MaltSci 麦伴科研

Appearance

Popular Reports / Neuroscience

This report is written by MaltSci based on the latest literature and research findings

What are the neural mechanisms of anxiety disorders? ​

Abstract ​

Anxiety disorders are prevalent mental health conditions characterized by excessive fear and anxiety responses, significantly impacting individuals' quality of life. Understanding the neural mechanisms underlying these disorders is crucial for developing effective treatments. This review synthesizes current research on the neuroanatomy of anxiety, highlighting the roles of key brain regions such as the amygdala, prefrontal cortex, and hippocampus. The amygdala is pivotal for emotional processing and threat detection, while the prefrontal cortex is essential for regulating fear responses and decision-making. Dysregulation of neurotransmitter systems, particularly serotonin, dopamine, and GABA, is also implicated in the pathophysiology of anxiety disorders. Genetic predispositions and environmental factors further complicate the presentation of these disorders, indicating a need for personalized treatment strategies. Current therapeutic approaches include pharmacological treatments, psychotherapy, and emerging therapies, with a growing emphasis on integrating neurobiological insights into clinical practice. Future research directions focus on utilizing neuroimaging and animal models to deepen our understanding of anxiety mechanisms and enhance treatment efficacy.

Outline ​

This report will discuss the following questions.

  • 1 引言
  • 2 Neuroanatomy of Anxiety Disorders
    • 2.1 The Role of the Amygdala
    • 2.2 Prefrontal Cortex Functionality
    • 2.3 Hippocampal Involvement
  • 3 Neurotransmitter Systems
    • 3.1 Serotonin and Anxiety
    • 3.2 The Dopaminergic System
    • 3.3 GABAergic Mechanisms
  • 4 Genetic and Environmental Factors
    • 4.1 Genetic Predispositions
    • 4.2 Environmental Influences
    • 4.3 Gene-Environment Interactions
  • 5 Current Therapeutic Approaches
    • 5.1 Pharmacological Treatments
    • 5.2 Psychotherapy
    • 5.3 Emerging Therapies
  • 6 Future Directions in Research
    • 6.1 Neuroimaging Studies
    • 6.2 Animal Models
    • 6.3 Personalized Medicine Approaches
  • 7 总结

1 Introduction ​

Anxiety disorders are among the most prevalent mental health conditions worldwide, affecting millions of individuals across various demographics. These disorders manifest through a range of symptoms, including excessive fear, worry, and avoidance behaviors, significantly impairing the quality of life and daily functioning of those affected. The economic burden imposed by anxiety disorders is substantial, underscoring the urgent need for effective treatment strategies. Understanding the neural mechanisms underlying these disorders is crucial for developing targeted interventions that can improve patient outcomes. Recent advances in neuroscience have illuminated the complex neurobiological pathways that contribute to anxiety disorders, paving the way for new therapeutic approaches.

The significance of exploring the neural mechanisms of anxiety disorders lies in the intricate interplay between various brain regions, neurotransmitter systems, and genetic factors that shape individual responses to stress and anxiety. Research has revealed that key brain structures, such as the amygdala, prefrontal cortex, and hippocampus, play critical roles in the regulation of fear and anxiety responses. For instance, the amygdala is primarily involved in emotional processing and threat detection, while the prefrontal cortex is crucial for higher-order cognitive functions, including decision-making and emotional regulation. The hippocampus, on the other hand, is essential for memory formation and contextual processing, which are vital for understanding and responding to anxiety-provoking situations. Recent studies have expanded our understanding of these regions, highlighting their interconnectedness and the broader neural circuits involved in anxiety regulation [1][2].

Current research has demonstrated that dysregulation of neurotransmitter systems, particularly those involving serotonin, dopamine, and gamma-aminobutyric acid (GABA), contributes significantly to the pathophysiology of anxiety disorders. Serotonin is known to modulate mood and anxiety, while dopamine plays a crucial role in reward processing and motivation. GABA, as the primary inhibitory neurotransmitter, is essential for maintaining a balance in neural excitability and preventing excessive anxiety. Understanding the specific roles of these neurotransmitters in anxiety disorders is vital for developing pharmacological treatments that can effectively target these systems [2][3].

Furthermore, genetic predispositions and environmental factors significantly influence the manifestation of anxiety disorders. Recent research has identified various genetic markers associated with increased susceptibility to anxiety, as well as the impact of environmental stressors, such as trauma and chronic stress, on the development of these disorders [4][5]. The interplay between genetic and environmental factors is complex, often leading to a heterogeneous presentation of anxiety disorders that challenges current diagnostic classifications.

This review aims to synthesize current research findings on the neural mechanisms involved in anxiety disorders, organized into several key sections. The first section will delve into the neuroanatomy of anxiety disorders, examining the roles of the amygdala, prefrontal cortex, and hippocampus in anxiety regulation. The subsequent section will focus on neurotransmitter systems, detailing the contributions of serotonin, dopamine, and GABA to anxiety pathology. Following this, we will explore genetic and environmental factors that influence anxiety disorders, highlighting the importance of gene-environment interactions. The review will also address current therapeutic approaches, including pharmacological treatments, psychotherapy, and emerging therapies, emphasizing the need for personalized medicine in anxiety treatment. Finally, we will discuss future directions in research, particularly the potential of neuroimaging studies, animal models, and novel therapeutic strategies to enhance our understanding of anxiety disorders and improve treatment outcomes.

By synthesizing these diverse strands of research, this review seeks to provide a comprehensive overview of the neural mechanisms involved in anxiety disorders, highlighting the critical need for continued exploration in this field to enhance therapeutic interventions and ultimately improve the lives of those affected by anxiety.

2 Neuroanatomy of Anxiety Disorders ​

2.1 The Role of the Amygdala ​

Anxiety disorders are significantly influenced by the neural mechanisms underlying the functioning of the amygdala, a critical brain region involved in emotional processing, particularly fear and anxiety responses. The amygdala is embedded in a complex regulatory circuit that is essential for the manifestation and modulation of anxiety. Various studies have elucidated the role of the amygdala and its circuitry in anxiety disorders, highlighting its intricate connections with other brain regions and its involvement in both adaptive and pathological anxiety behaviors.

The amygdala integrates sensory information from cortical and thalamic inputs to generate fear and anxiety-related behavioral outputs. Inhibitory neurotransmission within the amygdala is crucial for regulating these outputs. Research has demonstrated that the amygdala's functionality is heavily dependent on GABAergic inhibition, which plays a key role in controlling anxiety-related behaviors. Disruption of this inhibitory control can lead to increased anxiety-like behaviors, indicating that the balance of excitatory and inhibitory signals within the amygdala is vital for maintaining emotional stability (Babaev et al. 2018; Shekhar et al. 2003).

Recent advancements in neuroscience have expanded the understanding of the neural circuits associated with anxiety. Studies have identified specific regions within the amygdala, such as the basolateral amygdala (BLA) and the central nucleus of the amygdala (CeA), as critical components in the circuitry mediating anxiety. For instance, optogenetic studies have shown that precise stimulation of BLA projections to the CeA can exert reversible anxiolytic effects, while inhibition of these projections can enhance anxiety-like behaviors (Tye et al. 2011). This indicates that the connectivity and specific pathways within the amygdala are essential for regulating anxiety responses.

Moreover, the amygdala is influenced by top-down regulatory mechanisms from the prefrontal cortex (PFC), which typically downregulates amygdala activity. Conversely, the locus coeruleus (LC) can drive up amygdala activation via noradrenergic projections, highlighting the complexity of the neural mechanisms involved in anxiety disorders. Increased amygdala responsiveness is often observed in patients with anxiety disorders, suggesting that hyperactivity in this region may be a common neurobiological marker (Brehl et al. 2020; Fox & Shackman 2024).

Furthermore, the involvement of molecular pathways in the amygdala has been investigated, with findings indicating that the neuregulin 1 (NRG1)-ErbB4 signaling pathway is crucial for modulating GABAergic activity and anxiety-like behaviors (Bi et al. 2015). This points to the importance of molecular determinants in shaping the synaptic transmission within the amygdala circuitry.

In summary, the amygdala's role in anxiety disorders is characterized by its complex neural circuitry, which integrates various inputs and regulates emotional responses through a delicate balance of excitatory and inhibitory signals. The interactions between the amygdala and other brain regions, alongside molecular mechanisms, underscore the multifaceted nature of anxiety disorders and highlight potential avenues for therapeutic interventions aimed at restoring this balance. Understanding these neural mechanisms is crucial for developing effective treatment strategies for anxiety disorders in the future.

2.2 Prefrontal Cortex Functionality ​

Anxiety disorders are complex psychiatric conditions characterized by excessive fear and anxiety responses, which are often linked to dysfunction in specific neural circuits, particularly involving the prefrontal cortex (PFC). The PFC plays a crucial role in modulating emotional responses and regulating anxiety, with various studies highlighting its functional and structural alterations in individuals with anxiety disorders.

The prefrontal cortex is involved in higher-order cognitive processes, including decision-making, emotional regulation, and the management of threat responses. Dysfunction in this area can lead to impaired regulation of the amygdala, a key structure in the fear circuitry. For instance, the amygdala is critical for the acquisition and expression of fear, and it has been observed that anxiety disorders are associated with heightened amygdala activity coupled with reduced PFC activity, leading to an inability to properly regulate fear responses [6].

Recent research has indicated that the medial prefrontal cortex (mPFC) is particularly important in the context of anxiety regulation. It has been shown that norepinephrine (NE), a significant neuromodulator, plays a vital role in modulating PFC function. NE is synthesized in the locus coeruleus and is thought to affect PFC activity in a circuit-specific manner, contributing to the regulation of anxiety [7]. The relationship between NE and the PFC is complex; it follows an inverted-U model where both excessively high and low levels of NE can lead to suboptimal functioning of the PFC [7].

Furthermore, the dorsolateral prefrontal cortex (dlPFC) has been implicated in working memory processes that contribute to anxiety regulation. It has been proposed that the dlPFC facilitates the retention and suppression of affective information, which is crucial during emotionally charged situations. The lateralization of the dlPFC is also noteworthy, as the left and right dlPFC may process different types of information, with the left being more sensitive to verbal content and the right to non-verbal affective content [8].

In addition to the mPFC and dlPFC, the anterior cingulate cortex (ACC) serves as a critical intersection between limbic and prefrontal systems, influencing emotional control. Higher levels of trait anxiety have been associated with increased activation in the ACC but reduced functional connectivity with the lateral PFC, suggesting that anxiety may lead to inefficient high-order control characterized by a compensatory increase in ACC activation [9].

Neuroimaging studies have revealed structural and functional changes in the PFC of individuals with anxiety disorders, suggesting that these abnormalities contribute to the pathophysiology of anxiety. For instance, alterations in the communication between the PFC and subcortical structures, such as the amygdala, can disrupt the balance of fear and regulation, perpetuating anxiety symptoms [10].

Overall, the prefrontal cortex's role in anxiety disorders is multifaceted, involving intricate interactions with other brain regions, particularly the amygdala and ACC. The dysfunction in these circuits can lead to the characteristic symptoms of anxiety disorders, emphasizing the importance of understanding the neural mechanisms at play for developing effective treatment strategies.

2.3 Hippocampal Involvement ​

Anxiety disorders are complex psychiatric conditions that significantly impact individuals' emotional and physical well-being. The hippocampus plays a crucial role in the neural mechanisms underlying anxiety disorders, serving as a key area involved in anxiety modulation through its intricate anatomy and connectivity with other brain regions.

The hippocampus is a major target of stress mediators and is closely related to anxiety regulation. Recent advances in imaging techniques, virus tracking, and optogenetics/chemogenetics have enabled researchers to elucidate the activity, connectivity, and function of specific cell types within the hippocampus and its associated networks. This has provided mechanistic insights into the organization of hippocampal circuitry that underlies anxiety. Studies focusing on various neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, dopaminergic, and serotonergic systems, have contributed to a better understanding of the neural mechanisms involved in anxiety modulation. Additionally, neuropeptides and neuroinflammatory factors are implicated in the regulation of anxiety, further complicating the underlying mechanisms [11].

Specific subregions of the hippocampus, such as the dorsal hippocampus (DH) and ventral hippocampus (VH), exhibit distinct roles in modulating anxiety and visceral sensitivity. Research has shown that activation of DH can induce both visceral hypersensitivity and anxiety, while activation of VH primarily induces anxiety without affecting visceral sensitivity. Conversely, inhibiting DH reduces both visceral hypersensitivity and anxiety, whereas inhibiting VH alleviates anxiety but not visceral hypersensitivity. This highlights the differential contributions of hippocampal subregions to anxiety-related behaviors [12].

Moreover, the involvement of the bed nucleus of the stria terminalis (BNST) has been emphasized as a critical hub in the limbic system regulating anxiety. BNST consists of multiple subregions that project to various brain areas, exerting distinct regulatory effects on anxiety and stress behaviors. Recent findings suggest that BNST's complex circuitry and signaling pathways play significant roles in modulating anxiety responses [3].

In addition to structural and functional characteristics, the role of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), has been studied in relation to anxiety disorders. Increased levels of proBDNF in the hippocampus have been linked to the regulation of both anxiety and depressive behaviors, indicating a shared neurobiological basis for these affective disorders [13].

Furthermore, the hippocampus is implicated in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which is crucial for stress response and emotional regulation. Research indicates that alterations in HPA axis functioning are associated with anxiety disorders, although findings are heterogeneous, showing both hypo- and hyperresponsiveness under various conditions [14].

In summary, the neural mechanisms of anxiety disorders are multifaceted, with the hippocampus serving as a pivotal structure that integrates various neurotransmitter systems, neurotrophic factors, and neuroanatomical circuits. The differential roles of hippocampal subregions, alongside the involvement of the BNST and the HPA axis, underscore the complexity of anxiety regulation and highlight potential targets for therapeutic interventions in anxiety disorders.

3 Neurotransmitter Systems ​

3.1 Serotonin and Anxiety ​

Anxiety disorders are complex conditions influenced by various neurobiological mechanisms, with the serotonergic system playing a crucial role in their pathophysiology. Serotonin (5-HT), a key neurotransmitter in the central nervous system (CNS), modulates a broad spectrum of functions including mood, cognition, and anxiety. Dysregulation of serotonin transmission has been linked to various psychiatric disorders, including anxiety and depression.

The serotonergic system is intricately involved in the modulation of anxiety. Serotonin exerts its effects through a variety of receptors, classified into seven distinct families (5-HT1-7), each of which mediates different physiological and behavioral processes. For instance, the serotonin 1A receptor has been identified as significant in both the development of anxiety-like behaviors and the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs) in adults, suggesting a dual role for serotonin in anxiety regulation across different life stages[15].

Evidence indicates that abnormalities in serotonergic function are prevalent in individuals with anxiety disorders. The treatment for these disorders often involves pharmacological agents that target the serotonergic system, such as SSRIs, which enhance serotonergic transmission and have been shown to increase serotonergic function while decreasing noradrenergic function[16]. However, the complexity of serotonin's role is highlighted by conflicting data suggesting that it can have both anxiolytic and anxiogenic effects depending on various factors, including the specific anxiety disorder, the brain structures involved, and the behavioral tasks being assessed[15].

Recent research has elucidated the neurobiological underpinnings of anxiety disorders, emphasizing the importance of the serotonergic system in emotional regulation. For instance, studies have shown that the dysregulation of serotonin and norepinephrine neurotransmitter systems contributes to the symptoms of anxiety and depression. Notably, serotonin's role extends beyond mere neurotransmission; it is involved in the modulation of stress responses and emotional regulation, implicating it in the neural circuitry that governs anxiety[4].

Additionally, the bed nucleus of the stria terminalis (BNST) has been identified as a critical hub in the limbic system that modulates anxiety, with multiple signaling pathways in the BNST contributing to anxiety and stress behavior[3]. The complexity of the BNST's structure and its functional connections with other brain areas, illuminated by advanced imaging techniques, provides further insights into how serotonin interacts within these circuits to influence anxiety responses[3].

Overall, the serotonergic system is pivotal in understanding the neural mechanisms underlying anxiety disorders. The interplay between serotonin and other neurotransmitter systems, along with the involvement of various brain regions, underscores the multifaceted nature of anxiety and the need for targeted therapeutic approaches that consider these complex interactions.

3.2 The Dopaminergic System ​

The dopaminergic system plays a significant role in the pathophysiology of anxiety disorders, with various studies highlighting its involvement in both conditioned and unconditioned fear responses. Dopamine, traditionally recognized for its role in reward mechanisms, has been increasingly acknowledged for its contributions to anxiety regulation and fear processing.

Pharmacological and molecular imaging studies indicate that the dopaminergic system, particularly through the action of D2 dopamine receptors, is crucial in mediating anxiety responses. Specifically, the excitation of the mesocorticolimbic pathway, which originates from dopaminergic neurons in the ventral tegmental area (VTA), has been shown to be relevant for the development of anxiety. The amygdala, a key region involved in the neural circuitry of conditioned fear, is significantly innervated by this pathway. Current findings suggest that the dopamine D2 receptor-signaling pathway connecting the VTA to the basolateral amygdala modulates fear and anxiety, while circuits in the midbrain tectum are implicated in the expression of innate fear (Brandão and Coimbra 2019) [17].

Moreover, a systematic review of neuroimaging studies indicates alterations in the dopaminergic system among individuals with anxiety and obsessive-compulsive disorders (OCD). In OCD patients, a consistent finding is the decrease in striatal dopamine D2 receptors (D2R), although no significant correlation was observed between striatal D2R levels and disease severity. Interestingly, the dopamine transporter (DAT) levels did not show significant changes in anxiety disorder and OCD patients, indicating a complex relationship between dopamine signaling and these disorders (Dong et al. 2020) [18].

Additionally, the concept of dopamine rebound-excitation has been proposed as a mechanism that may help in regulating stress resilience and fear learning. This theory posits that the rebound-excitation of dopaminergic neurons at the cessation of fearful experiences acts as a "brake," providing intrinsic safety signals to fear-processing circuits. Such physiological responses could be influenced by genetic and experiential factors, potentially serving as biomarkers for individual resilience to stress and anxiety (Lee et al. 2016) [19].

Overall, the intricate interplay between dopamine signaling and anxiety disorders underscores the importance of this neurotransmitter system in the modulation of fear and anxiety. Future therapeutic strategies may benefit from targeting specific dopaminergic pathways to enhance treatment outcomes for individuals suffering from anxiety disorders.

3.3 GABAergic Mechanisms ​

Anxiety disorders are complex conditions characterized by dysregulation in various neurobiological systems, particularly involving the GABAergic system. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system, playing a crucial role in maintaining neuronal homeostasis and regulating emotional and cognitive functions. Dysfunctions in GABAergic signaling have been implicated in the pathophysiology of anxiety disorders.

Research indicates that alterations in GABAergic neurotransmission can lead to increased anxiety-like behaviors. For instance, in a study involving temporal lobe epilepsy (TLE) mice, it was found that anxiety-like behavior was associated with a decrease in GABAergic interneurons and an increase in GABA type A receptor (GABAAR) β3 subunit expression in the hippocampus. The activation of GABAARs produced an anxiolytic-like effect, while their inhibition elicited anxiogenic-like effects, suggesting that targeting GABAergic signaling may provide effective anxiolytic treatment options for patients with epilepsy and anxiety comorbidities[20].

The role of GABA in anxiety disorders is further emphasized by the findings of various studies that highlight the involvement of GABAergic dysfunction in mood disorders, which often coexist with anxiety disorders. It has been reported that GABA levels may be decreased in animal models of depression, and clinical studies show low plasma and cerebrospinal fluid (CSF) GABA levels in patients with mood disorders. These findings suggest that reduced GABAergic activity could contribute to the manifestation of anxiety and mood-related symptoms[21].

Additionally, the amygdala, a key brain region involved in the modulation of anxiety, has been shown to express GABAergic neurons that play a significant role in anxiety regulation. Neuregulin 1 (NRG1) signaling in GABAergic neurons of the basolateral amygdala (BLA) has been identified as critical for modulating anxiety-like behaviors and GABA release. Administration of NRG1 into the BLA of high-anxiety mice alleviated anxiety and enhanced GABAergic neurotransmission, indicating a potential pathway for therapeutic intervention[22].

Moreover, the GABAergic system's involvement extends to the dynamics of neurotransmitter interactions within anxiety disorders. GABA is known to counterbalance the excitatory effects of glutamate. Dysregulation of this balance can lead to heightened anxiety responses, as evidenced by studies showing that glucocorticoid receptors (GRs) in glutamatergic neurons of the BLA significantly influence fear and anxiety-related behaviors. The deletion of GRs in these neurons resulted in hypothalamic-pituitary-adrenal axis hyperactivity and reduced anxiety behaviors, underscoring the importance of GABAergic signaling in the context of stress and anxiety[23].

In summary, the GABAergic system plays a pivotal role in the neural mechanisms underlying anxiety disorders. Alterations in GABA levels, receptor expression, and the interaction with other neurotransmitter systems contribute to the pathophysiology of these disorders. Understanding these mechanisms is crucial for developing targeted therapies aimed at restoring GABAergic function and alleviating anxiety symptoms.

4 Genetic and Environmental Factors ​

4.1 Genetic Predispositions ​

Anxiety disorders are complex conditions influenced by a combination of genetic and environmental factors, which interact to shape individual susceptibility to these disorders. The underlying neural mechanisms of anxiety disorders involve multiple brain regions and neurotransmitter systems, as well as genetic predispositions that contribute to the manifestation of anxiety symptoms.

Neural circuits regulating anxiety are intricate and involve areas such as the prefrontal cortex, amygdala, and hippocampus. Dysregulation within these circuits can lead to excessive or prolonged anxiety. Genetic research has identified several genetic variants associated with anxiety disorders through genome-wide association studies (GWAS), which have highlighted novel neurobiological pathways involved in the etiology of these conditions [24]. For instance, specific genetic mutations can increase vulnerability to anxiety when combined with environmental stressors, illustrating the gene-environment interaction critical to understanding anxiety [25].

Research indicates that genetic factors account for approximately 30% to 50% of the heritability of anxiety disorders [26]. This genetic basis is complex, involving both common and rare genetic factors that contribute to the development of anxiety [26]. For example, mutations in the gene encoding the serotonin transporter have been shown to heighten anxiety levels, particularly when individuals are exposed to stressful environments during development [25]. Additionally, twin studies suggest that certain anatomical features, such as a smaller hippocampus, may predispose individuals to post-traumatic stress disorder (PTSD) [25].

The serotonergic and GABAergic systems are two key neurotransmitter systems implicated in anxiety disorders. The interplay between these systems is critical for the regulation of anxiety-related behaviors. While there has been substantial progress in identifying genetic variants associated with anxiety, the translation of these findings into effective pharmacological treatments has been limited, in part due to the heterogeneous nature of anxiety disorders and the complexities of gene-environment interactions [27].

Furthermore, recent advances in neuroscience research and big data analytics have begun to uncover the multimolecular participation in anxiety disorders, emphasizing the need for a comprehensive understanding that integrates genetic, neurobiological, and psychosocial factors [5]. The ongoing identification of specific gene-environment interactions and the development of translational models are expected to enhance our understanding of the neurobiological mechanisms underlying anxiety disorders and may inform future therapeutic strategies [28].

In summary, the neural mechanisms of anxiety disorders are characterized by the interaction of genetic predispositions with environmental influences, leading to dysregulation in neural circuits that govern anxiety. Understanding these mechanisms is essential for the development of more effective treatments for individuals suffering from anxiety disorders.

4.2 Environmental Influences ​

Anxiety disorders are complex psychiatric conditions influenced by a combination of genetic and environmental factors. Recent research highlights the significant role that environmental influences play in the development and manifestation of anxiety disorders. For instance, specific mutations in genes, such as those encoding the serotonin transporter, have been shown to increase anxiety when combined with stressful environmental conditions during development. This interaction exemplifies how genetic predispositions can be exacerbated by adverse environmental factors, leading to heightened vulnerability to anxiety disorders [25].

The interaction between genetic and environmental factors is further illustrated by findings from twin studies, which suggest that certain structural brain characteristics, such as a smaller hippocampus, can predispose individuals to conditions like post-traumatic stress disorder (PTSD). Such structural vulnerabilities can increase susceptibility to environmental stressors, ultimately resulting in the development of anxiety disorders [25].

Moreover, the neurobiological underpinnings of anxiety are influenced by the activity of neurotransmitter systems, particularly in the hippocampus, which is a critical region for stress regulation and emotional processing. The hippocampus integrates signals from various stress mediators and is intricately connected to other brain regions involved in anxiety modulation. Advances in imaging and genetic manipulation techniques have allowed researchers to explore the specific cellular and circuit-level features of the hippocampus, providing insights into how these structures contribute to anxiety [11].

In addition to structural changes, environmental factors can lead to stable alterations in gene expression and neural circuit function, which are mediated by epigenetic mechanisms. These epigenetic changes can result from chronic stress and may influence the behavioral responses associated with anxiety. Understanding how environmental stressors induce these epigenetic modifications is crucial for unraveling the complex pathogenesis of anxiety disorders [29].

The heterogeneity of anxiety disorders, influenced by varying environmental contexts, complicates the development of effective treatments. Research indicates that in-depth explorations of biological mechanisms, including the interaction between genetic predispositions and environmental stressors, are essential for advancing our understanding and treatment of anxiety disorders [5]. Therefore, future research must focus on identifying specific environmental triggers and their interactions with genetic factors to enhance therapeutic strategies and improve patient outcomes [4].

4.3 Gene-Environment Interactions ​

Anxiety disorders are complex conditions influenced by a combination of genetic and environmental factors, with gene-environment interactions playing a significant role in their manifestation. Genetic epidemiology has provided compelling evidence that anxiety disorders are influenced by multiple genetic factors that are polygenic and interact with environmental influences. This complexity suggests that specific genetic variants may predispose individuals to anxiety disorders, particularly when coupled with adverse environmental conditions.

Recent studies have identified that genetic predispositions can interact with environmental stressors, leading to heightened anxiety symptoms. For instance, research indicates that mutations in the serotonin transporter gene can result in increased anxiety when combined with a stressful environment during developmental stages [25]. This underscores the notion that genetic factors do not operate in isolation but rather in conjunction with environmental influences to shape anxiety-related behaviors.

The mechanisms underlying these interactions have been explored in various studies. For example, gene-environment interactions have been observed in pediatric populations, where genetic sensitivity to environmental stressors can significantly affect the likelihood of developing anxiety disorders [30]. Such interactions highlight the importance of understanding how genetic vulnerabilities may manifest under specific environmental conditions, thus contributing to the onset of anxiety disorders.

In addition, animal models have been instrumental in elucidating the neurobiological mechanisms involved in anxiety. Research utilizing knockout mice has shown that inactivation of specific genes related to neurotransmitter systems, such as serotonin and gamma-aminobutyric acid (GABA), can lead to anxiety-like behaviors [31]. These findings suggest that disruptions in neurotransmitter signaling pathways are critical in the development of anxiety disorders.

Furthermore, genome-wide association studies (GWAS) have identified genetic variants associated with anxiety disorders, paving the way for a better understanding of the neurobiological mechanisms involved [24]. These studies have emphasized the need for larger sample sizes and a focus on specific anxiety traits to enhance our understanding of gene-environment interactions.

In summary, the neural mechanisms of anxiety disorders are intricately linked to both genetic and environmental factors, with gene-environment interactions playing a pivotal role in their etiology. Continued research into these interactions is essential for developing effective interventions and therapeutic strategies for individuals affected by anxiety disorders. The complexity of these interactions necessitates a multifaceted approach that incorporates both genetic insights and environmental contexts to fully understand and address anxiety disorders.

5 Current Therapeutic Approaches ​

5.1 Pharmacological Treatments ​

Anxiety disorders are complex conditions characterized by dysregulation in various neural mechanisms, which are crucial for understanding their pathophysiology and developing effective therapeutic strategies. Recent research has identified several key neurobiological underpinnings, including neurotransmitter imbalances, dysfunctions in neural circuits, and alterations in neurophysiological systems.

The hippocampus plays a pivotal role in anxiety modulation and serves as a primary target for stress mediators. Its complex anatomy has posed challenges in elucidating the mechanisms of anxiety regulation. However, advancements in imaging and optogenetics have enabled researchers to investigate the activity and connectivity of specific cell types within the hippocampus. Studies have shown that neurotransmitter systems such as glutamatergic, GABAergic, cholinergic, dopaminergic, and serotonergic pathways contribute significantly to the neural mechanisms underlying anxiety disorders. Additionally, neuropeptides and neuroinflammatory factors are also implicated in anxiety modulation, highlighting the intricate interplay of various biological systems involved in these disorders [11].

The neural circuit basis of pathological anxiety involves dysfunctions across several neurobehavioural systems, including those related to negative and positive valence, cognitive processes, and social interactions. Research indicates that anxiety arises not only from heightened reactivity in fear circuits but also from alterations in circuits that mediate sustained threat and reward processing. This suggests that the emergence and maintenance of anxiety disorders are linked to specific neural abnormalities that can be exacerbated by maladaptive behaviors [2].

Pharmacological treatments for anxiety disorders have traditionally focused on modulating neurotransmitter systems. Current therapeutic approaches include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and benzodiazepines, which target serotonergic, noradrenergic, and GABAergic mechanisms. While these treatments have shown efficacy, they also exhibit limitations, such as delayed onset and side effects, which underscore the need for novel therapeutic strategies [32].

In addition to conventional pharmacotherapy, recent research has explored alternative approaches such as melatonin, which has demonstrated anxiolytic properties in both animal models and clinical settings. Melatonin's mechanisms of action may involve its sympatholytic effects, modulation of neuroendocrine responses, and antioxidant properties, making it a potential adjunct or alternative treatment for anxiety disorders [33].

Overall, the understanding of the neural mechanisms of anxiety disorders is evolving, and ongoing research aims to bridge the gap between basic science and clinical applications. By integrating insights from neurobiology with pharmacological innovations, future therapeutic interventions may become more targeted and personalized, improving outcomes for individuals suffering from anxiety disorders [4][34].

5.2 Psychotherapy ​

Anxiety disorders are characterized by complex neurobiological mechanisms that significantly affect individuals' quality of life. The understanding of these mechanisms has evolved, revealing a network of brain regions and pathways involved in anxiety regulation. Key areas implicated in anxiety include the amygdala, bed nucleus of the stria terminalis (BNST), and lateral habenula (LHb). The amygdala is central to emotional processing, while the BNST is associated with prolonged anxiety states, and the LHb plays a crucial role in encoding negative signals that exacerbate aversive emotions (Gong 2025) [1].

Research indicates that neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, dopaminergic, and serotonergic pathways, are critical in modulating anxiety. The hippocampus, in particular, is a major target of stress mediators and is closely related to anxiety modulation. Advances in imaging and optogenetics have facilitated the exploration of hippocampal circuitry, elucidating the role of specific cell types and neurotransmitter systems in anxiety regulation (Shi et al. 2023) [11].

In addition to these neurotransmitter systems, neuroinflammatory pathways and the hypothalamic-pituitary-adrenal (HPA) axis have also been implicated in anxiety disorders. Dysregulation of the HPA axis, particularly concerning cortisol levels and inflammatory cytokines, contributes to the pathophysiology of anxiety (Furtado & Katzman 2015) [35]. Understanding these mechanisms is essential for developing effective therapeutic strategies.

Current therapeutic approaches for anxiety disorders primarily involve pharmacotherapy and psychotherapy. Pharmacological treatments often include selective serotonin reuptake inhibitors (SSRIs) and other agents that target the serotonergic system. However, these medications can have limitations, such as delayed onset of action and potential side effects (Lin et al. 2023) [32].

Psychotherapy plays a crucial role in the treatment of anxiety disorders. Various techniques, including cognitive-behavioral therapy (CBT), exposure therapy, and mindfulness-based approaches, have shown efficacy in managing anxiety symptoms. These therapies focus on modifying maladaptive thought patterns and behaviors associated with anxiety, providing individuals with coping strategies to manage their symptoms effectively (Das & Gavade 2024) [36].

The integration of pharmacological and non-pharmacological interventions is often recommended to enhance treatment outcomes. While conventional psychotherapy can be resource-intensive and may not be readily accessible in all regions, the development of artificial intelligence (AI) applications has emerged as a promising avenue to improve the precision and accessibility of therapeutic interventions for anxiety disorders (Das & Gavade 2024) [36].

In summary, the neural mechanisms underlying anxiety disorders involve intricate interactions among various brain regions, neurotransmitter systems, and neuroinflammatory pathways. Current therapeutic approaches, including pharmacotherapy and psychotherapy, aim to address these complex mechanisms, with ongoing research seeking to refine and personalize treatment strategies for better patient outcomes.

5.3 Emerging Therapies ​

Anxiety disorders are characterized by a range of neurobiological mechanisms that have been elucidated through recent research. Key insights into these mechanisms include neurotransmitter imbalances, dysregulation of stress response systems, and dysfunctions within neural circuits that govern emotion regulation. The amygdala, bed nucleus of the stria terminalis (BNST), and lateral habenula (LHb) are critical brain regions involved in mediating anxiety-like behaviors. The amygdala is central to emotional processing, the BNST is associated with prolonged anxiety states, and the LHb encodes negative signals that enhance aversive emotions [1]. Additionally, the hippocampus plays a significant role in anxiety modulation, being a primary target for stress mediators. Recent advancements in imaging and optogenetics have provided insights into the hippocampal circuitry, highlighting the involvement of various neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, dopaminergic, and serotonergic pathways [11].

Current therapeutic approaches for anxiety disorders primarily involve pharmacotherapy and psychotherapy. Conventional pharmacological treatments include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other agents targeting neurotransmitter systems. However, these treatments often have limitations such as delayed onset of action and variable efficacy [32]. Psychotherapeutic interventions, including cognitive-behavioral therapy (CBT), relaxation techniques, and exposure therapies, are also employed. Despite their effectiveness, many patients experience inadequate responses, necessitating further exploration of underlying mechanisms and innovative treatment strategies [36].

Emerging therapies are being developed to address the limitations of existing treatments. These include optogenetic and chemogenetic approaches that allow for precise manipulation of neural circuits associated with anxiety [37]. Additionally, the role of epigenetics and microRNAs in the pathophysiology of anxiety is being investigated, with potential pharmacological interventions targeting these mechanisms [38]. Artificial intelligence (AI) is also gaining traction in the management of anxiety disorders, with AI-enabled applications designed to enhance diagnostic precision and personalize therapeutic interventions [36].

In summary, the neural mechanisms underlying anxiety disorders involve complex interactions among various brain regions and neurotransmitter systems. Current therapies, while effective for some, have notable limitations, prompting research into emerging therapies that may offer more targeted and personalized treatment options.

6 Future Directions in Research ​

6.1 Neuroimaging Studies ​

Anxiety disorders are complex conditions characterized by heightened fear and anxiety responses, and their neural mechanisms are intricately linked to specific brain circuits and neurobiological systems. Recent advancements in neuroimaging techniques have significantly enhanced our understanding of the neural substrates underlying these disorders, revealing a multifaceted network of brain regions involved in anxiety regulation.

The amygdala has been consistently identified as a central structure in the neurocircuitry of anxiety disorders. It is crucial for processing emotional stimuli and is often hyperactivated in individuals with anxiety disorders, such as post-traumatic stress disorder (PTSD), social anxiety disorder, and specific phobia [39][40]. In contrast, the anterior cingulate cortex (ACC) and insula also play vital roles in the emotional regulation of anxiety, with evidence suggesting that patients with anxiety disorders exhibit both hyperactivation in these regions and hypoactivation in the rostral ACC [39][40].

Recent studies emphasize the importance of the bed nucleus of the stria terminalis (BNST) as a hub in the limbic system, which modulates anxiety responses through its connections with various brain regions [3][3]. The BNST's unique circuit characteristics allow it to exert independent regulatory effects on anxiety and stress behaviors, indicating its critical role in the pathogenesis of anxiety disorders [3].

Functional neuroimaging has revealed that anxiety disorders are associated with abnormalities in several neurobehavioural systems related to both negative and positive valence, cognitive processes, and social interactions [2]. This highlights that pathological anxiety arises not solely from heightened reactivity in fear circuits but also from disruptions in circuits that manage sustained threat and cognitive control [2].

Moreover, neuroimaging studies have suggested that alterations in the connectivity and activity of the amygdala, insula, and other associated regions may predict treatment outcomes for psychotherapy in anxiety disorders [41]. These findings underscore the potential for using neuroimaging as a tool to inform personalized treatment strategies, enhancing therapeutic efficacy by targeting specific neural pathways involved in anxiety.

Future research directions in the field should focus on further elucidating the complex interactions among these neural circuits, as well as exploring the neurochemical and molecular mechanisms that contribute to anxiety disorders [1][5]. Investigating the role of neuropeptides and neuroinflammatory factors in anxiety modulation could provide new insights into therapeutic targets [11].

In summary, the neural mechanisms of anxiety disorders are characterized by intricate networks involving the amygdala, ACC, insula, and BNST, among others. Continued advancements in neuroimaging will be essential for refining our understanding of these mechanisms and for developing more effective, targeted interventions for individuals suffering from anxiety disorders.

6.2 Animal Models ​

The neural mechanisms of anxiety disorders are complex and multifaceted, influenced by various biological, psychological, and environmental factors. Animal models play a crucial role in elucidating these mechanisms, as they provide insights into the neurobiological underpinnings of anxiety. Research indicates that specific brain areas, such as the prefrontal cortex, hippocampus, and amygdala, are significantly involved in the anxiety response.

Studies have shown that the amygdala is critical for the acquisition and expression of fear, which is a fundamental aspect of anxiety disorders. However, animal models of conditioned fear, while useful, have limitations. They often fail to capture the intricate cognitive processes associated with human anxiety, such as excessive worry about future events [6]. The prefrontal cortex, which is more developed in humans than in other mammals, has been implicated in modulating the subcortical fear response, suggesting that differential activity in this region may contribute to the pathophysiology of anxiety disorders [6].

Furthermore, various animal models have been developed to assess anxiety-like behaviors and the efficacy of anxiolytic drugs. These models often focus on specific behavioral paradigms, such as fear conditioning, to simulate aspects of human anxiety disorders. The validity of these models can be evaluated based on their face, construct, and predictive validity [42].

Recent advances in understanding the pathogenesis of anxiety disorders have highlighted the importance of genetic and environmental interactions. For instance, the identification of candidate genes associated with anxiety disorders, such as TMEM132D, demonstrates the potential for translational approaches that connect genetic findings from animal models to human clinical research [43]. Additionally, integrating neuroimaging data with animal studies can enhance our understanding of the neural circuitry involved in anxiety [43].

Future research directions should focus on refining existing animal models to better represent the heterogeneity of anxiety disorders observed in humans. This includes exploring individual differences in vulnerability and incorporating a broader range of environmental and genetic factors. A multidisciplinary approach that combines insights from psychiatry, psychology, and neuroscience is essential for developing more effective treatments and advancing our understanding of anxiety disorders [44].

Overall, while significant progress has been made in utilizing animal models to explore the neural mechanisms of anxiety disorders, continued efforts are needed to bridge the gap between preclinical findings and clinical applications. This will require ongoing collaboration between basic and clinical researchers to improve the relevance and applicability of animal models in understanding and treating anxiety disorders.

6.3 Personalized Medicine Approaches ​

Anxiety disorders represent a significant public health concern, characterized by complex neurobiological underpinnings that have been the focus of extensive research. The neural mechanisms underlying anxiety disorders are multifaceted, involving various neurotransmitter systems, neurocircuitry, and genetic factors.

The hippocampus is a critical brain region implicated in anxiety modulation. It serves as a major target for stress mediators and has been associated with the regulation of anxiety-related behaviors. Recent advances in imaging techniques, such as optogenetics and chemogenetics, have allowed researchers to investigate the activity and connectivity of specific cell types within the hippocampus and its associated circuits, providing insights into the neural circuitry that governs anxiety responses. The interplay between neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, dopaminergic, and serotonergic pathways, has been shown to play a pivotal role in the neural mechanisms of anxiety disorders. Additionally, neuropeptides and neuroinflammatory factors contribute to the modulation of anxiety, indicating a complex biochemical landscape at play (Shi et al. 2023) [11].

Current research has highlighted the dysfunctions within neural circuits that regulate emotions, which include the amygdala-prefrontal cortex circuitry. These circuits are crucial for processing threats and regulating fear responses. Pathological anxiety is characterized by heightened reactivity within these circuits, as well as alterations in systems that mediate cognitive control and social processing. Studies utilizing functional neuroimaging techniques have revealed that these abnormalities can persist and be exacerbated by maladaptive behaviors, further complicating the treatment landscape (Akiki et al. 2025) [2].

From a genetic and epigenetic perspective, anxiety disorders exhibit significant heterogeneity, and their etiology is influenced by a combination of genetic predispositions and environmental factors. Recent investigations into the genetic basis of anxiety have identified polymorphisms that correlate with anxiety-related behaviors, suggesting that personalized medicine approaches could be informed by individual genetic profiles (Merkouris et al. 2025) [34].

In terms of future research directions, there is a growing emphasis on the integration of neurobiological insights with clinical applications to develop personalized treatment strategies. This includes leveraging biomarkers derived from neurobiological studies to refine diagnostic criteria and treatment protocols. The incorporation of advanced technologies, such as artificial intelligence, into therapeutic frameworks may also enhance the precision of anxiety disorder management by tailoring interventions to individual patient profiles (Das & Gavade 2024) [36].

Moreover, ongoing research is needed to explore the interaction between neurobiological factors and psychosocial elements in anxiety disorders. Understanding these dynamics can facilitate the development of more effective, individualized therapeutic approaches, thereby improving patient outcomes in anxiety management. By bridging foundational research with clinical practice, future studies can contribute to a more comprehensive understanding of anxiety disorders and foster innovative treatment paradigms that prioritize personalization and efficacy (Pan et al. 2025) [4].

7 Conclusion ​

The exploration of neural mechanisms underlying anxiety disorders reveals significant insights into the complex interplay between brain regions, neurotransmitter systems, and genetic and environmental factors. Key findings indicate that the amygdala, prefrontal cortex, and hippocampus are central to anxiety regulation, with dysregulation in these areas contributing to the pathophysiology of anxiety disorders. The amygdala's hyperactivity, coupled with diminished prefrontal cortex function, highlights the need for targeted therapeutic strategies that can restore balance in these neural circuits. Furthermore, the involvement of neurotransmitters such as serotonin, dopamine, and GABA underscores the multifaceted nature of anxiety, suggesting that pharmacological treatments must consider these interactions for effective outcomes. Genetic predispositions and environmental stressors significantly shape the expression of anxiety disorders, emphasizing the importance of personalized medicine approaches that integrate individual genetic profiles with environmental contexts. Future research should focus on advancing neuroimaging techniques and refining animal models to enhance our understanding of anxiety disorders, ultimately leading to innovative and effective treatment paradigms that improve patient outcomes.

References ​

  • [1] Wenxuan Gong. Research progress on the neural circuits mechanisms of anxiety.. Frontiers in neural circuits(IF=3.0). 2025. PMID:40635883. DOI: 10.3389/fncir.2025.1609145.
  • [2] Teddy J Akiki;Jenna Jubeir;Claire Bertrand;Leonardo Tozzi;Leanne M Williams. Neural circuit basis of pathological anxiety.. Nature reviews. Neuroscience(IF=26.7). 2025. PMID:39604513. DOI: 10.1038/s41583-024-00880-4.
  • [3] Mingjun Xie;Ying Xiong;Haijun Wang. The regulative role and mechanism of BNST in anxiety disorder.. Frontiers in psychiatry(IF=3.2). 2024. PMID:39698215. DOI: 10.3389/fpsyt.2024.1437476.
  • [4] Han-Qing Pan;Tian Xia;Yu-Ya-Nan Zhang;Hui-Jie Zhang;Meng-Jie Xu;Jing Guo;Yan Liu;Xue-Ying Bai;Qian Liu;Wei-Zhu Liu;Wen-Hua Zhang;Qi-Gang Zhou;Wei-Hua Yue;Bing-Xing Pan. Unveiling the enigma of anxiety disorders and depression: from pathogenesis to treatment.. Science China. Life sciences(IF=9.5). 2025. PMID:40900421. DOI: 10.1007/s11427-025-3024-y.
  • [5] Qianmei Yu;Meihua Ruan;Yongjun Chen;Chun Wang. Advances in neuroscience research and big data's analysis on anxiety disorder.. Wiley interdisciplinary reviews. Cognitive science(IF=3.8). 2025. PMID:39390772. DOI: 10.1002/wcs.1692.
  • [6] Rachel Lisa Berkowitz;Jeremy D Coplan;Dorothy P Reddy;Jack M Gorman. The human dimension: how the prefrontal cortex modulates the subcortical fear response.. Reviews in the neurosciences(IF=4.1). 2007. PMID:18019606. DOI: 10.1515/revneuro.2007.18.3-4.191.
  • [7] Nadia N Bouras;Nancy R Mack;Wen-Jun Gao. Prefrontal modulation of anxiety through a lens of noradrenergic signaling.. Frontiers in systems neuroscience(IF=3.5). 2023. PMID:37139472. DOI: 10.3389/fnsys.2023.1173326.
  • [8] Lauren K White;Walid Makhoul;Marta Teferi;Yvette I Sheline;Nicholas L Balderston. The role of dlPFC laterality in the expression and regulation of anxiety.. Neuropharmacology(IF=4.6). 2023. PMID:36442650. DOI: 10.1016/j.neuropharm.2022.109355.
  • [9] Magali Comte;Aïda Cancel;Jennifer T Coull;Daniele Schön;Emmanuelle Reynaud;Sarah Boukezzi;Pierre-François Rousseau;Gabriel Robert;Stéphanie Khalfa;Eric Guedj;Olivier Blin;Daniel R Weinberger;Eric Fakra. Effect of trait anxiety on prefrontal control mechanisms during emotional conflict.. Human brain mapping(IF=3.3). 2015. PMID:25664956. DOI: 10.1002/hbm.22765.
  • [10] Yihua Chen;Nengyuan Hu;Jianming Yang;Tianming Gao. Prefrontal cortical circuits in anxiety and fear: an overview.. Frontiers of medicine(IF=3.5). 2022. PMID:35943704. DOI: 10.1007/s11684-022-0941-2.
  • [11] Hu-Jiang Shi;Shuang Wang;Xin-Ping Wang;Rui-Xin Zhang;Li-Juan Zhu. Hippocampus: Molecular, Cellular, and Circuit Features in Anxiety.. Neuroscience bulletin(IF=5.8). 2023. PMID:36680709. DOI: 10.1007/s12264-023-01020-1.
  • [12] Wei Lin;Yifei Zhou;Yuan Liu;Congxu Liu;Mengying Lin;Ying Tang;Aiqin Chen;Bin Wu;Chun Lin. Dorsoventral hippocampus distinctly modulates visceral sensitivity and anxiety behaviors in male IBS-like rats.. Journal of neuroscience research(IF=3.4). 2024. PMID:38284854. DOI: 10.1002/jnr.25289.
  • [13] Feng Zhong;Lei Liu;Jia-Li Wei;Zhao-Lan Hu;Li Li;Shuang Wang;Jun-Mei Xu;Xin-Fu Zhou;Chang-Qi Li;Zhao-Yun Yang;Ru-Ping Dai. Brain-Derived Neurotrophic Factor Precursor in the Hippocampus Regulates Both Depressive and Anxiety-Like Behaviors in Rats.. Frontiers in psychiatry(IF=3.2). 2018. PMID:30740068. DOI: 10.3389/fpsyt.2018.00776.
  • [14] Angelika Erhardt;Marcus Ising;Paul Gerson Unschuld;Nikola Kern;Susanne Lucae;Benno Pütz;Manfred Uhr;Elisabeth B Binder;Florian Holsboer;Martin E Keck. Regulation of the hypothalamic-pituitary-adrenocortical system in patients with panic disorder.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology(IF=7.1). 2006. PMID:16841071. DOI: 10.1038/sj.npp.1301168.
  • [15] Joshua A Gordon;Rene Hen. The serotonergic system and anxiety.. Neuromolecular medicine(IF=3.9). 2004. PMID:15001810. DOI: 10.1385/NMM:5:1:027.
  • [16] K J Ressler;C B Nemeroff. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders.. Depression and anxiety(IF=3.3). 2000. PMID:11098410. DOI: 10.1002/1520-6394(2000)12:1+<2::AID-DA2>3.0.CO;2-4.
  • [17] Marcus L Brandão;Norberto C Coimbra. Understanding the role of dopamine in conditioned and unconditioned fear.. Reviews in the neurosciences(IF=4.1). 2019. PMID:30179855. DOI: .
  • [18] Mei-Xue Dong;Guang-Hui Chen;Ling Hu. Dopaminergic System Alteration in Anxiety and Compulsive Disorders: A Systematic Review of Neuroimaging Studies.. Frontiers in neuroscience(IF=3.2). 2020. PMID:33343291. DOI: 10.3389/fnins.2020.608520.
  • [19] Jason C Lee;Lei Philip Wang;Joe Z Tsien. Dopamine Rebound-Excitation Theory: Putting Brakes on PTSD.. Frontiers in psychiatry(IF=3.2). 2016. PMID:27729874. DOI: 10.3389/fpsyt.2016.00163.
  • [20] Xinjian Zhu;Yuanyuan Yao;Xiaolin Li;Jingde Dong;Aifeng Zhang. Alteration of GABAergic signaling is associated with anxiety-like behavior in temporal lobe epilepsy mice.. Progress in neuro-psychopharmacology & biological psychiatry(IF=3.9). 2019. PMID:30951784. DOI: 10.1016/j.pnpbp.2019.03.020.
  • [21] P Brambilla;J Perez;F Barale;G Schettini;J C Soares. GABAergic dysfunction in mood disorders.. Molecular psychiatry(IF=10.1). 2003. PMID:12888801. DOI: 10.1038/sj.mp.4001362.
  • [22] Lin-Lin Bi;Xiang-Dong Sun;Jie Zhang;Yi-Sheng Lu;Yi-Hua Chen;Jue Wang;Fei Geng;Fang Liu;Meng Zhang;Ji-Hong Liu;Xiao-Wen Li;Lin Mei;Tian-Ming Gao. Amygdala NRG1-ErbB4 is critical for the modulation of anxiety-like behaviors.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology(IF=7.1). 2015. PMID:25308353. DOI: 10.1038/npp.2014.274.
  • [23] J Hartmann;N Dedic;M L Pöhlmann;A Häusl;H Karst;C Engelhardt;S Westerholz;K V Wagner;C Labermaier;L Hoeijmakers;M Kertokarijo;A Chen;M Joëls;J M Deussing;M V Schmidt. Forebrain glutamatergic, but not GABAergic, neurons mediate anxiogenic effects of the glucocorticoid receptor.. Molecular psychiatry(IF=10.1). 2017. PMID:27240530. DOI: 10.1038/mp.2016.87.
  • [24] Maija-Kreetta Koskinen;Iiris Hovatta. Genetic insights into the neurobiology of anxiety.. Trends in neurosciences(IF=15.1). 2023. PMID:36828693. DOI: 10.1016/j.tins.2023.01.007.
  • [25] Cornelius Gross;René Hen. Genetic and environmental factors interact to influence anxiety.. Neurotoxicity research(IF=3.3). 2004. PMID:15639782. DOI: 10.1007/BF03033286.
  • [26] Heike Weber;John M Hettema;Jürgen Deckert;Angelika Erhardt-Lehmann. Genomics of Anxiety Disorders.. The Psychiatric clinics of North America(IF=3.4). 2025. PMID:40348424. DOI: 10.1016/j.psc.2025.01.012.
  • [27] Jocelien D A Olivier;Christiaan H Vinkers;Berend Olivier. The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders.. Frontiers in pharmacology(IF=4.8). 2013. PMID:23781201. DOI: 10.3389/fphar.2013.00074.
  • [28] Helga Ask;Rosa Cheesman;Eshim S Jami;Daniel F Levey;Kirstin L Purves;Heike Weber. Genetic contributions to anxiety disorders: where we are and where we are heading.. Psychological medicine(IF=5.5). 2021. PMID:33557968. DOI: 10.1017/S0033291720005486.
  • [29] Rosemary C Bagot;Benoit Labonté;Catherine J Peña;Eric J Nestler. Epigenetic signaling in psychiatric disorders: stress and depression.. Dialogues in clinical neuroscience(IF=8.9). 2014. PMID:25364280. DOI: .
  • [30] Jennifer Y F Lau;Daniel S Pine. Elucidating risk mechanisms of gene-environment interactions on pediatric anxiety: integrating findings from neuroscience.. European archives of psychiatry and clinical neuroscience(IF=3.7). 2008. PMID:18343966. DOI: 10.1007/s00406-007-0788-1.
  • [31] S J Wood;M Toth. Molecular pathways of anxiety revealed by knockout mice.. Molecular neurobiology(IF=4.3). 2001. PMID:11817214. DOI: 10.1385/MN:23:2-3:101.
  • [32] Jianwen Lin;Wenxin Liu;Jing Guan;Jianing Cui;Ruolin Shi;Lu Wang;Dong Chen;Yi Liu. Latest updates on the serotonergic system in depression and anxiety.. Frontiers in synaptic neuroscience(IF=4.1). 2023. PMID:37228487. DOI: 10.3389/fnsyn.2023.1124112.
  • [33] Kristina Repova;Tomas Baka;Kristina Krajcirovicova;Peter Stanko;Silvia Aziriova;Russel J Reiter;Fedor Simko. Melatonin as a Potential Approach to Anxiety Treatment.. International journal of molecular sciences(IF=4.9). 2022. PMID:36555831. DOI: 10.3390/ijms232416187.
  • [34] Ermis Merkouris;Alexandra Brasinika;Meropi Patsiavoura;Chrysanthi Siniosoglou;Dimitrios Tsiptsios;Andreas S Triantafyllis;Christoph Mueller;Ioulia Mpikou;Myrto T Samara;Nikolaos Christodoulou;Konstantinos Tsamakis. Molecular Basis of Anxiety: A Comprehensive Review of 2014-2024 Clinical and Preclinical Studies.. International journal of molecular sciences(IF=4.9). 2025. PMID:40508224. DOI: 10.3390/ijms26115417.
  • [35] Melissa Furtado;Martin A Katzman. Neuroinflammatory pathways in anxiety, posttraumatic stress, and obsessive compulsive disorders.. Psychiatry research(IF=3.9). 2015. PMID:26296951. DOI: .
  • [36] K P Das;P Gavade. A review on the efficacy of artificial intelligence for managing anxiety disorders.. Frontiers in artificial intelligence(IF=4.7). 2024. PMID:39479229. DOI: 10.3389/frai.2024.1435895.
  • [37] Brian G Dias;Sunayana B Banerjee;Jared V Goodman;Kerry J Ressler. Towards new approaches to disorders of fear and anxiety.. Current opinion in neurobiology(IF=5.2). 2013. PMID:23402950. DOI: .
  • [38] Daniela Tardito;Alessandra Mallei;Maurizio Popoli. Lost in translation. New unexplored avenues for neuropsychopharmacology: epigenetics and microRNAs.. Expert opinion on investigational drugs(IF=4.1). 2013. PMID:23253113. DOI: 10.1517/13543784.2013.749237.
  • [39] Lisa M Shin;Israel Liberzon. The neurocircuitry of fear, stress, and anxiety disorders.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology(IF=7.1). 2010. PMID:19625997. DOI: 10.1038/npp.2009.83.
  • [40] Amit Etkin;Tor D Wager. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.. The American journal of psychiatry(IF=14.7). 2007. PMID:17898336. DOI: 10.1176/appi.ajp.2007.07030504.
  • [41] Veruska Andrea Santos;Dessana David Carvalho;Michael Van Ameringen;Antonio Egidio Nardi;Rafael Christophe Freire. Neuroimaging findings as predictors of treatment outcome of psychotherapy in anxiety disorders.. Progress in neuro-psychopharmacology & biological psychiatry(IF=3.9). 2019. PMID:29627509. DOI: 10.1016/j.pnpbp.2018.04.001.
  • [42] Joachim D K Uys;Dan J Stein;Willie M U Daniels;Brian H Harvey. Animal models of anxiety disorders.. Current psychiatry reports(IF=6.7). 2003. PMID:12857530. DOI: 10.1007/s11920-003-0056-7.
  • [43] Angelika Erhardt;Victor I Spoormaker. Translational approaches to anxiety: focus on genetics, fear extinction and brain imaging.. Current psychiatry reports(IF=6.7). 2013. PMID:24234873. DOI: 10.1007/s11920-013-0417-9.
  • [44] Eberhard Fuchs;Gabriele Flïugge. Experimental animal models for the simulation of depression and anxiety.. Dialogues in clinical neuroscience(IF=8.9). 2006. PMID:17117614. DOI: .

MaltSci Intelligent Research Services ​

Search for more papers on MaltSci.com ​

Anxiety Disorders · Neural Mechanisms · Amygdala · Prefrontal Cortex · Neurotransmitters

© 2025 MaltSci