top-down regulation. The roles of these structures and proposed changes in anxiety and depressive disorders are summarized in Table 2.

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

HIPPOCAMPUS-AMYGDALA INTERACTION IN ANXIETY AND DEPRESSION

Hippocampus-amygdala coupling links contextual memory to emotional salience. During adaptive emotional processing, information from the hippocampus is used as a contextual guide to determine whether an emotional reaction is necessary. The amygdala assigns emotional salience to and supports affective learning. When this crosstalk is perturbed, emotional memories can be generalized to the point where neutral contexts themselves are perceived as threatening or negative[4,11].

In anxiety disorders, dysfunctional hippocampal-amygdala communication may promote fear generalization. An individual may treat uncertain situations as dangerous because they have a diminished capacity for contextual discrimination. This process is clinically relevant for excessive worry and avoidance. The hippocampus may not encode safety signals, whereas the amygdala assigns high emotional salience to ambiguous stimuli[8,15].

The fear conditioning and extinction paradigms also offer an informative template for examining this interaction. Extinction learning is believed to require interaction between the amygdala, hippocampus, and ventromedial prefrontal cortex[18]. Contextual information provided by the hippocampus indicates an extinguished fear response to stay suppressed or return to a subsequent environment. When hippocampal contextual control is breached, fear temporally reemerges despite previous extinction training[12,20].

In depression, dysregulation of the hippocampal-amygdala may underlie the maintenance of negative memory bias. The amygdala may also influence hippocampal memory consolidation and promote the persistence of emotionally significant memories[21,22]. This process is clinically important because the repetitive processing of information that is characteristic of depressive symptomatology often consists of repeated retrieval of negative events and an inability to use positive information. When hippocampal-based memory systems abnormally interface with the amygdala, negative memories may be biased toward becoming more emotionally potent and easily accessed. This may lead to depressive rumination[13,17].

This interaction is further supported by findings in major depressive disorders, thereby increasing its clinical relevance. Tang et al[7] described several abnormal amygdala-hippocampal and para-hippocampal couplings in adults with depression. This means that emotional salience and memory processing systems are modified together in depressive illnesses. Nevertheless, direct evidence associating hippocampus-amygdala coordination with depressive rumination is not as rich as that of more general emotional memory processes. For this reason, the interpretation should be considered biologically plausible and not scientifically proven.

Hippocampal-amygdala interplay may also explain this comorbidity. Anxiety and depression are fused by a shared bias toward upsetting interpretation, affective inertia, and inflexibility in revising emotional information. Anxiety can manifest as inflated threat expectations. Depression may manifest as unrelenting negative self-referential memories. In the comorbid form, these mechanisms potentially amplify one another.

AMYGDALA-PREFRONTAL DYSREGULATION AND IMPAIRED EMOTIONAL CONTROL

The amygdala-prefrontal pathway is one of the most studied circuits in anxiety and depression. This pathway serves as a top-down regulator of emotional salience. In the context of adaptive functioning, the prefrontal areas regulate amygdala activity based on contextual significance and behavioral objectives. When this modulation is dysfunctional, emotional reactions may become overblown or unremitting[1,18].

Amygdala-prefrontal dysregulation may produce a heightened sensitivity to threats in anxiety disorders. The amygdala may respond strongly to ambiguous or negative stimuli, whereas prefrontal control may be insufficient to regulate this response. However, this relationship does not always involve a simple reduction in prefrontal regulation. An observational study of unmedicated generalized and social anxiety disorders described a dorsal medial prefrontal anterior cingulate cortex-amygdala aversive amplification circuit[9]. This suggests that some anxiety states may involve exaggerated prefrontal-amygdala coupling during aversive processing, rather than reduced regulatory control.

Structural connectivity also supported the relevance of this pathway. Kim and Whalen[23] reported that the structural integrity of the amygdala-prefrontal pathway predicts trait anxiety. This finding suggests that the anatomical features of frontolimbic communication may influence vulnerability to anxiety.

In depressive disorders, amygdala-prefrontal dysregulation may contribute to negative emotional bias and impaired affective control. Patients with depression may have difficulty disengaging from negative stimuli and have a reduced ability to reinterpret emotional experiences. These symptoms are consistent with abnormal communication between the amygdala and prefrontal regulatory regions[7,24].

The direction of amygdala-prefrontal abnormalities may vary across studies due to differences in task design, medication status, illness duration, and symptom profiles. Resting-state studies capture intrinsic connectivity patterns, whereas emotional-task studies capture state-dependent responses to specific stimuli. Therefore, these inconsistent findings should not be interpreted as failures of the circuit model. This more likely indicates that the amygdala-prefrontal interaction is dynamic and context-dependent.

HIPPOCAMPUS-PREFRONTAL DYSREGULATION IN STRESS, MEMORY CONTROL, AND RUMINATION

The hippocampal-prefrontal pathway links memory systems to cognitive control. This pathway enables the evaluation, update, and regulation of emotional memory. This system also mediates flexible adaptations to changing environmental demands. Disruptions in this path may hinder the ability to reframe past events and pacify worries about the future[10,12].

Animal studies have provided important mechanistic evidence for this pathway. Padilla-Coreano et al[10] reported that direct ventral hippocampal-prefrontal input is required for anxiety-related neural activity and behavior. This result provides additional evidence supporting the causal involvement of hippocampal-prefrontal interactions in regulating anxiety-like behavior in animal models and increases the biological plausibility of the circuit model.

In anxiety disorders, hippocampal-prefrontal dysfunction may contribute to excessive anticipation and impaired contextual updating. A person may continue to expect danger even when current evidence indicates safety. In depressive disorders, this pathway may contribute to rumination and cognitive inflexibility because negative memories may repeatedly enter conscious thought, while the prefrontal systems fail to shift attention or update their meaning[13,25].

This pathway is also associated with stress. For example, chronic stress may affect hippocampal plasticity and prefrontal function[26,27]. As the ability of the hippocampus to perform contextual discrimination wanes, and the ability of the prefrontal cortex to provide cognitive regulation wanes, emotional responses are increasingly likely to reflect rigidity. This inflexibility is evident in the clinic in terms of enduring worry and repetitive negative thinking.

SYMPTOM MAPPING IN ANXIETY DISORDERS

As an application of the circuit framework, anxiety symptoms can be mapped onto the different components of the hippocampus-amygdala-prefrontal cortex circuit. Threat hypervigilance is strongly associated with increased amygdalar salience and altered prefrontal modulation. Fear overgeneralization may reflect a greater impairment in hippocampal contextual discrimination or an inability to distinguish between what is safe and dangerous[9]. These behaviors of overanticipation and chronic worry may be related to hippocampus-prefrontal circuit abnormalities because threat estimation related to the future relies on both contextual memory and cognitive control.

This mapping based on symptoms does not imply that each symptom is generated by a single pathway. Instead, anxiety symptoms may emerge from a circuit that is preferentially tuned to quickly detect threats and slowly learn safety. Avoidance may also sustain this asymmetry by creating a gap between exposure and disconfirmatory safety evidence. Ongoing threat monitoring may increase cognitive load and reduce flexible prefrontal regulation over time.

SYMPTOM MAPPING IN DEPRESSIVE DISORDERS

Another application of the circuit framework is that depressive symptoms can be interpreted through symptom-level circuit mechanisms. Negative memory bias may indicate altered hippocampus-amygdala interactions underlying the dysfunction in hippocampal memory systems modulated by emotionally salient amygdala activity. Weakened hippocampal-prefrontal regulation may also characterize rumination because a repetitive negative thinking style hinges on sustained memory retrieval and poor cognitive disengagement. Disrupted reappraisal may represent diminished or suboptimal amygdala-prefrontal modulation, constraining the capacity to cognitively reframe negative events.

This model aligns with the concept that major depressive disorders involve widespread network disruptions, such as in the limbic and prefrontal areas. Resting-state and multimodal neuroimaging meta-analyses on a large scale suggest that depressive pathology should not be distilled down to a single circuit[28,29]. Instead, the hippocampus-amygdala-prefrontal cortex circuit may be considered to be a clinically significant subnetwork within a broader affective and cognitive control system.

SHARED AND DISTINCT MECHANISMS BETWEEN ANXIETY AND DEPRESSION

Anxiety and depression have multiple circuit-level abnormalities in common, but they are not one and the same. The similarities and differences between the 2 disorders can be understood in terms of common underlying deficits in emotional salience and regulatory control, disturbed emotions, and differential deficits in memory-related processing and cognitive appraisal[2,30].

A shared mechanism involves an imbalance between limbic reactivity and prefrontal regulation. Emotional signals may be difficult to regulate in both anxiety and depression. Anxiety often emphasizes threat anticipation, whereas depression often emphasizes negative self-referential interpretations. Both processes require interactions among the amygdala, hippocampus, and prefrontal cortex.

Another shared mechanism involves abnormal processing of negative information. In anxiety, negative information is often interpreted as dangerous. In patients with depression, negative information is often integrated into memory and self-evaluation. The hippocampus and amygdala may support both forms of negative bias, whereas the prefrontal cortex may influence whether the bias is corrected or maintained.

However, these disorders may differ in the dominant direction of dysregulation. Anxiety may be more closely related to threat hypervigilance and the generalization of fear. Depression is closely associated with negative memory persistence and impaired cognitive flexibility. This distinction is clinically useful because it suggests that the same circuit can produce different symptoms, depending on which process dominates.

However, comorbidities may occur when these processes converge. Patients with anxiety and depression may exhibit excessive anticipation of threats and persistent negative memory biases. The same individual may also exhibit reduced prefrontal capacity to regulate both future-oriented worry and past-oriented rumination. A systematic review and meta-analysis of volumetric brain differences in clinical depression with anxiety supported the relevance of anxiety comorbidities when interpreting structural findings in depression[31].

As such, direct comparative studies are necessary. One study reported that the intrinsic connectivity of the prefrontal cortex and striato-limbic system may help differentiate major depressive disorder from generalized anxiety disorder[32]. This finding suggests that shared symptoms do not necessarily indicate identical neural mechanisms. Therefore, future studies should investigate both transdiagnostic and disorder-specific circuit features.

This differentiation is not merely conceptual but will be translated for practical use in future research. By combining anxious and depressive samples without accounting for comorbidities, research that does not specifically model these disorders may be less clear in identifying features unique to each disorder. Conversely, research showing that anxiety comorbidity is merely a secondary clinical feature may neglect perhaps the most substantial heterogeneity source in depression research. Therefore, further research should examine anxiety symptoms, depressive symptoms, and their interactions rather than treating comorbidities only as an exclusion criterion.

MOLECULAR AND PHYSIOLOGICAL MECHANISMS UNDERLYING CIRCUIT DYSREGULATION

Circuit abnormalities do not occur in isolation. They are influenced by the molecular, cellular, and physiological processes that affect synaptic plasticity and neural communication. Stress-related endocrine changes, excitatory-inhibitory imbalance, neuroplasticity alterations, and inflammation may contribute to dysregulation of the hippocampus-amygdala-prefrontal cortex circuit. Regulation via the hippocampus and prefrontal cortex can be affected by chronic stress because limbic activation is potentiated[26,27]. Chronic stress may attenuate context-based processing in the hippocampus, increase the responsivity of the amygdala, and impair regulation mediated by the prefrontal cortex. This could render the circuit more sensitive to negative inputs and less capable of flexible updating, which is consistent with clinical observations that protracted stress leads to vulnerability to anxiety and depression.

Excitatory and inhibitory actions may also play a role in the circuit dynamics. Glutamatergic and GABAergic signaling regulate local processing and long-range interactions among the hippocampus, amygdala, and the prefrontal cortex[33,34]. Hippocampal fidelity of encoding may be influenced by an excitation-inhibitory imbalance, strengthened amygdala salience signaling, and weakened prefrontal control. These pathways may explain why some glutamatergic treatments lead to rapid alterations in depression-related behaviors.

Neuroplasticity is a critical mechanism. The hippocampus and prefrontal cortex are particularly vulnerable to stress-induced structural and functional synaptic modifications[14,26]. Diminished plasticity can reduce an individual’s capacity to update adverse memories and acquire new emotional associations. By contrast, maladaptive plasticity may strengthen anxiety in threat-related circuits.

Circuits may also play a role in peripheral inflammation, which may further influence neurotransmission, endocrine function, and neuronal connectivity[35,36]. Although the causal pathway remains unclear, inflammatory signaling may affect this circuit through direct effects on synaptic plasticity and functional connectivity in the prefrontal and limbic regions. This is an area for further research because inflammatory processes may be useful in delineating clinically meaningful subgroups of anxiety and depression.

THERAPEUTIC IMPLICATIONS

The hippocampal-amygdala-prefrontal cortex model has therapeutic implications because it frames the treatment response as a change in circuit communication, rather than only as symptom reduction. Pharmacological treatments may influence this circuit by affecting neurotransmission, stress responsiveness, and synaptic plasticity. Rapid-acting antidepressant strategies further suggest that plasticity-related changes in the prefrontal and limbic systems may be clinically relevant, although current evidence does not justify the simple claim that these treatments directly normalize the full three-node circuit in all patients[1,14,34].

Neuromodulation is particularly relevant, because repetitive transcranial magnetic stimulation commonly targets the dorsolateral prefrontal cortex. Although stimulation is delivered to the cortical region, its clinical effects may involve broader changes in prefrontal-limbic communication[37]. This makes neuromodulation a useful approach for testing whether strengthening prefrontal control can improve emotional symptoms.

Specific treatment-related findings support the relevance of the circuit perspective. For example, studies on repetitive transcranial magnetic stimulation have shown that stimulation of the dorsolateral prefrontal cortex may influence broader networks involved in depressive symptoms, including prefrontal-limbic and default-mode network interactions. Past research on rapid-acting antidepressants also suggests that glutamatergic modulation and synaptic plasticity may alter prefrontal and limbic circuit functions. In psychotherapy, exposure-based approaches can be interpreted through fear extinction mechanisms involving the amygdala, hippocampus, and ventromedial prefrontal cortex, whereas cognitive behavioral therapy may strengthen reappraisal-related prefrontal regulation[18,20]. These examples therefore suggest that effective interventions may influence symptoms, partly by modifying communication within or around the hippocampus-amygdala-prefrontal cortex circuit.

LIMITATIONS OF CURRENT EVIDENCE

Despite the positive implications of this review, it has some limitations. First, most human neuroimaging studies have used cross-sectional rather than longitudinal designs. These can reveal associations between symptoms and connectivity but cannot address whether circuitry dysfunction is a cause of anxiety or depression. Second, anxiety and depression are heterogeneous. There are different symptom constellations in major depressive disorders, and even within anxiety disorders, the type of threat-processing that predominates within the clinical picture differs. Heterogeneous patients in such analyses may also obscure circuit patterns related to subpopulations. In addition, medication status, illness duration, trauma history, sleep disturbance, and age have been found to influence findings in the brain, which may explain inconsistencies across studies, but better control for these variables or conceptualize them as clinically meaningful moderators become necessary in future studies. Meanwhile, the hippocampus, amygdala, and prefrontal cortex differ in function and connectivity, and global region-of-interest analyses may, therefore, miss critical subregional effects. Thus, more targeted analyses of these subregions could potentially improve mechanistic interpretations. Finally, animal studies and human imaging are conducted at different levels of analysis; therefore, integrating insights from both can clarify how experimentally identified mechanisms in animals inform the understanding of human psychiatric symptoms and guide translational progress.

FUTURE DIRECTIONS

Future investigations should advance from local regional abnormalities to study the hippocampus-amygdala-prefrontal cortex network as a whole. Longitudinal imaging studies can determine whether circuit dysregulation is predictive of illness onset, relapse, or response to treatment. Multimodal investigations can integrate structural scans with functional connectivity to yield a more holistic understanding of circuit function[29]. Research should distinguish between shared and disorder-specific mechanisms. Therefore, direct comparisons between anxiety disorders, depressive disorders, and comorbid presentations are required. Future studies should examine whether threat anticipation, negative memory bias, and rumination are associated with different patterns of circuit dysregulation[31,32].

Treatment studies should test whether changes in circuit connectivity mediate symptom improvements. This would help to determine whether the circuit is only a marker of illness or a modifiable mechanism. This study may also support personalized treatment selection. Future studies should examine whether baseline resting-state functional connectivity can predict treatment outcomes in major depressive disorder.

Moving forward, research should integrate the developmental stages. Adolescence, adulthood, and aging may have relatively distinct prefrontal cortex functional patterns. A direct comparison meta-analysis of amygdala resting-activity connectivity in both adults and adolescents with major depressive disorder further reinforces the significance of the developmental stage[7]. Finally, circuit-defined biomarker approaches may contribute to bridging group-based neuroimaging findings with the clinical care of individual patients. Nevertheless, these approaches should be verified in independent cohorts and cautiously interpreted before clinical use.

Future studies should strengthen the causal inferences by combining longitudinal cohort designs, intervention studies, and causal modeling approaches. Prospective imaging studies may clarify whether circuit alterations precede symptom onset or emerge because of persistent symptoms. Intervention studies may further determine whether changes in hippocampus-amygdala-prefrontal connectivity mediate clinical improvements. Computational approaches, including dynamic causal modeling or related network-based methods, may help test the directional interactions among the three nodes.

Future studies should also examine circuit patterns across different clinical subtypes and symptom dimensions. Anxiety disorders differ in their predominance of fear, worry, avoidance, and somatic arousal, whereas depressive disorders vary in their degree of rumination, anhedonia, cognitive impairment, and anxiety comorbidities. Stratifying patients based on comorbidity patterns and dominant symptom dimensions may help to identify more specific circuit signatures than broad diagnostic categories alone.

CONCLUSION

Anxiety and depressive disorders exhibit shared and disorder-specific alterations in emotion regulation, memory processing, and cognitive control. The hippocampus-amygdala-prefrontal cortex circuit offers a parsimonious explanation for these disruptions. The hippocampus provides contextual and mnemonic data. The amygdala assigns emotional salience and mediates threat-related learning. The prefrontal cortex regulates affective responses and supports flexible appraisal. Dysfunction of this circuit may result in distinct clinical manifestations depending on the dominant type of aberrant signaling. This circuit may shift toward threat detection, fear generalization, and hyperanticipation in anxiety. In depression, this circuit may be biased toward negative memory persistence, rumination, and diminished cognitive flexibility. In comorbid conditions, these processes may potentiate one another, resulting in more chronic or severe symptoms.

Modern neuroimaging, meta-analyses, and experimental evidence support the relevance of this circuit model. However, most of the results have been correlational; as such, further longitudinal and mechanistic investigations are required. The hippocampus-amygdala-prefrontal cortex circuit should be viewed as a convergent explanatory framework - rather than a complete etiological framework - for anxiety and depression. A circuit-based perspective may help link biological mechanisms with clinical symptoms and define the future direction of biomarkers and mechanism-based therapeutics.