Silent regulators of trauma: the microRNA blueprint underlying post-traumatic stress disorder biology

Abstract

Post-traumatic stress disorder (PTSD) is a chronic and disabling psychiatric condition that affects millions of people worldwide, producing persistent disturbances in emotional regulation, cognition, and physiological functioning. Although exposure to traumatic or life-threatening events is a defining feature of PTSD, only a subset of exposed individuals develop enduring symptoms, highlighting variability in vulnerability and recovery. The biological mechanisms underlying PTSD remain incompletely understood. Increasing evidence suggests that epigenetic processes play a central role in shaping individual responses to trauma. Among these, microRNAs (miRNAs), small, noncoding RNA molecules that fine-tune gene expression by regulating the translation and stability of multiple target genes simultaneously, have emerged as important epigenetic regulators of PTSD-related neurobiology. Because a single miRNA can influence extensive gene networks, alterations in miRNA expression affect a broad range of biological processes relevant to PTSD, including hypothalamic–pituitary–adrenal (HPA) axis function, synaptic plasticity, immune signaling, and memory formation. Recent studies demonstrate that dysregulated miRNAs can modify glucocorticoid receptor sensitivity, shape fear memory acquisition and extinction, and contribute to the proinflammatory phenotype frequently observed in PTSD. Progress of miRNA research in this field has been driven by integrative strategies that combine human peripheral tissues, plasma, and extracellular vesicles, complemented by animal models of stress and fear learning, including fear conditioning, restraint stress, and single-prolonged stress paradigms. Together, these approaches provide converging evidence for a critical role of miRNAs in PTSD pathophysiology. This review synthesizes findings across species to clarify miRNA-mediated mechanisms and highlight future directions for biomarker discovery and therapeutic development.

Graphical Abstract

Graphical Abstract.

Introduction

Post-traumatic stress disorder (PTSD) is a chronic, debilitating psychiatric illness that develops following exposure to a traumatic event. Those suffering from PTSD exhibit symptoms such as involuntary re-experiencing of the trauma (flashbacks) and actively avoid reminders of the trauma [1]. In 2013, the World Health Organization (WHO) estimated that 3.6% of the world’s population had suffered from PTSD [2], making it a moderately common and widespread disorder. A study combined data from the WHO World Mental Health Surveys in 24 countries worldwide and found that 70.4% of participants experienced at least one traumatic event in their lifetime, with 30.5% exposed to four or more events [3]. Follow-up analysis of the surveys corroborates the lifetime prevalence of PTSD in ∼4% of the total respondents (∼5.6% of trauma-exposed respondents) [4, 5]. The majority of people will experience some form of trauma, yet not everyone exposed will develop persistent symptoms.

The effects of PTSD can harm an individual’s health, increasing the risk of comorbid disorders and potentially leading to suicide [6–10]. It can also be a burden to the economy through lost productivity and be expensive for the individual and their loved ones seeking treatment [6, 11]. Therefore, it is crucial to understand who is at greater risk of developing PTSD and how to treat patients with PTSD effectively. This has prompted further research into the neurobiological mechanisms behind PTSD to identify predisposing factors. Ultimately, the goal is to find biomarkers for predicting PTSD susceptibility and to develop more effective therapies or treatments.

Recent studies have explored epigenetic modifications (such as DNA methylation and histone acetylation) as potential biological processes involved in PTSD pathophysiology [12–16]. In particular, microRNAs (miRNAs), a type of small noncoding RNAs, have recently gained significant attention for their role in various psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, and PTSD [17–23]. They can widely influence the expression of multiple coding genes after transcription. The dysregulation of any single miRNA can affect numerous signaling pathways, contributing to the overall disease process [24]. With this review, we seek to comprehensively assess the current state of miRNA research as it relates to PTSD, integrating evidence across molecular, behavioral, and translational domains. Our goal is to examine miRNAs within the broader neurobiological framework of PTSD, highlighting how these small noncoding RNAs contribute to vulnerability, symptom persistence, and the diverse physiological alterations observed following trauma. To establish this foundation, we first provide an overview of the key features of PTSD, including its diagnostic criteria, heterogeneous clinical presentation, and documented neurobiological abnormalities. We also present a concise description of miRNA biosynthesis and function, outlining the major steps of their biogenesis, and emphasizing how individual miRNAs can regulate extensive gene networks through post-transcriptional repression. Following this conceptual groundwork, we summarize findings from recent empirical studies examining miRNA regulation in PTSD using both animal models and human patient samples. These investigations span a wide array of methodological approaches, including fear-conditioning paradigms, acute and chronic stress models, analysis of peripheral tissues, and emerging work on extracellular vesicles (EVs). By comparing convergent themes across species and experimental contexts, we highlight key miRNAs implicated in synaptic plasticity, hypothalamic–pituitary–adrenal (HPA) axis regulation, inflammatory signaling, and trauma-related memory processes. Particular attention is given to miRNAs targeting FKBP5, stress-responsive transcription factors, and inflammatory cytokines, as these molecules represent some of the most consistently dysregulated pathways across the current literature. Altogether, this review aims to synthesize diverse lines of evidence to elucidate the significance of miRNAs in PTSD pathophysiology. By critically evaluating the strengths and limitations of existing research, we also identify knowledge gaps and propose future directions to advance the field. These include longitudinal assessments, deeper integration of central and peripheral measures, and translational efforts that may ultimately support the development of miRNA-based biomarkers or therapeutic targets.

PTSD overview

The first diagnostic criterion for PTSD in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), is that it must be preceded by an “exposure to actual or threatened death, serious injury, or sexual violence” [1]. Symptoms of PTSD include intrusion symptoms, including reliving the traumatic event(s) through persistent memories, distressing dreams, or dissociative flashbacks; persistent avoidance of stimuli associated with the traumatic event(s) (including people, places, objects, situations, or other reminders); negative changes in cognitions (e.g. amnesia for part or all of the event) and mood; and alterations in arousal and reactivity (e.g. irritability or exaggerated startle) [1].

Recently described in the WHO International Classification of Diseases, 11th Revision (ICD-11), complex PTSD (CPTSD) is gaining recognition as a related but distinct form of the disorder [25]. This related disorder typically arises from more prolonged or repeated exposure to trauma rather than a single incident [26]. CPTSD entails the same symptoms as PTSD with the addition of affect dysregulation, more severe negative cognitions (e.g., lost self-worth, excessive guilt), and difficulty maintaining relationships [25]. The more dissociative nature of CPTSD makes it more debilitating and potentially more difficult to distinguish from borderline personality disorder [27].

Traumatic events that predispose to the development of PTSD are varied. Some of the most commonly suffered traumas are accident or injury to oneself (such as an automobile accident), directly witnessing injury or death of another, an unexpected death of a close relative or friend, or sexual trauma [3]. Certain types of traumatic events may confer a higher risk of developing PTSD [4, 28]. For example, Kessler et al. determined that sexual abuse by an intimate partner carries a higher risk but is less common than the unexpected death of a loved one; both exhibit a considerable burden in the form of subsequent PTSD symptoms [28]. Results from the WHO World Mental Health surveys found some of the traumatic events with the highest percentage of following PTSD prevalence are rape (17.4%), kidnapping (11.3%), and other sexual assaults (11.0%) [4].

Symptoms lasting longer than a month are necessary for a clinical diagnosis of PTSD [1, 29]; however, it can continue for much longer. In their analysis of World Mental Health survey data, Kessler et al. reported the average duration of symptoms across all trauma types to be approximately 72.3 months, with high variability depending on the trauma type [28]. War-related trauma and physical or sexual violence resulted in more persistent symptoms than other types, such as natural disasters [28]. More severe and repeated traumatic experiences lead to both more persistent and more severe symptoms, as observed in CPTSD [26, 27].

In addition to behavioral changes, PTSD involves significant physiological alterations. Imaging studies have revealed abnormal connectivity in several key brain regions responsible for mood regulation and memory formation, including the prefrontal cortex (PFC), inferior frontal gyrus, anterior cingulate cortex, hippocampus, and amygdala [30, 31]. The connection between the brainstem and these areas can also be disrupted, impacting arousal and responsiveness [32]. Neuronal or synaptic plasticity in these critical regions is often diminished, reducing the brain’s ability to function properly [33, 34]. Peripheral tissue research has identified a dysregulated immune system in PTSD, with proinflammatory cytokines such as IL-1β, IL-6, and TNF-α elevated in patients [35–38]. Changes in glucocorticoid receptor (GR) sensitivity and HPA axis activity can also be linked to abnormal stress responses, which are a core aspect of PTSD physiology [12, 39]. However, findings vary, with some studies showing decreased activity [40] and others showing increased activity [41].

These behavioral and physiological changes can significantly affect quality of life. Reduced motivation and social withdrawal may lead to the loss of valuable relationships and career opportunities [6]. Sleep disturbances commonly associated with PTSD can deteriorate overall health and elevate the risk of other medical conditions [8]. Increased stress and immune responses may accelerate cellular aging and raise the likelihood of cardiovascular disease [42, 43]. PTSD is strongly linked to substance use disorders (SUDs) [44–48]. Sometimes, this occurs as an effort to self-medicate; other times, substance abuse may have triggered the traumatic event that led to PTSD [45].

PTSD increases the risk of developing other comorbid psychiatric illnesses, and vice versa [49, 50]. This is especially true for major depressive disorder (MDD) and anxiety disorders, which share similar etiopathogenesis [50]. An abnormal physiological stress response (HPA axis and GR activity) is a common feature in these disorders, and they show similar epigenetic changes [17, 50]. In some cases, extreme trauma [49]. Compean and Hamner suggest that PTSD with secondary psychotic features (PTSD-SP) could be viewed as a distinct subtype of PTSD that requires different treatment [49].

Traumatic brain injury (TBI) is often found alongside PTSD, especially in soldiers, where warzone conditions can cause both physical and psychological trauma [51–53]. TBIs frequently involve damage to the PFC, impacting emotional and fear regulation [52]. The overlapping symptoms can make it difficult to distinguish between and accurately diagnose these conditions [51, 52]. A patient with mild or remote TBI may not recognize it, and the condition can be missed. Treating only one of the two conditions may lead to less effective treatment and longer-lasting symptoms [52].

Among the more serious consequences of PTSD is the increased risk of suicide [54]. Researchers initially studied increased suicidality among military personnel and veterans [54, 55]; however, this issue also affects civilian populations [54, 56, 57]—particularly adolescents with PTSD [58, 59] or those who experienced adverse childhood experiences [60–62]. A meta-analysis found that rates of both suicidal thoughts and attempts were similarly high, if not higher, in adolescents with PTSD compared to adults [58]. Among the potential factors contributing to this problem, comorbid MDD has been strongly implicated [7, 54, 63, 64]. Sleep disturbances have also been identified as a key cofactor in increased suicidality, though further research is needed to clarify how these factors influence the relationship between PTSD and suicide [8, 65, 66].

Thoroughly understanding the neurobiology of PTSD may help explain its interactions with comorbid disorders, and it can also guide the development of future treatments.

MiRNA overview

miRNAs play key regulatory roles in cells by binding to mRNAs, thus dynamically controlling protein levels. Mature miRNAs are about 22 nucleotides (nt) long and mainly function to decrease the stability or availability of target mRNAs, rather than encode a protein [67]. They are highly abundant and involved in many regulatory pathways; more than 2500 human mature miRNAs have been identified and studied [68, 69], and the functions of many miRNAs appear to be conserved through evolution [70, 71]. miRNA expression profiles differ depending on tissue type and an organism’s developmental stage, highlighting their significance in cell differentiation and maintenance in complex organisms [72–74].

Genes encoding miRNAs are transcribed by either RNA polymerase (RNA pol) II or III in order to produce a primary miRNA (pri-miRNA) [75]. The presence of a 5′ 7-methylguanylate cap (m7g) and 3′ poly(A) tail on many pri-miRNA transcripts suggests that RNA pol II is the more prominently used enzyme [76, 77]. A key region of the pri-miRNA transcript forms a secondary hairpin structure with a stem ∼33 nt in length [75]. The pri-miRNA is then cleaved within the nucleus by the “microprocessor complex”, a multiprotein complex whose principal units are the RNase III endonuclease Drosha and DiGeorge syndrome critical region 8 (DGCR 8). The RNase functionality of Drosha serves to cleave off the 5′ and 3′ regions surrounding the hairpin, leaving a 2 nt overhang on the 3′ end [71]. The result is a stem-loop structure ∼60–70 nt long, known as a precursor miRNA (pre-miRNA) [67]. The pre-miRNA is transported from the nucleus to the cytosol by exportin 5 (XPO5) for additional processing. The RNase III endonuclease Dicer1, assisted by transactivation-responsive RNA-binding protein (TRBP), cleaves the loop end of the pre-miRNA, leaving a 2 nt overhang on the 3′ end. This produces a mature miRNA/miRNA* duplex ∼22 nts long [20]. The duplex, along with Dicer1 and TRBP, combines with an Argonaute protein. This multiprotein complex, known as RNA-induced silencing complex (RISC), retains only one of the two miRNA strands and releases the other back into the cytosol for degradation [20]. Although either strand of the duplex could potentially function, the strand whose 5′ end most easily fits into the Argonaute protein is usually retained [71] (Fig. 1).

Figure 1.

Schematic illustration summarizing the biogenesis and functional roles of miRNAs, including their transcription, processing by Drosha and Dicer, incorporation into the RISC, and regulation of target mRNA translation and degradation. Primary miRNA (pri–miRNA) transcripts are processed in the nucleus by the Drosha–DGCR8 complex into precursor miRNAs (pre–miRNAs), exported to the cytosol, and further cleaved by Dicer to generate mature miRNA duplexes. One strand is then loaded into the RISC, where the miRNA guides RISC to partially or fully complementary sequences in target mRNAs, typically within the 3′ untranslated region. miRNA–mRNA binding leads to translational repression and/or mRNA degradation, reducing protein output. The illustration was created with Biorender.com.

RISC uses a 2–7 nt seed sequence in the loaded miRNA to bind partially or fully to a short, complementary sequence in the 3′ untranslated region of a target mRNA. The fact that this process uses only a 2–7 nt sequence and does not need perfect complementarity, it allows miRNAs to target multiple mRNA species [20]. By binding to the mRNA transcript, RISC can compete with translational machinery, such as elongation factors, to reduce translation. Alternatively, RISC can promote mRNA degradation by recruiting deadenylation factors to cleave the 3′ poly(A) tail [67]. Ultimately, the interaction between RISC and mRNA most often leads to reduced expression of the target protein (Fig. 2A). Although miRNAs are primarily known to negatively regulate gene expression through mRNA degradation or translational repression, emerging evidence suggests that some miRNAs may also increase gene or protein expression under specific conditions [78, 79]. This positive regulatory effect can occur indirectly through suppression of transcriptional repressors or, in certain cellular contexts, through direct enhancement of translation and transcript stabilization [79–81]. However, a recent study highlighted their role as positive regulators of gene expression by targeting the enhancer elements, miRNA response element, or MRE [82, 83]. Such context-dependent regulatory activity demonstrates the complexity of miRNA-mediated gene regulation and suggests that miRNA function cannot be considered exclusively inhibitory [84, 85]. Therefore, both suppressive and stimulatory effects of miRNAs should be considered when interpreting their contribution to PTSD-associated molecular pathways [86].

Figure 2.

(A) Schematic illustration of key mechanisms by which microRNAs (miRNAs) alter gene expression at the post–transcriptional level. miRNA-loaded RISC (containing Ago1–4) binds complementary sites in the 3′UTR of target mRNAs and regulates their expression through two major post–transcriptional mechanisms. Target mRNA degradation: RISC recruits deadenylase complexes that shorten the poly(A) tail, leading to deadenylation, followed by decapping of the 5′ m7G cap and 5′→3′ exonucleolytic decay, with reduced mRNA output. Translational repression: RISC binding interferes with translation initiation and promotes premature ribosome dissociation (“ribosome drop–off”), and, in some contexts, is coupled with enhanced proteolysis of nascent or existing polypeptides, diminishing protein output even when mRNA is still present. (B) Together, these miRNA–dependent pathways fine–tune the expression of genes involved in synaptic plasticity, memory formation, fear extinction, neuroinflammation, neuronal growth, and neuronal death, leading to the molecular pathophysiology of PTSD. The illustration provides an overview of the pathways that may be affected by miRNA changes in the PTSD brain. The illustration was created with BioRender.com.

MiRNA studies in PTSD

Studies investigating miRNAs related to PTSD select targets based on their predicted roles in regulating signaling pathways or physiological changes associated with PTSD. Modern techniques, such as next-generation sequencing, enable the identification of a pool of dysregulated miRNAs from a pilot group. Biological databases assist in selecting promising miRNAs based on their predicted gene targets. Subsequently, the regulatory roles of the selected miRNAs are further examined through analysis of patient samples (peripheral tissue, imaging, and postmortem brain tissue) and animal models.

While no single animal model can fully replicate the disorder, focusing PTSD research on specific biological mechanisms or markers instead of symptoms enhances the relevance of some animal model findings [87–89]. Since PTSD development is linked to a specific traumatic event, researchers typically use paradigms with a distinct, intense stressor that mimics this [90]. Restraint stress, which involves physically immobilizing the animal for a period, induces generalized avoidance, depression-like behaviors, and impairments in fear extinction. This model is commonly used to assess acute stress responses and recovery [87]. Similarly, inescapable foot or tail shocks affect the subjects, but their longer-term effects are better documented. Repeated exposure to these paradigms can produce a learned helplessness model, useful for studying susceptibility or resilience [87]. Single-prolonged stress (SPS) is a more targeted paradigm that combines restraint, forced swimming, and ether anesthesia to induce GR hypersensitivity and increased negative feedback of the HPA axis, features observed in PTSD [91]. Other models, such as social defeat stress and unpredictable mild stress, are employed to observe more sustained physiological adaptations to stress [87, 90]. Meanwhile, fear conditioning is frequently used to investigate the mechanisms underlying the formation and extinction of fear memories [90].

Using human patient samples and animal models, numerous miRNAs have been evaluated for their potential roles in regulating stress-response pathways, including GR hypersensitivity and HPA axis hypoactivation. Significant focus has been placed on miRNAs that regulate FKBP5 expression, a key component in moderating GR sensitivity [92–94]. Other miRNAs have been studied for their roles in synaptic plasticity and fear memory formation. The miRNAs exert a significant influence on the long-term consolidation of fear memories by regulating synaptic plasticity, particularly in the amygdala [33, 34]. Additionally, miRNA regulation of inflammation has been observed [95–97]. Due to their multifaceted nature, individual miRNAs may exhibit overlapping roles in these and other cell signaling pathways. Besides studies elucidating the regulatory roles of specific miRNAs, there are investigations focused on identifying distinct epigenetic signatures or biomarkers of PTSD [98, 99]. In the following sections, we overview how miRNA regulates key neurobiological processes implicated in PTSD, beginning with miRNAs in the brain and then in the peripheral circulation. Next, we summarize findings from preclinical, clinical, and human postmortem studies of PTSD that have examined miRNA dysregulation.

Key neurobiological roles of miRNAs in regulating PTSD-related functions

The influence of miRNAs on synaptic plasticity in PTSD

Synaptic plasticity is a fundamental neurobiological process that governs many aspects of adaptive learning, affective regulation, and stress responsiveness. Dysregulation of synaptic remodeling has been implicated in the PTSD brain, including the amygdala, hippocampus, and PFC [100–102]. Numerous miRNAs regulate genes involved in dendritic spine formation, neurotransmitter signaling, and long-term potentiation. For example, miR-132 and miR-134 are associated with activity-dependent synaptic remodeling and neuronal connectivity [103, 104]. Altered expression of these miRNAs has been linked to impaired fear extinction and increased sensitivity to stress [105, 106]. Additionally, miRNAs that target brain-derived neurotrophic factor (BDNF) signaling pathways may contribute to maladaptive neuroplastic changes observed in individuals with PTSD [107, 108].

The role of miRNAs in regulating memory formation in PTSD

PTSD is characterized by persistent traumatic memories and impaired extinction learning, both of which reflect disruptions in the neural processes that govern fear-related memory [109, 110]. miRNAs play essential roles in regulating cellular pathways involved in long-term memory formation, including consolidation, reconsolidation, and fear conditioning [105, 111]. Experimental evidence suggests that dysregulated miRNA expression may disrupt hippocampal-dependent memory processing by modulating GR signaling, cAMP response element-binding protein (CREB) activation, and the expression of synaptic proteins [112–114]. Specific miRNAs, including miR-34c, miR-124, and miR-182, have been implicated in the maintenance of fear memory and stress-related behavioral responses [105, 115, 116]. Collectively, these findings indicate that altered miRNA expression may contribute to maladaptive memory formation in PTSD, thereby promoting intrusive recollections and associated cognitive disturbances.

MiRNAs as regulators of neuroinflammatory processes in PTSD

Converging evidence indicates that neuroinflammatory dysregulation is a core component of PTSD pathophysiology, extending beyond peripheral immune abnormalities to include maladaptive signaling within central stress-responsive circuits [117, 118]. miRNAs are well positioned to regulate this process because they coordinate post-transcriptional control of inflammatory cytokine production, microglial activation states, and neurovascular integrity [119]. In particular, miR-146a and miR-155 are prominent modulators of NF-κB-associated immune signaling and have been implicated in shaping the magnitude and duration of inflammatory responses under chronic stress-related conditions [120–122]. It has also been noted that under chronic stress, NF-κB-driven upregulation of lin-28 suppresses let-7. Several let-7 family of miRNAs, including let-7a, 7f, and 7i, have been verified as candidates for NF-κB regulation. Suppression of let-7 family members, in turn, can promote the upregulation of IL-6 and sustained activation of NF-κB signaling and inflammatory activation, a common chronic stress-related central nervous system (CNS) pathology [123, 124]. Dysregulation of these and related inflammatory miRNAs may therefore amplify cytokine signaling, disturb blood–brain barrier homeostasis, and alter neuron–glia communication, thereby promoting persistent circuit-level dysfunction in the amygdala, hippocampus, and PFC [125, 126]. Such changes are likely to reinforce fear generalization, impair extinction learning, and sustain the intrusive memory states that characterize PTSD [88, 110, 127]. Taken together, these findings support a model in which miRNAs function as mechanistic nodes linking stress exposure, neuroimmune activation, and maladaptive plasticity in PTSD.

MiRNAs and fear extinction

Impaired fear extinction is a core neurobiological feature of PTSD that contributes to persistent trauma-related memories, fear generalization, and reduced behavioral flexibility [109, 128]. Extinction is an active form of inhibitory learning that depends on coordinated plasticity across the amygdala, hippocampus, and medial PFC (mPFC), together with molecular programs governing synaptic remodeling, neuronal excitability, and memory updating [129, 130]. miRNAs are increasingly recognized as important regulators of these processes because they can simultaneously modulate multiple downstream targets within stress- and plasticity-related signaling networks [131]. Several miRNAs have emerged as candidate regulators of extinction-related mechanisms [34]. For example, miR-29b-3p has been linked to extinction-associated molecular programs and facilitates fear-extinction memory, potentially in part through regulation of Dnmt3a-dependent epigenetic mechanisms [88, 132]. Likewise, miR-144-3p promotes extinction learning and protects against fear renewal in extinction-impaired models, consistent with effects on plasticity-related signaling pathways involving PTEN, SPRED1, and NOTCH1 [106, 131]. In contrast, miR-598-3p has been associated with stress-enhanced remote fear memory and extinction resistance in the basolateral amygdala, suggesting that elevated expression of specific miRNAs may bias neural circuits toward persistent, trauma-like memory states [106]. Together, these findings support the view that miRNA dysregulation can shift the balance between adaptive inhibitory learning and maladaptive memory persistence in PTSD.

Building on these mechanistic insights, the fact that the individual miRNAs coordinately regulate broad gene networks has led to their increasing recognition as plausible therapeutic entry points rather than merely descriptive biomarkers [133]. For example, interventions that normalize miRNAs governing extinction circuitry could, in principle, enhance adaptive plasticity, improve extinction retention, and reduce relapse after trauma-focused treatment [88]. Although translational development remains at an early stage and requires validation in longitudinal and clinical studies, current evidence supports the idea that miRNA-based strategies may ultimately complement exposure-based therapies by targeting mechanisms that underlie extinction failure in PTSD [105].

Neural circuits, HPA axis dysfunction, and miRNAs

PTSD is associated with functional alterations in neural circuits that mediate fear processing, affective regulation, and stress responsiveness, particularly within the amygdala, hippocampus, and mPFC [102, 134]. Hyperactivity of the amygdala, together with reduced regulatory control from the PFC and hippocampus, is thought to contribute to exaggerated fear responses and persistence of traumatic memories [135]. miRNAs are important modulators of these circuits because they regulate genes involved in synaptic transmission, neuronal plasticity, and stress signaling [136]. In experimental models, altered expression of miR-132, miR-124, and members of the miR-34 family has been linked to changes in synaptic activity, fear conditioning, and emotional behavior, supporting their role in stress-related neurocircuit dysfunction [137, 138].

Dysregulation of the HPA axis is another central feature of PTSD and may further reinforce chronic stress vulnerability through abnormal glucocorticoid signaling and altered cortisol responses [139]. miRNAs contribute to this process by modulating GR function, FKBP5 expression, and stress-responsive inflammatory pathways [140]. Consistent with this view, experimental studies show that stress-induced shifts in miRNA expression can influence both neuroendocrine responses and trauma-related behavioral outcomes [141, 142].

Together, these findings support a model in which miRNAs contribute to PTSD pathophysiology through coordinated effects on neural circuitry and HPA axis regulation, while intersecting with synaptic plasticity, neuroinflammation, and fear-memory processes (Fig. 2B). Their ability to influence multiple stress-associated pathways simultaneously further supports their potential as biomarkers and mechanistically informed therapeutic targets in PTSD.

Brain-derived EV miRNAs in PTSD

Recent studies identify EVs, particularly exosomes, as important carriers of miRNAs that mediate communication between the brain and peripheral tissues [143, 144]. Because brain-derived EVs can cross the blood–brain barrier and protect miRNAs from enzymatic degradation, EV-associated miRNAs detected in peripheral blood may provide a relatively stable and minimally invasive readout of CNS changes relevant to PTSD [145, 146]. Stress exposure and trauma-related neurobiological alterations appear to modify EV-miRNA cargo linked to synaptic plasticity, neuroinflammation, glucocorticoid signaling, and fear-memory processing, supporting their potential utility as biomarkers of PTSD-related pathophysiology [147]. Mechanistic support for this model comes from evidence that stress-induced changes in EV cargo can produce long-lasting biological and behavioral effects, suggesting that EV-mediated miRNA transfer may contribute directly to PTSD pathophysiology rather than merely reflect it [147, 148]. Although further validation in larger clinical cohorts is needed, circulating EV-associated miRNAs remain promising candidates for improving PTSD diagnosis, monitoring disease progression, and identifying new therapeutic targets [146].

Neuroimaging as a tool to examine PTSD-associated brain pathologies induced by MiRNA changes

Across imaging modalities, PTSD has been consistently associated with hyperactivity of the amygdala, reduced engagement of the mPFC and anterior cingulate cortex during affective and fear-processing tasks, and reduced hippocampal volume or altered hippocampal connectivity, findings that support impaired contextual memory processing and weakened top-down regulation of threat responses [149]. Resting-state functional magnetic resonance imaging and diffusion tensor imaging studies further indicate disrupted connectivity between brainstem nuclei and limbic–cortical regions, including the amygdala, hippocampus, and PFC, consistent with abnormalities in arousal regulation, autonomic control, and stress responsivity [150, 151]. These imaging findings define a circuit-level framework through which miRNA may affect synaptic plasticity, neuroinflammation, and stress signaling, which may contribute to PTSD pathophysiology [152]. The evidence of impaired synaptic plasticity comes primarily from animal models of chronic stress and PTSD-like behavior, which show reduced dendritic spine density, impaired long-term potentiation, and altered synaptic protein expression in the hippocampus and PFC [153, 154]. Integrating multimodal neuroimaging in PTSD with blood serum analyses, a study found that specific miRNAs (e.g., FKBP5-associated miRNA signatures) directly map to differential brain activation and symptom severity [155].

Taken together, these convergent imaging and molecular findings support the view that miRNA dysregulation is not merely an epiphenomenon of PTSD, but a plausible contributor to the circuit-level abnormalities that sustain impaired fear regulation, maladaptive stress responsivity, and persistent trauma-related symptoms.

MiRNA studies in PTSD

Animal studies

Preclinical miRNA studies in animal models (summarized in Table 1) have been particularly informative for dissecting how miRNAs shape stress regulation and fear-related learning in PTSD-relevant circuits [156, 157]. Most of these investigations converge on two broad themes: the modulation of synaptic plasticity underlying fear memory formation and extinction, and the regulation of stress-response pathways that influence vulnerability or resilience [158–160]. Among the available animal models of PTSD, the predator-based psychosocial stress (PPS) model developed by Diamond and colleagues has demonstrated strong translational relevance because it reproduces several key features of the disorder observed in humans, including persistent traumatic memory, heightened anxiety-like behavior, hyperarousal, impaired fear extinction, and stress-related physiological alterations. These observations support the use of the PPS model as a valuable experimental approach for investigating the neurobiological mechanisms of PTSD and for evaluating potential therapeutic interventions [161].

Table 1.

miRNA studies in animal models of post-traumatic disorder.

Species	Tissue	miRNAs	Target	Reference
Rat	Amygdala	miR-182	Cortactin and Rac1	[116]
Mouse	PFC	miR-1971, miR-33-5p	Organic molecule metabolism	[167]
Rat	Serum, amygdala	miR-142-5p, miR-19b, miR-1928, miR-223-3p, miR-322*, miR-324, miR-421-3p, miR-463*, miR-674*	Anxiety regulation, GR signaling	[177]
Mouse	Amygdala	miR-34a	Notch1	[111]
Mouse	Amygdala	miR-19b	Adrb1	[169]
Rat, Mouse	Hippocampus	miR-153	SNARE-mediated vesicle exocytosis	[162]
Mouse	Amygdala	miR-15a	FKBP5	[168]
Rat	Amygdala	miR-142-5p	Npas4	[172]
Mouse	Amygdala	miR-132	GAT1, PTEN	[164]
Mouse	Amygdala	miR-135b-5p	ECM–receptor interaction, thyroid hormone signaling	[166]
Mouse	mPFC	miR-200b-3p, miR-433-3p, miR-10a-5p, miR-10b-5p, miR-199a-3p, miR-224-5p, miR-146a-5p, miR-143-3p, miR-1247-5p, miR-363-5p, miR-346-5p, miR-486-5p, miR-193b-3p, miR-362-3p, miR-542-3p	FKBP5-associated signaling	[140]
Rat	Hippocampus	miR-132-3p	FXR1	[174]
Rat	Hippocampus	miR-142-5p	FMRP, PSD95	[173]
Rat	PFC	miR-132-3p	MeCP2	[175]
Mouse	mPFC, hippocampus, hypothalamus	miR-15a-5p, let-7d-5p, miR-497a-5p, miR-511-5p	FKBP5, BDNF	[170]
Rat	Hippocampus	miR-153-3p	Sigma-1 Receptor	[176]
Rat	Hippocampus	miR-124-3p	TRAF6	[138]
Rat	Hippocampus, amygdala	miR-9, miR-34c	Synaptic plasticity, Stress response (CRF1)	[163]

Within the amygdala, a key hub for fear processing, one study reported that miR-182 is downregulated in the lateral amygdala of fear-trained mice following an auditory fear-conditioning paradigm [116]. Further analysis revealed that miR-182 targets the actin-regulating proteins (ARPs) Cortactin and Rac1, indicating that learning-induced downregulation of miR-182 facilitates structural remodeling and improved synaptic plasticity. Consistent with this interpretation, artificially induced overexpression of miR-182 suppresses the long-term consolidation of fearful memories [116]. In a complementary line of work, Dias et al. showed that miR-34a exerts a somewhat converse effect in the mouse basolateral amygdala (BLA): upregulated miR-34a enhances synaptic plasticity by targeting the Notch1 gene, which encodes a transmembrane receptor involved in intercellular signaling, whereas inhibition of miR-34a reduces fear memory consolidation [111]. Together, these findings suggest that distinct amygdala miRNAs, such as miR-182 and miR-34a, fine–tune the strength and persistence of fear memories by differentially modulating plasticity-related pathways.

The hippocampus, a central structure for memory formation and contextual processing, represents another critical site of miRNA action in PTSD-like phenotypes. MiR-153 targets genes in the SNARE-mediated vesicular exocytosis signaling pathway, which is essential for neurotransmitter release from synaptic vesicles. Following fear conditioning, miR-153 expression increases, and inhibiting it in the dentate gyrus enhances fear memory consolidation, indicating that miR-153 normally constrains the long-term strengthening of fear-associated synapses [162]. Extending this work to inter-individual differences in fear regulation, Wisłowska-Stanek et al. divided Wistar rats into PTSD-resistant and PTSD-susceptible groups after fear conditioning and observed that the resistant group showed decreased levels of miR-9-3p in the hippocampus compared to susceptible animals [163]. Reduced expression of miR-9-3p was associated with facilitated fear memory extinction, implying that lower levels of this miRNA may promote recovery from traumatic learning. Jiang et al. further broadened the scope by profiling miRNA expression in the mPFC following extinction training and identifying 63 differentially expressed miRNAs enriched for dendritic and synaptic functions [164]. By integrating these findings with publicly available miRNA datasets from PBMCs of PTSD patients, they reported 250 differentially expressed miRNAs, including three extinction training-induced miRNAs that were downregulated in both a mouse model and human samples. Among these, miR-29b-3p emerged as a key regulator: it enhances fear-extinction memory and targets the 3′ untranslated region (UTR) of Dnmt3a, a DNA methyltransferase involved in de novo non–CG methylation. Collectively, these observations underscore the importance of miRNAs such as miR-153, miR-9-3p, and miR-29b-3p in extinction learning and highlight miR-29b-3p as a promising biomarker for PTSD-related processes [162, 163].

Beyond classical fear conditioning, some studies have explicitly contrasted fear learning with safety learning. Ronovsky et al., for example, compared fear-conditioned mice, unconditioned controls, and a third group of learned safety-conditioned animals in which the conditioned stimulus was presented in an explicitly unpaired manner from the unconditioned stimulus, signaling safety rather than threat [164]. In this paradigm, miR-132 was upregulated in the BLA of learned safety mice relative to both learned fear and control groups. Mechanistic experiments showed that miR-132 regulates neuronal excitability and plasticity by targeting the GABA transporter 1 (GAT1) and phosphatase and tensin homolog (PTEN). Overall, these results suggest that increased miR-132 expression contributes to fear extinction and the encoding of safety signals [164]. To probe more persistent, trauma-like adaptations, Sillivan et al. used a stress-enhanced fear learning (SEFL) paradigm in which animals were exposed to restraint stress prior to fear conditioning, thereby inducing extinction–resistant changes reminiscent of chronic PTSD [165, 166]. After fear extinction and remote memory retrieval 30 days post-stress, miR-135-5p was found to be upregulated in the amygdala of the more stress-susceptible, fear-trained mice. Similar increases were observed in serum samples from human PTSD patients, and lentiviral overexpression of miR-135-5p in mice enhanced fear memory expression, pointing to this miRNA as a potential cross-species marker of heightened stress susceptibility [166].

The studies described thus far collectively support the idea that miRNAs can epigenetically regulate the formation and extinction of persistent fear memories, particularly during and after traumatic events, which is central to PTSD etiology. This regulation is achieved primarily by modulating plasticity-related genes in brain regions critical for memory, especially the hippocampus and amygdala. A second major line of work focuses on how miRNAs orchestrate stress responses and maladaptation. Using a foot-shock mouse model, Schmidt et al. showed that miR-1971 and miR-33-5p are upregulated in the PFC of stressed mice and that this upregulation is attenuated by fluoxetine treatment, linking these miRNAs to stress-induced molecular changes that are at least partially reversible by antidepressant intervention [167]. Two studies by Volk and colleagues extended this perspective using a social defeat stress model in mice, isolating Ago2-associated miRNAs from amygdala tissue to enrich for miRNAs actively engaged in RISC-mediated regulation [168, 169]. One of these studies identified increased amygdala miR-19b, which targets adrenergic receptor β-1 (Adrb1) and thereby influences both memory formation and anxiety-like behavior [169]. The other reported increased expression of amygdala miR-15a in response to stress; miR-15a targets FKBP5, a key modulator of GR sensitivity and stress-response regulation [168]. Complementing these findings, Maurel et al. sought to delineate miRNAs involved more broadly in stress regulation by selecting candidates predicted to target FKBP5 and BDNF and examining their expression in a restraint stress model using C57BL/6J mice [170]. MiR-15a-5p, let-7d-5p, miR-497a-5p, and miR-511-5p were identified as particularly relevant to the stress response, and both these miRNAs and their targets exhibited distinct expression patterns across the mPFC, hippocampus, and hypothalamus in control, stress-resilient, and stress-susceptible groups. Together, these studies highlight a network of stress-responsive miRNAs that converge on FKBP5-, BDNF-, and Adrb1-related pathways, thereby shaping adaptation or maladaptation to chronic stress [167–170]. Additional mechanistic support for the involvement of EV-associated miRNAs in stress-related phenotypes comes from the work of Chan et al., who demonstrated in the stress mouse model that stress-induced alterations in EV cargo can mediate long-lasting biological effects and influence stress-related behavioral outcomes [171]. These findings further support the hypothesis that exosome-mediated miRNA signaling may contribute to the molecular mechanisms underlying PTSD and other stress-associated disorders.

SPS paradigms in rats provide additional evidence that miRNAs integrate stress, synaptic plasticity, and inflammatory signaling. In one SPS model, miR-142-5p levels were increased in the amygdala of stressed animals, and this miRNA was shown to target neuronal PAS domain protein 4 (Npas4), a transcription factor involved in neuronal stress responses and synaptic plasticity [172]. Subsequent work demonstrated that miR-142-5p also decreases the levels of fragile X mental retardation protein (FMRP) and postsynaptic density protein–95 (PSD95) in the hippocampus of SPS rats, thereby affecting both inflammatory processes and synaptic structure [173]. Using the same SPS paradigm, Nie et al. observed increased levels of miR-132-3p in the hippocampus, which were associated with reduced expression of the RNA-binding protein FXR1 and decreased synaptic plasticity [174]. Follow-up experiments showed that injecting a miR-132-3p inhibitor alleviated anxiety-like behaviors, directly linking this miRNA to stress-induced behavioral phenotypes [175]. In parallel, Chen et al. reported increased expression of miR-153-3p in the hippocampus of SPS rats, where it regulates the sigma-1 receptor; blocking sigma-1 receptor activity alleviated PTSD-like behaviors, suggesting that miR–153–3p contributes to maladaptive stress responses through this pathway [176]. By contrast, miR-124-3p had an opposite pattern: Chen et al. found it to be downregulated in SPS rats, and lentiviral overexpression of miR-124-3p downregulated its target TRAF6 and reduced PTSD-like behaviors, highlighting a potentially protective role for this miRNA in stress adaptation [138].

Finally, several animal studies have moved beyond single candidates to identify broader miRNA signatures that might serve as biomarkers of PTSD-like physiology. Balakathiresan and colleagues subjected rats to inescapable shock stress and collected serum and amygdala samples immediately after stress and again 14 days later [177]. Their analysis identified nine miRNAs that were upregulated in both serum and amygdala samples at the delayed time point—miR-142-5p, miR-19b, miR-1928, miR-223-3p, miR-322*, miR-324, miR-421-3p, miR-463*, and miR-674*—suggesting a coordinated, persistent peripheral and central response to traumatic stress. Building on this approach, Kang et al. examined FKBP5 knockout mice and reported 41 differentially expressed miRNAs (23 downregulated and 18 upregulated) in the mPFC [140]. Fifteen of these were grouped into three clusters based on predicted regulatory functions: “composite marker 1” (miR-200b-3p, miR-433-3p, miR-10a-5p, miR-10b-5p, miR-199a-3p, miR-224-5p, miR-146a-5p, and miR-143-3p), “composite marker 2” (miR-1247-5p, miR-363-5p, miR-346-5p, and miR-486-5p), and “composite marker 3” (miR-193b-3p, miR-362-3p, and miR–542–3p). Notably, “composite marker 1” corresponded most closely to a PTSD-like phenotype when compared with serum and exosomal miRNAs from human PTSD patients, indicating that FKBP5-related miRNA patterns in the mPFC may translate across species [140].

Taken together, animal studies demonstrate that specific miRNAs in the amygdala, hippocampus, and PFC regulate fear learning and extinction, synaptic plasticity, and stress–response pathways central to PTSD-like behaviors. MiRNAs such as miR-182, miR-34a, miR-135-5p, miR-153, miR-142-5p, miR-132-3p, and miR-124-3p can enhance or suppress memory consolidation, plasticity, inflammation, or FKBP5-related stress signaling, thereby shaping both susceptibility and resilience. In parallel, biomarker-oriented models identify coordinated panels of stress-responsive miRNAs that may serve as peripheral indicators of PTSD-like physiology and provide mechanistic entry points for future translational research.

Human studies

Building on evidence from animal models, human miRNA studies in PTSD have begun to map how trauma-related molecular changes appear in accessible peripheral tissues. As summarized in Table 2, investigators have profiled miRNAs in blood, PBMCs, plasma, and EVs from trauma-exposed individuals with and without PTSD. These studies consistently identify sets of dysregulated miRNAs that regulate inflammatory cytokines, stress-hormone signaling, and neural plasticity-related pathways. In doing so, they not only support a mechanistic role for miRNAs in PTSD pathophysiology but also nominate candidate markers that may aid in risk stratification, diagnosis, and monitoring of treatment response.

Table 2.

miRNA studies in patients with post-traumatic disorder.

Species	Tissue	miRNAs	Target	Reference
Human	PBMC	miR-125a	IFN-γ	[97]
Human	Blood	miR-3130-5p	MRPL35	[181]
Human	Plasma, PBMC	miR-193-5p	IL-12	[180]
Human	Blood, PBMC	miR-let-7a, miR-15b, miR-223, miR-155, miR-150, miR-181a, miR-23(a,b), miR-19b, miR-103a, miR-24, miR-320(a,b,d), miR-532-3p, miR-339-3p, miR-1207-5p, miR-423-5p, miR-199a-3p, miR-193a-5p, miR-29a, miR-146a, miR-130a, miR-487b, miR-432, miR-503, miR-877, miR-27b, miR-455-3p, miR-152, miR-145, miR-185, miR-149*, miR-125a-5p, miR-874	Inflammatory pathways (JAK2, STAT1, IL23A, TGFB1, TGFB2, TGFB3, T-BET)	[95]
Human	Blood	miR-19a-3p, miR-486-3p, miR-128-3p, miR-15b-3p, miR-125b-5p, miR-101-3p, miR-20b-5p, miR-20a-5p	Axon guidance, Wnt signaling pathway	[156]
Human	Blood	miR-320a	FKBP5	[182]
Human	Blood, plasma, exosomes	miR-203a-3p, miR-339-5p	Synapse function, inflammatory pathways	[96]
Human	Blood, serum	miR-221-3p, miR-335-5p, miR-138-5p, miR-222-3p, miR-146-5p	Apoptotic processes, protein binding, RNA binding	[184]
Human	Blood	miR-19b	Circadian rhythm, homeostasis	[183]
Human	Blood, PBMC	miR-7113-5p	Wnt signaling pathway (WNT10B)	[179]
	Serum exosomes	miR-10a-5p, -10b-5p, -199a-3p, -224-5p, -146a-5p, and -143-3p		[140]
Human	PBMC	let-7a	Inflammatory pathways	[178]
Human	Plasma extracellular vesicles	miR-372-3p, miR-1185-1-3p, miR-3196, miR-3190-3p, miR-139-5p, miR-615-5p	cAMP response element-binding protein signaling, peripheral and central inflammatory diseases, promotion of the expression of cytokines such as TNF-α and IL-6, axonal guidance and synaptogenesis	[187]
Human	Plasma extracellular vesicles	miR-139-5p, miR-5001-5p, miR-18a-5p, miR-204-5p, miR-324-3p, miR-361-3p, miR-3190-3p, miR-376b-3p, miR-619-3p, miR-1268b, miR-5010-3p, miR-767-5p, miR-1233-3p, miR-615-5p, miR-631, miR-197-5p, miR-1304-3p, miR-567, miR-3615, let-7e-5p, miR-4792, miR-326, miR-372-3p, miR-516a-5p	Oxidative phosphorylation, mitochondrial dysfunction, neuroinflammation, axonal guidance and synaptogenesis, cell signaling mediated by integrins and growth factors	[186]
Human	Plasma extracellular vesicles	miR-93-5p, miR-23a-5p, miR-9-5p, miR-146a-3p, miR-1185,-1-3p, miR-3120-3p, miR-655-3p, miR-21-5p, miR-330-5p, miR-26a-5p, let-7a-5p, miR-205-5p, miR-374b-3p, miR-4446-3p, miR-16-5p, miR-224-3p, miR-191-5p, miR-215-5p, miR-99b-3p, miR-146a-5p, miR-124-3p	Inflammation and oxidative stress, angiogenesis, epithelial dysfunction	[188]
Human	Whole blood	miR-146a, miR-505, miR-181a, miR-494, miR-1228, miR-29b, miR-338-5p, let-7i, miR-29b-2, miR-487b, miR-652, -339-5p, miR-532-3p, miR-17, miR-103, miR-421, miR-30d, miR-125a-5p, miR-22a, miR-222, miR-93, miR-210, miR-342-3p, miR-1826, miR-668-3p, miR-185, miR-16, miR-200c, miR-519a, miR-29a, miR-532-5p, let-7f, miR-301a, miR-31, miR-18a, miR-29b-1, miR-1275, miR-99a, miR-425, miR-193a-5p, miR-22, miR-92a-1, miR-802, miR-186, miR-1281, miR-455-3p, miR-637, miR-181b, miR-432, miR-923, let-7b, miR-128, miR-26a, miR-23a, miR-769-5p, miR-24, miR-24-2, let-7a, miR-19b, miR-193b, miR-409-3p, miR-330-3p, miR-1224-5p, miR-197, miR-363, miR-106a, miR-181c, miR-584, miR-542-5p, miR-130a, miR-345, miR-1207-5p, miR-1231, miR-192, miR-570, miR-324-5p, miR-130b, miR-491-5p, miR-15b, miR-331-5p, miR-140-3p, miR-155, miR-151-5p, miR-139-5p, miR-503, miR-324-3p, miR-744, miR-99b, miR-625, miR-188-3p, miR-25, miR-27a, miR-219-1-3p	Neutrophil activation involved in immune response, Fc-gamma receptor signaling pathway, Positive regulation of reactive oxygen species metabolic process, receptor-mediated endocytosis, Regulation of mRNA splicing, via spliceosome	[185]

Analyzing a cohort of PTSD combat veterans revealed decreased expression of miR-125a in peripheral blood mononuclear cells (PBMCs) [97]. This decrease was linked to increased levels of the proinflammatory cytokine interferon-gamma (IFN-γ), which contributes to immune system dysfunction in PTSD patients [97]. Blood and PBMCs from this cohort also showed downregulation of miR-193-5p, which targets interleukin-12 (IL-12) [111], along with many other miRNAs (listed in Table 2) that regulate inflammatory responses [95]. Downregulation of AGO2 and Dicer1 reduced the presence and function of these regulatory miRNAs, leading to increased inflammation [95].

Follow-up work focused on specific miRNAs within this inflammatory network. Busbee et al. examined let–7a, a miRNA involved in the regulation of Th17 cell development and function, and found that its expression was reduced in PBMCs from PTSD patients [178]. This downregulation was associated with heightened Th17 activity and a more pronounced inflammatory phenotype, reinforcing the notion that miRNA deficits can skew immune cell profiles toward proinflammatory states. Additional research identified dysregulation of miR-7113-5p and its target WNT10B, linking altered miR-7113-5p expression to changes in WNT signaling and promotion of inflammatory processes [179]. Collectively, these studies indicate that decreased expression of multiple immune-regulating miRNAs, compounded by reduced AGO2 and Dicer1 levels, may underlie the elevated cytokine profiles and chronic low-grade inflammation frequently observed in PTSD patients [95, 97, 178–180].

A second major focus of human miRNA research in PTSD has centered on DICER1 itself. DICER1 is a key RNase III endonuclease required for the maturation of most miRNAs, and thus plays a central role in post-transcriptional gene regulation in the brain and other tissues. In a large genetic study of individuals with PTSD and depression, Wingo and colleagues reported that blood levels of DICER1 were markedly lower in affected subjects compared with controls; this finding was replicated in two independent cohorts [181]. Importantly, reduced DICER1 expression was associated with stronger amygdala responses to fearful images, a pattern commonly observed in PTSD. A variant in the 3′ untranslated region of DICER1 (rs10144436) was further linked to both DICER1 expression and amygdala reactivity, and this association was confirmed in a separate group of participants [181]. When miRNA profiles were examined in blood, individuals with PTSD showed widespread decreases in miRNA levels, with four significantly upregulated miRNAs (miR-19a-3p, miR-101-3p, miR-20b-5p, and miR-20a-5p) and four downregulated miRNAs (miR-486-3p, miR-128-3p, miR-15b-3p, and miR-125b-5p), many of which target genes involved in axon guidance and Wnt signaling pathways [156]. These convergent results suggest that reduced DICER1 expression may compromise global miRNA regulation, leading to perturbations in synaptic and developmental signaling cascades relevant to PTSD and related mood disorders.

Human studies have also examined how allelic variation in stress-related genes interacts with miRNA regulation to influence PTSD risk. FKBP5, a critical modulator of GR sensitivity, has received particular attention. In work examining FKBP5 gene variants, Linnstaedt et al. found that the rs3800373 variant diminishes the ability of miR–320a to bind and regulate FKBP5 transcripts [182]. This reduced binding capacity leads to less effective post-transcriptional repression of FKBP5, resulting in abnormal regulation of the stress response and increased vulnerability to chronic stress. The same research group also identified associations between miR-19b and posttraumatic stress and persistent pain outcomes [183]. Their study examined human subjects who had experienced motor vehicle collisions or sexual assault, alongside animal models exposed to unpredictable sound stress or SPS. Bioinformatic analyses suggested that miR-19b may participate in the regulation of circadian rhythm and homeostasis, although the specific molecular pathways remain to be fully elucidated [183]. Together, these findings highlight how interactions between miRNAs and genetic variants in FKBP5 and other stress-regulatory genes can shape individual trajectories following trauma.

As techniques for isolating and characterizing EVs have advanced, investigators have begun to dissect the distribution of miRNAs across distinct blood fractions. One study demonstrated that PTSD-associated miRNA profiles differ depending on whether miRNAs are measured in whole plasma, EV-depleted (EVD) plasma, or isolated EVs [96]. In this work, miR–203a–3p was found to be explicitly upregulated in EVs from PTSD patients, whereas miR–339–5p was downregulated in EVD plasma, indicating that certain PTSD-related miRNAs may be preferentially packaged into vesicles and transported systemically [96]. These findings raise the possibility that EV-derived miRNAs could serve as more brain-proximal biomarkers, given EVs' capacity to cross the blood-brain barrier and carry neuron-derived molecular cargo.

Beyond single-cohort studies, more recent work has taken a systems-level approach, integrating data across larger samples and multiple analytic pipelines. Snijders and colleagues compared blood samples from PTSD patients not only with healthy controls but also with PTSD-resilient individuals—those exposed to comparable trauma who did not develop PTSD psychopathology [184]. Using weighted gene co-expression network analysis (WGCNA), they identified a cluster of five miRNAs (miR–221–3p, miR–335–5p, miR–138–5p, miR–222–3p, and miR–146–5p) that distinguished PTSD patients from controls, with miR–138–5p emerging as a hub gene overexpressed in the PTSD group [184]. This work illustrates how network-based analyses can reveal coordinated miRNA modules that better capture PTSD-related biology than isolated miRNAs alone.

Several large-scale bioinformatic and transcriptomic studies have since reinforced and expanded these observations. Bolouki et al. conducted a systems-level analysis of publicly available whole–blood datasets and reported 171 differentially expressed miRNAs in PTSD, predominantly downregulated, along with 3909 enriched gene targets and a regulatory network highlighting hub miRNAs from the miR–15/107 and miR–17 families [185]. The predicted targets of these hub miRNAs were enriched in pathways related to neutrophil activation, Fc–gamma receptor signaling, reactive oxygen species metabolism, receptor-mediated endocytosis, and regulation of mRNA splicing, suggesting broad immune and transcriptional dysregulation in PTSD [185]. These findings align with prior reports of widespread inflammatory and immune perturbations in affected individuals and underscore the potential of miRNA network analyses to uncover higher-order regulatory themes.

Another rapidly developing area has examined miRNAs in the context of mild TBI (mTBI) and its frequent co-occurrence with PTSD. Neurotrauma and psychological trauma often overlap, particularly in military populations, making it important to identify molecular markers that reflect both neural injury and stress-related psychopathology. Devoto et al. analyzed plasma EVs in veterans with blast-related mTBI, blunt mTBI, and controls, identifying 39 differentially expressed miRNAs and reporting distinct miRNA signatures that were more pronounced in blast injuries and aligned with greater symptom severity Field [186]. Guedes et al. further stratified cohorts into mTBI with PTSD, mTBI without PTSD, and healthy controls, and found that specific miRNAs—such as miR–139–5p and miR–1185–1–3p—were differentially expressed across groups and correlated with PTSD symptom severity, reinforcing their potential relevance as biomarkers of combined neurotrauma and PTSD [187]. In a large veteran cohort, Muhie et al. reported that plasma exosomal miRNAs associated with inflammatory responses, oxidative stress, angiogenesis, and cardiovascular function were significantly dysregulated in PTSD. Several miRNAs—including miR–146a–3p, miR–16–5p, miR–124–3p, and miR–205–5p—showed PTSD-specific expression patterns, implicating overlapping molecular pathways involving inflammation, oxidative stress, and vascular integrity [188].

Collectively, human studies of miRNAs in PTSD converge on several key conclusions. First, PTSD is associated with consistent alterations in miRNAs that regulate inflammatory cytokines (e.g. IFN–γ and IL–12), immune cell differentiation, and broader immune signaling cascades, often in the direction of proinflammatory bias [95, 97, 178–180]. Second, reductions in DICER1 expression and other components of the miRNA processing machinery contribute to widespread decrements in mature miRNAs, disrupting pathways involved in axon guidance, Wnt signaling, and synaptic plasticity Field [156, 181, 114, 115]. Third, genetic variation in stress-related genes such as FKBP5 can alter miRNA binding and regulation, thereby modulating individual vulnerability to chronic stress and posttraumatic psychopathology [140, 182, 183]. Finally, systems-level and EV-focused analyses reveal coordinated miRNA signatures across blood fractions and patient subgroups, including those with comorbid mTBI, and point to shared molecular pathways involving inflammation, oxidative stress, and neural injury [96, 146, 184]. Together with animal data, these human findings strengthen the view that miRNA dysregulation represents a core feature of PTSD biology and a promising avenue for biomarker discovery and targeted intervention.

Implications of miRNAs in PTSD biology

Growing evidence supports an important role for miRNAs in the molecular mechanisms underlying PTSD, particularly in pathways associated with stress regulation, neuroinflammation, synaptic plasticity, and fear memory processing [88]. Because individual miRNAs can regulate multiple downstream targets simultaneously, they are considered promising candidates for both biomarker development and therapeutic intervention [189]. Circulating miRNAs, including EV-associated miRNAs, may serve as minimally invasive biomarkers required for early diagnosis, disease stratification, and tracking treatment responses in PTSD [99]. Their relative stability in peripheral blood and association with CNS processes make them attractive candidates for translational research [147]. In addition, advances in miRNA-based therapeutics, including miRNA mimics and antagomiRs, raise the possibility of targeting dysregulated stress-responsive pathways involved in PTSD pathophysiology [88]. In Fig. 3, we have illustrated the ability of miRNAs to influence a gene network that affects biological processes such as HPA axis function, synaptic plasticity, and immune signaling. At the same time, we have provided a schematic overview of the consensus miRNAs and their overlapping functional consequences identified in both human and animal models of PTSD.

Figure 3.

miRNA–gene networks and convergent miRNA signatures in PTSD. (A) miRNA–gene interaction networks regulating key PTSD-relevant pathways, derived from animal studies. miRNAs implicated in synaptic plasticity and fear learning (e.g. miR-182, miR-34a, miR-153, miR-132, miR-9-3p, miR-29b-3p), stress response and HPA axis regulation (e.g. miR-15a, miR-19b, miR-135-5p), and synaptic proteins/neuroinflammation (e.g. miR-142-5p, miR-132-3p, miR-153-3p, miR-124-3p) are shown together with validated or reported target genes (e.g. Cortactin, Rac1, Notch1, SNARE genes, GAT1, PTEN, Dnmt3a, Adrb1, Npas4, FMRP, PSD95, FXR1, sigma-1 receptor, TRAF6). Arrows and inhibitory symbols indicate direct suppression of targets and indirect pathway crosstalk converging on core biological processes, including synaptic plasticity and neuronal function (actin cytoskeleton remodeling, neurotransmitter release, dendritic spine density, and neuron excitability), HPA axis and regulation of stress hormone, adrenergic and stress signaling, neuroinflammation and synaptic integrity (cytokine/inflammatory signaling, neuronal stress responses, and synaptic protein expression), and epigenetic regulation (DNA methylation, chromatin remodeling, transcriptional control). (B) Overlap of miRNAs reported in animal models (brain, serum, blood) and human PTSD studies (blood, serum, extracellular vesicles, brain). The Venn diagram illustrates miRNAs detected in both preclinical and clinical studies, underscoring convergent dysregulation of pathways related to synaptic plasticity and neuronal function, the HPA axis/stress response, immune and inflammatory signaling, and epigenetic regulation across species and sample types. The illustration was created with BioRender.com.

Conclusions and future directions

Current research increasingly demonstrates that alterations in microRNA (miRNA) expression play a crucial role in shaping both the biological mechanisms and behavioral manifestations associated with PTSD. miRNAs act as fine-tuning regulators of gene expression, and changes in their levels can significantly impact pathways involved in stress reactivity, memory formation, and emotional regulation. For example, several studies have highlighted the influence of miRNAs on key stress-related genes such as FKBP5, a regulator of GR sensitivity. Dysregulation of FKBP5 has been consistently associated with altered stress-response dynamics, heightened vulnerability to trauma, and impaired recovery following stressful experiences. Additionally, specific miRNAs appear to reinforce trauma-related memories by modulating neuronal plasticity—affecting how neurons strengthen, weaken, or reorganize their connections in response to environmental stimuli. While these findings collectively suggest a promising mechanistic link between miRNA variability and PTSD pathology, numerous aspects still warrant more comprehensive investigation.

One major challenge in interpreting the current body of evidence is distinguishing short-term stress-induced miRNA shifts from long-lasting, PTSD-relevant molecular changes. Many animal studies document rapid fluctuations in miRNA expression immediately following acute stress exposure. However, PTSD is fundamentally a chronic condition, characterized by enduring neurobiological alterations that evolve over extended periods, weeks, months, and sometimes years. Processes such as altered synaptic plasticity, persistent fear- and memory consolidation, and long-term changes in neural circuitry cannot be fully captured by short-window observations. Although increased plasticity may facilitate the initial strengthening of fear memories, such plasticity is also vital for extinction learning, the process through which traumatic memories diminish over time. A subset of studies has attempted to address this temporal complexity by examining miRNA levels at delayed time points, often several weeks after stress exposure, thereby revealing how immediate vs. prolonged epigenetic changes may differentially contribute to PTSD development. Nonetheless, more systematic, longitudinal research is needed to untangle these dynamics.

Another significant limitation lies in the translational gap between animal models and human PTSD. While animal studies allow controlled experimentation and mechanistic exploration, they often simplify trauma exposure paradigms and behavioral outcomes. In contrast, PTSD in humans presents with substantial heterogeneity—ranging from cognitive and emotional symptoms to physiological dysregulation—and frequently co-occurs with anxiety, depression, or SUDs. This complexity makes it challenging to map specific animal behaviors onto the full spectrum of human clinical presentations. Although some investigators have begun integrating findings from animal models with data from human patient samples, an approach that helps identify shared molecular signatures across species, far more cross-species comparative studies are required to strengthen the translational validity of miRNA-based conclusions.

Human research to date has also been constrained by methodological limitations, particularly the reliance on peripheral tissues, such as blood, serum, plasma, or PBMCs, to measure miRNA expression. While these samples are accessible and minimally invasive, it remains uncertain how accurately peripheral miRNA levels reflect the molecular environment of the brain, where many PTSD-related processes are thought to originate. Ideally, peripheral findings should be corroborated using postmortem brain samples, but such tissues are scarce and often difficult to standardize. As a potential solution, researchers have turned their attention to miRNAs contained within EVs, including exosomes [190–192]. These vesicles can cross the blood-brain barrier and carry neuron-derived molecular cargo into the bloodstream, offering a promising, noninvasive window into brain-specific changes in miRNA. Although only a handful of studies have employed this technique so far, it represents a critical and rapidly emerging direction for future PTSD biomarker discovery.

Taken together, the existing literature strongly supports a meaningful role for miRNAs in modulating stress responses, shaping trauma-associated memory formation, and contributing to the long-term neurobiological changes characteristic of PTSD. Moving forward, research should prioritize identifying the most influential miRNAs, mapping how they interact within wider regulatory networks, and validating their relevance across both central (brain) and peripheral systems. Achieving these aims will be essential for developing reliable miRNA-based biomarkers, improving early screening and diagnosis, and informing new therapeutic strategies aimed at targeting molecular pathways specific to PTSD.

Author contributions

Yogesh Dwivedi (Conceptualization [equal], Data curation [equal], Formal Analysis [equal], Funding acquisition [equal], Investigation [equal], Project administration [equal], Resources [equal], Supervision [equal], Writing—original draft [equal], Writing—review & editing [equal]), Kevin Prall (Data curation [equal], Formal Analysis [equal], Investigation [equal], Writing—original draft [equal], Writing—review & editing [equal]), and Richard S. Shelton (Data curation [equal], Formal Analysis [equal], Writing—original draft [equal], Writing—review & editing [equal])

Conflicts of interest

Yogesh Dwivedi received royalties from Taylor and Francis for an edited book. Yogesh Dwivedi received grants from the American Foundation for Suicide Prevention and NIH. Richard Shelton is supported by AbbVie Inc., Alto Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Denovo Biopharma, Gate Neuroscience, InMune Bio, Intra-Cellular Therapies, Johnson & Johnson Innovative Medicine, LivaNova PLC, Navitor Pharmaceuticals, Neumora, Neurocrine Biosciences, Neurorx, Novartis AG, Otsuka Pharmaceuticals, Sumitomo Pharma America, and Supernus Pharmaceuticals. He is also a consultant for Boehringer Ingelheim, Denovo Biopharma, Equulus Therapeutics, Evecxia Therapeutics LLC, Johnson & Johnson Innovative Medicine, Neurorx, Novartis AG, Otsuka Pharmaceuticals, Seelos Therapeutics, Inc., Sumitomo Pharma America, and Supernus Pharmaceuticals and receives royalties from Springer-Nature Group and Wolters-Kluwer NV. Kevin Prall declares no conflict of interest with this work.

Funding

This work was supported by funding from the National Institute of Mental Health (R01MH130539, R01MH124248, R01MH118884, R01MH128994, R01MH107183, R01MH137153, R56MH138596) and the American Foundation for Suicide Prevention (DIG-0-047-24) to Dr Dwivedi.

Data Availability

No data were used for the research described in the article.