From classic circuits to novel mechanisms: How lncRNA, neuroinflammation, and iPSC models address the translational crisis in PTSD research.

From classic circuits to novel mechanisms: How lncRNA, neuroinflammation, and iPSC models address the translational crisis in PTSD research - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. 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Learn more: PMC Disclaimer | PMC Copyright Notice Compr Psychoneuroendocrinol . 2026 Apr 2;26:100345. doi: 10.1016/j.cpnec.2026.100345 Search in PMC Search in PubMed View in NLM Catalog Add to search From classic circuits to novel mechanisms: How lncRNA, neuroinflammation, and iPSC models address the translational crisis in PTSD research Yue Zhang Yue Zhang a Department of Jinling Clinical Medical College, Nanjing Medical University, Nanjing, 210002, China Find articles by Yue Zhang a, 1 , Yao Zhang Yao Zhang b Department of Anesthesiology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, 210002, China Find articles by Yao Zhang b, 1 , Yinyin Shu Yinyin Shu c Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, China Find articles by Yinyin Shu c , Lidong Zhang Lidong Zhang a Department of Jinling Clinical Medical College, Nanjing Medical University, Nanjing, 210002, China c Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, China Find articles by Lidong Zhang a, c, ⁎ , Qingzhen Liu Qingzhen Liu c Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, China Find articles by Qingzhen Liu c, ⁎⁎ Author information Article notes Copyright and License information a Department of Jinling Clinical Medical College, Nanjing Medical University, Nanjing, 210002, China b Department of Anesthesiology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, 210002, China c Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, China ⁎ Corresponding author. Department of Jinling Clinical Medical College, Nanjing Medical University, Nanjing, 210002, China. [email protected] ⁎⁎ Corresponding author. [email protected] 1 These authors contributed to equally to this work. Received 2025 Dec 3; Revised 2026 Feb 24; Accepted 2026 Mar 27; Collection date 2026 May. © 2026 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). PMC Copyright notice PMCID: PMC13091171  PMID: 42004399 Abstract Post-traumatic stress disorder (PTSD) faces a translational crisis in psychopharmacology, evidenced by the limited efficacy of approved selective serotonin reuptake inhibitors (SSRIs) and the recent failure of novel monoaminergic strategies. Classical neurobiological models, centered on the amygdala, prefrontal cortex, and hippocampus, have proven insufficient for therapeutic development. A primary bottleneck remains the failure of preclinical animal models to capture core human symptoms, such as spontaneous intrusive memories. This review argues for a paradigm shift, integrating three key domains to elucidate PTSD pathophysiology. First, we examine neuroinflammation, moving beyond general immune activation to a specific mechanism of C1q-independent, C3-mediated pathological synaptic pruning in the medial prefrontal cortex (mPFC). Second, we analyze epigenetic scaffolds, highlighting the role of the long non-coding RNA (lncRNA) as a synaptic coordinator essential for fear extinction memory consolidation. We propose a feedforward loop where inflammation drives pathological lncRNA expression, which in turn suppresses neuroprotection and promotes synaptic erosion. Third, we evaluate human induced pluripotent stem cell (iPSC) models, not as platforms for modeling acquired trauma, but as crucial tools for identifying inherent cellular susceptibility, such as glucocorticoid hypersensitivity. By integrating these domains, this review proposes a multi-scale model where trauma-induced molecular and cellular dysfunction underlies the persistent circuit-level impairment observed in PTSD. This integrated framework provides a novel, mechanistically-driven roadmap for identifying and validating the next generation of therapeutic targets. Keywords: Post-traumatic stress disorder, Neuroinflammation, lncRNA, Induced pluripotent stem cells Highlights • Current animal models may fail to capture intrusive traumatic memories. • LncRNAs might link inflammation to persistent fear extinction deficits. • Human iPSC models may reveal inherent cellular vulnerabilities to stress. • We explore if specific immune molecules drive synaptic loss in PTSD circuits. 1. Introduction 1.1. The translational crisis in post-traumatic stress disorder research Post-traumatic stress disorder (PTSD) is a severe mental illness that may emerge following exposure to traumatic events such as war, natural disasters, or violent assaults [ 1 ]. As defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [ 2 ], PTSD is no longer classified as an anxiety disorder but rather under “Trauma and Stressor-Related Disorders.” This disorder leads to significant medical, economic, and social problems, imposing a heavy burden on individuals and families. Its primary symptoms involve impaired fear extinction due to persistent and prolonged exposure to direct or vicarious traumatic events, accompanied by mild cognitive impairments, learning difficulties, and nightmares [ 3 ]. Over decades, neurobiological research has successfully identified a fundamental “fear circuit” comprising the amygdala (AMY), medial prefrontal cortex (mPFC), and hippocampus (HC)—structures critical for fear memory formation and regulation [ 4 ]. However, this understanding has yielded limited success in developing novel effective therapies. This disconnect highlights the “translation crisis” in psychopharmacology research. For over two decades, the U.S. Food and Drug Administration (FDA) has approved only two medications for treating PTSD: sertraline and paroxetine, both selective serotonin reuptake inhibitors (SSRIs). In 2025, the FDA formally rejected the supplemental new drug application for the combination of brexpiprazole and sertraline in treating PTSD. This decision signifies that even strategies optimizing and combining traditional monoaminergic systems failed to successfully bridge the translational gap between mechanism and clinical benefit. Existing SSRIs commonly exhibit slow onset of action, suboptimal response rates among patients, and high recurrence rates [ 5 ]. To bridge this therapeutic gap, research perspectives must shift from macro-circuitry to micro-molecular and cellular levels. This paper aims to drive this transition by critically evaluating limitations in classical neuroanatomy and animal models, while integrating three key emerging domains: (1) neuroimmunology and neuroinflammatory dysregulation; (2) epigenetic regulation of long non-coding RNAs (lncRNAs); (3) human induced pluripotent stem cell (iPSC) disease models. We contend that integrating these domains is essential for elucidating PTSD pathogenesis and identifying novel therapeutic targets. 2. The foundations and limitations of classical neural circuitry The core symptoms of PTSD are mediated by a well-defined yet dysfunctional neural circuit [ 6 ]. While this knowledge is fundamental, its limitations define the problems that new molecular approaches must now address. 2.1. Amygdala: the fear center The AMY serves as the primary hub for emotional processing and fear learning [ 7 ]. Animal studies indicate that fear information first enters the basolateral amygdala (BLA), where fear-associated associative learning occurs [ 8 ]. This signal then transmits to the central amygdala (CeA), which modulates the output of fear behaviors [ 9 ]. In PTSD patients, the AMY exhibits excessive reactivity to emotional or threat-related stimuli. This suggests that AMY dysfunction is a primary cause for the persistence of fear memories and other emotional symptoms [ 6 ]. Drugs developed based on the concept of “sedating the amygdala” ultimately became broad-spectrum anxiolytics. These are not specific to PTSD and carry issues such as tolerance, dependence, and cognitive side effects. They fail to address the core pathology of PTSD, such as the persistence and hyperconsolidation of traumatic memories [ 10 ]. 2.2. Prefrontal cortex (PFC): Impairment in extinction The PFC, particularly the anterior cingulate cortex (ACC) and mPFC, is crucial for regulating and extinguishing fear memories by processing safety signals and inhibiting the AMY [ 11 ]. In healthy brains, the PFC suppresses fear expression when threats subside. In individuals with PTSD, this inhibitory control function is impaired [ 12 , 13 ]. Research indicates that PTSD severity negatively correlates with ACC volume [ 14 ]. Dysfunction in the prefrontal cortex and the resulting failure to regulate the AMY are hallmark features of this disorder [ 15 , 16 ]. Attempts at direct pharmacological intervention in the mPFC have largely failed, as it involves the fine-tuning of higher cognitive functions rather than a simple “on” or “off” switch. Current medications cannot precisely strengthen specific neural connections at the appropriate time like psychotherapy can. 2.3. Hippocampus: context and memory The HC is critical for learning and memory, particularly for encoding the context in which fear memories form. A primary symptom of PTSD is the persistent re-experiencing of traumatic events, often triggered by stimuli only indirectly related to the original trauma. This indicates a deficit in contextual processing. A hallmark finding in human structural MRI studies is reduced hippocampal volume in PTSD patients [ 17 ]. Gilbertson et al. confirmed that smaller hippocampal volume may even represent a pre-existing vulnerability factor, predicting an individual's pathological susceptibility to trauma [ 18 ]. This structural deficit, whether causal or consequential, correlates with neuronal loss and impaired neurogenesis. While hippocampal volume reduction correlates with PTSD symptoms, whether it represents a cause or consequence remains debated [ [19] , [20] , [21] ]. For “atrophy” itself, we lack drugs that specifically promote hippocampal neurogenesis and precisely repair its circuits [ 22 ]. Simply enhancing hippocampal function may amplify both traumatic and normal memories, potentially causing unwanted side effects. 2.4. Circuit-level dysfunction PTSD arises not from dysfunction in a single brain region but from disordered functioning across entire brain networks. The PFC typically exerts top-down regulation over the AMY [ 23 ]. Functional imaging studies in PTSD patients confirm disruption of this relationship: AMY activity shows a negative correlation with medial frontal gyrus activity. As PFC signaling weakens, the inhibitory influence of the AMY diminishes, leading to uncontrolled fear responses in PTSD patients [ 24 , 25 ]. The core challenge lies in the fact that while this macroscopic model is descriptive, it has yet to identify drug targets capable of restoring circuit balance. This macroscopic model is not incorrect, but incomplete. It provides the necessary anatomical scaffold (as shown in Fig. 1 ) upon which microscopic molecular and cellular pathologies are built. Fig. 1. Open in a new tab The Classical (Incomplete) Neural Circuit Model of PTSD This figure illustrates the classical neural circuit model used to describe PTSD. (A) An anatomical diagram showing the locations of the medial Prefrontal Cortex (mPFC), Amygdala (AMY), and Hippocampus (HC). (B) A diagram of the pathological state of this circuit in PTSD. The AMY, the brain's fear center, is hyperactive. The mPFC, which regulates fear, is hypoactive. The HC, which processes context, is in a state of atrophy. The central dysfunction is the "Impaired Inhibition/Failed Extinction Regulation" (dashed arrow), which shows the mPFC's failure to control the hyperactive AMY, leading to persistent fear. The manuscript argues this model is incomplete because it describes the circuit's failure but not the underlying molecular causes. 3. Translation gap: limitations of preclinical animal models To study these neural circuits and screen drugs, the field has long relied on preclinical animal models centered on fear conditioning. While these models have elucidated the basic logic of fear acquisition and extinction, equating rodent freezing behavior with the complex, sensory-rich human experience of PTSD requires a significant "leap of faith" (as shown in Table 1 ) (see Table 2 ). Table 1. Translational failures of common preclinical PTSD models. Preclinical Model Stressor(s) Modeled Rodent Behaviors Core Human PTSD Symptoms Not Modeled Foot Shock (FS) Inescapable electric shock Conditioned freezing, enhanced startle, sleep disturbance Intrusive memories, guilt, shame, moral injury Single Prolonged Stress (SPS) Restraint, forced swim, ether Enhanced HPA negative feedback, anxiety-like behaviors, extinction deficits Sensory flashbacks, complex emotional changes Predator Scent Stress (PSS) Fox/cat urine/fur Avoidance, hypervigilance, enhanced fear learning Spontaneous re-experiencing, persistent guilt Underwater Trauma (UWT) Forced immersion/drowning Heightened startle, anxiety-like behaviors Emotional numbing, complex cognitive shifts Chronic Social Defeat Stress (CSDS) Repeated social defeat and threat Social avoidance, anhedonia Trauma-related amnesia, dissociative states Open in a new tab Table 2. Representative lncRNAs and Their Biological Associations in PTSD. lncRNA Species Expression Trend Tissue/Model Biological Association Gas5 [ 52 ] Upregulated mPFC (rodent/human) Synaptic coordinator; GRE decoy; NF-κB regulator Gomafu (MIAT) [ 53 ] Downregulated Hippocampus (rodent) Synaptic plasticity; neural homeostasis; anxiety regulator Malat1 [ 54 ] Decorated (m6A) Synapses (rodent) Dendritic spine formation; synaptic remodeling CYP1B1-AS1 [ 47 ] Upregulated Olfactory Mucosa (human) Neuroprotection; potential vulnerability marker SLC7A11-AS1 [ 47 ] Upregulated Olfactory Mucosa (human) Anti-inflammatory role; elevated in resilience BDNF-AS [ 51 ] Upregulated CNS Injury (rodent) Negative regulator of BDNF; promotes neurotoxicity Open in a new tab 3.1. Limitations and evolution of traditional fear extinction models Traditional models, such as Foot Shock (FS), primarily capture conditioned fear and heightened startle but fail to robustly simulate "spontaneous intrusive memories," which are the most pathogenic feature of the human disorder [ 26 ]. Furthermore, many physical stressors do not mirror the psychological complexity of human trauma, such as moral injury or complex grief [ 27 ]. Table 1 summarizes the translational failures of common models while incorporating newer paradigms aimed at capturing negative cognitive alterations. 3.2. Memory reconsolidation: emerging paradigms and unfulfilled translational promises Recognizing the limitations of simple extinction, research focus has shifted toward the more transformative “memory reconsolidation” paradigm [ 28 , 29 ]. This approach is based on the discovery that memories enter a brief “reconsolidation window” after retrieval, during which they become unstable [ 30 ]. Post-retrieval extinction (PRE) is the core behavioral approach within this paradigm. It involves administering extinction training during the post-retrieval window, aiming to directly update or weaken the original traumatic memory trace rather than form a competing memory [ 31 ]. Both animal and human studies indicate that PRE more persistently attenuates fear responses and effectively prevents various forms of relapse. This makes it the behavioral model with the greatest current translational potential [ 30 , 32 , 33 ]. Consequently, the field has begun exploring underlying molecular mechanisms, such as epigenetic regulation and protein synthesis-dependent pathways, viewing them as ultimate pharmacological targets capable of “selectively attenuating or rewriting specific traumatic memory traces” [ 34 , 35 ]. However, even within this more advanced paradigm, a significant translational gap persists. Existing animal models focus on inducing distinct persistent endocrine, behavioral, and neuroplastic changes. Yet their shared core limitation lies in their inability to robustly and quantitatively simulate the most pathogenic feature of human PTSD: “spontaneous intrusive memories.” These models can measure fear acquisition, expression, and extinction, but struggle to capture the phenomenon of traumatic memories abruptly “intruding” into consciousness without explicit cues [ 26 , 36 ]. Therefore, even within the PRE paradigm, while we can identify compounds effective at updating “cue-associated fear memories,” whether these drugs can penetrate the complex cognitive networks of the human brain to genuinely eliminate endogenous, sensory-rich flashbacks remains a significant unknown. 4. Inflammatory brain: neuroinflammation as a core pathogenic driver Psychological trauma is not an isolated cerebral event but a systemic, whole-body disruption that leads to chronic neuroinflammatory activation. PTSD patients typically exhibit a marked imbalance between pro-inflammatory and anti-inflammatory cytokines, a disparity present not only in peripheral blood but also reflected in the microenvironment of the central nervous system [ 37 ]. 4.1. Glucocorticoid resistance and the sustained Inflammatory environment Psychological trauma leads to chronic dysregulation of the HPA axis and sympathetic-adrenal-medullary (SAM) axis. Many PTSD patients exhibit hypocortisolism alongside elevated pro-inflammatory cytokines, suggesting functional glucocorticoid receptor (GR) resistance [ 38 ]. Peripheral inflammatory mediators cross the blood-brain barrier, activating microglia and creating sustained neuroinflammation that impairs neuronal function in the hippocampus and mPFC [ 39 , 40 ]. In human, biomarkers such as soluble urokinase plasminogen activator receptor (suPAR) have emerged as stable indicators linking early-life stress to chronic inflammation and PTSD risk [ 41 ]. 4.2. The complement system: molecular tagging of synapses for elimination Trauma hijacks a developmental pruning machinery: the complement cascade. In the healthy brain, C1q tags weak synapses for elimination via C3 cleavage and microglial CR3 recognition. Under chronic stress, this process becomes pathologically reactivated [ 42 ]. Genetic studies have placed this pathway at the center of PTSD pathogenesis. Large-scale GWAS identified C4A within the MHC region as a strong risk locus [ 43 ]. C4A exhibits copy number variation and efficiently binds synaptic membranes. Its long form contains an HERV-K insertion activatable by environmental stressors, linking trauma exposure to complement upregulation [ 44 ].In mice, chronic corticosterone induces layer-specific C3 deposition in mPFC layers 2/3 without C1q increase, tagging VGlut2+ synapses for microglial phagocytosis [ 45 ]. C3 knockout mice resist stress-induced synaptic loss and behavioral deficits, establishing C3-mediated pruning as a causal link between inflammation and circuit dysfunction. 4.3. Regional heterogeneity in neuroimmune responses A nuanced understanding of PTSD pathology requires acknowledging the regional dichotomy of neuroimmune responses. While the hippocampus and mPFC undergo "over-pruning" and subsequent volume loss, the amygdala may exhibit "under-pruning". In stress models, a reduction in microglial CR3 (the receptor for C3) activity in the amygdala leads to an excessive retention of excitatory synapses, manifesting as hyperconnectivity and fear generalization [ 46 ]. This regional divergence suggests that neuroinflammation is not a uniform "brain-wide" event but a complex phenomenon where specific circuits are differentially affected, leading to the characteristic cognitive and emotional symptoms of the disorder. These regionally distinct pruning patterns are not merely passive consequences of inflammation; they may be actively maintained by epigenetic mechanisms, including lncRNAs that stabilize microglial activation states. This link between neuroinflammation and epigenetic regulation is explored in Section 5 . 5. Epigenetic scaffolds: lncRNAs as regulators of fear memory The persistent alterations in gene expression observed in PTSD are increasingly attributed to epigenetic mechanisms. lncRNAs, which are highly sensitive to environmental inputs and participate in diverse cellular processes, have emerged as ideal candidates for mediating the long-term effects of trauma [ 47 ]. 5.1. The Inflammation-lncRNA feedback loop As shown in human single-cell studies [ 48 ] and rodent models [ 49 ], chronic neuroinflammation creates a signaling environment that induces pathological epigenetic reprogramming through the continuous activation of pathways such as NF-κB and JAK-STAT. Upon entering the nucleus, these activated transcription factors bind to the promoter regions of certain lncRNA genes, inducing their pathological overexpression [ 47 ]. This evidence suggests a potential feedforward loop: elevated lncRNAs can further enhance NF-κB activity and microglial activation, reinforcing the inflammatory state. For example, pathologically elevated lncRNAs can recruit repressive chromatin complexes to the promoters of neuroprotective genes like BDNF, causing their persistent silencing and suppressing the brain's natural repair capacity [ 50 , 51 ]. 5.2. Differential expression landscapes in PTSD Transcriptomic studies have identified a wide array of lncRNAs that are differentially expressed in response to traumatic stress across various species and tissues. 5.3. Synaptic coordination by activity dependent lncRNAs It is becoming increasingly clear that lncRNAs do not merely operate in the nucleus as transcriptional regulators or molecular sponges. A number of them are directly involved in synaptic function. These synapse enriched transcripts tend to be responsive to neuronal activity and appear to play local roles in coordinating the trafficking, translation, or stability of messenger RNAs that are essential for plasticity. In the context of fear extinction, a form of learning that demands precise remodeling of synapses within the medial prefrontal cortex, several lncRNAs have been implicated in shaping the underlying molecular events. Gomafu, also known as MIAT, is one such molecule. It has been shown to decrease in the hippocampus after acute stress, and it appears to influence alternative splicing of genes tied to synaptic structure and neuronal differentiation. Its downregulation could contribute to the destabilization of neural networks under chronic stress [ 53 ]. Malat1, a highly conserved nuclear lncRNA, has been linked to dendritic spine formation via m 6 A dependent mechanisms, and its expression at synapses shifts with neuronal activity. Then there is BDNF-AS, a natural antisense transcript of the brain derived neurotrophic factor gene [ 54 ]. It suppresses BDNF production and is upregulated in various injury models, suggesting that its dysregulation might compromise the trophic support needed for extinction related plasticity [ 51 ]. Another example comes from work on Gas5. A study by Liau and colleagues [ 52 ] identified a synapse specific variant of Gas5 in the infralimbic prefrontal cortex of mice. This variant interacts with RNA binding proteins such as G3BP2 and CAPRIN1, and through these interactions it helps regulate the activity dependent transport and clustering of RNA granules at dendritic spines. When an animal undergoes fear extinction learning, this local coordination is thought to ensure that plasticity related mRNAs reach the synapses that need them, thereby supporting the consolidation of extinction memory. Consistent with this idea, knocking down Gas5 specifically at synapses in the ILPFC impairs fear extinction, offering direct evidence that the lncRNA is required for the circuit level changes that underlie safety learning. Collectively, these observations point to a broader network of activity dependent lncRNAs converging on the synapse, each fine tuning distinct aspects of the molecular machinery behind fear extinction. Gas5 is perhaps the best understood mechanistically, but it should be seen as part of a larger non coding regulatory ecosystem that includes molecules like Gomafu, Malat1, and BDNF-AS. Figuring out how these transcripts interact, and how their collective disruption contributes to the stubborn extinction deficits seen in PTSD, will be an important challenge for future research. The convergence of these molecular events, sustained neuroinflammation, complement mediated synaptic pruning, and pathological lncRNA expression, forms a feedforward loop that drives the core circuit dysfunction in PTSD. Trauma initiates systemic inflammation and microglial activation. NF-κB induces pathological overexpression of lncRNAs, and these lncRNAs reinforce inflammation while promoting C3 dependent synaptic erosion in the mPFC [ 50 ]. The resulting physical dismantling of microcircuits leads to mPFC hypoactivity and disinhibition of the amygdala, manifesting as impaired fear extinction and hyperarousal. Repressive lncRNA scaffolds further silence neuroprotective factors like BDNF, locking this pathological state into chronicity. This integrated model explains how acute trauma transitions to persistent disease and identifies multiple nodes for therapeutic intervention. 6. Human iPSC models: modeling inherent cellular susceptibility The advent of iPSC technology offers a platform to investigate the complex pathophysiology of PTSD within a human cellular environment, bridging the gap between simplified rodent circuitry and human psychopathology. By differentiating patient-derived iPSCs into neurons and glial cells, researchers can construct "disease-in-a-dish" models to investigate intrinsic susceptibility factors that precede and enable circuit-level failure [ 55 , 56 ]. 6.1. Reconciling single cells with circuit-level dysfunction A primary critique of iPSC models is their lack of inherent circuitry, making them seemingly unsuitable for modeling a disorder defined by mPFC-amygdala interactions. However, the unique value of iPSCs lies in stripping away acquired adult experiences to reveal the "genetic and epigenetic preset" of the disease [ 57 ]. Somatic reprogramming extensively erases the epigenetic marks acquired by donor cells throughout their lifespan, meaning that stable molecular differences observed in iPSC-derived neurons strongly suggest a pre-traumatic, inherent biological susceptibility [ 58 ]. 6.2. Glucocorticoid hypersensitivity: A pre-traumatic "hyper-reactive" Imprint A pivotal study [ 59 ] utilized glutamatergic neurons derived from combat veterans with and without PTSD. They found that neurons from PTSD patients exhibited a "glucocorticoid hypersensitivity" phenotype: when exposed to low-dose hydrocortisone (simulating stress), PTSD neurons showed a substantially amplified transcriptional response across thousands of genes compared to controls. This hyper-reactive physiological imprint is diagnostically specific and consistent with transcriptomic signatures observed in human post-mortem brain tissue. This molecular-level reactivity functions as a cellular-level proxy for the circuit dysfunction (e.g., hyperactive amygdala response) seen in vivo, providing a vital logical bridge between single-cell hypersensitivity and macro-scale circuit failure. 6.3. Progress in model maturity and complexity The reliability of iPSC models is being continuously enhanced through technical advances in cell maturity and 3D culture systems. For instance, the NGN2 induction protocol can now yield neurons with mature electrophysiological properties within four weeks, allowing for the study of activity-dependent regulators like Gas5 in a cellular environment closer to the adult state [ 60 ]. Furthermore, the field is moving beyond monolayer cultures toward brain organoids and "assembloids"—fused organoid systems representing different regions, such as cortical-amygdalar assembloids [ 61 , 62 ]. These systems facilitate the study of inter-regional neural interactions and coordinated network activity in a human context, addressing the "lack of circuitry" limitation. Acknowledging the substantial existing body of iPSC work in other neuropsychiatric disorders, such as schizophrenia and bipolar disorder, helps contextualize these developments in PTSD research [ 63 ]. 7. Targeting the traumatized brain: from mechanism to precision medicine The multi-scale pathological mechanisms identified in this framework are redefining the therapeutic challenges of PTSD and pointing toward a more targeted pharmacological future. 7.1. Psychotherapies and the need for biological adjuncts Psychotherapy remains the first-line treatment for PTSD, with trauma-focused therapies like Cognitive Processing Therapy (CPT) and Eye Movement Desensitization and Reprocessing (EMDR) strongly recommended by 2023 clinical guidelines. However, high dropout rates and partial response emphasize the need for effective biological adjuncts. The failure of brexpiprazole in 2025 highlights the limitations of purely monoaminergic drugs, which target symptoms rather than the root molecular causes of circuit dysfunction [ 64 ]. 7.2. Emerging pharmacological targets and delivery strategies Several emerging strategies aim to target the molecular drivers of PTSD more directly: Ketamine: An NMDAR antagonist that rapidly alleviates symptoms, potentially through the upregulation of BDNF and induction of synaptogenesis [ 65 , 66 ]. Complement Inhibition: Preclinical studies have suggested that natural products such as Tanshinone I may modulate the C3-CR3 axis [ 67 ], though this work remains at an early stage. lncRNA Modulation: Targeting molecules like Gas5 using antisense oligonucleotides (ASOs) offers a precise method to reverse the pathological silencing of neuroprotective genes [ 68 ]. A major constraint in translated medicine is the blood-brain barrier (BBB), which prevents approximately 98% of therapeutic molecules from entering the CNS [ 69 ]. Traditional intrathecal delivery is invasive and leads to uneven distribution, with lower drug concentrations reaching deeper brain regions [ 70 ]. Technological advances in "nanobody shuttle" systems are transforming this paradigm. By targeting the transferrin receptor (TfR1) expressed on brain capillary endothelial cells, these engineered transport vehicles can ferry ASOs and enzymes across the BBB via receptor-mediated transcytosis following systemic administration. Preclinical studies have demonstrated that these vehicles can achieve widespread and sustained knockdown of target genes across all major brain cell types, including neurons, astrocytes, and microglia [ 68 ]. 8. Future directions: Toward precision Psychoneuroendocrinology The resolution of the translational crisis in PTSD requires a move toward precision medicine strategies that can account for the disorder's heterogeneity and multi-scale complexity. 8.1. Precision patient stratification Utilizing peripheral inflammatory biomarkers in combination with iPSC-derived euronal signatures can help identify patient subgroups with distinct molecular patterns [ 71 ]. For instance, individuals exhibiting a "hypersensitivity" profile in iPSC neurons may require different therapeutic interventions than those whose pathology is driven primarily by acquired epigenetic modifications. Machine learning models are already being trained on functional imaging and molecular data to predict symptom trajectory and treatment response [ 72 ]. 8.2. Region-specific and context-dependent Interventions Future therapeutics must move beyond broad anti-inflammatory inhibition toward region-specific and reversible modulation of the neuroimmune-synapse interface. Targeting the C3-CR3 axis specifically within the mPFC could prevent pathological pruning without causing systemic immunosuppression. Furthermore, pharmacological intervention windows should be timed to coincide with memory reactivation, utilizing TfR-targeted nanocarriers to deliver ASOs during the reconsolidation window, thereby maximizing the chances of "rewriting" specific traumatic memory traces [ 31 , 73 ]. 8.3. Expanding the non-coding regulatory toolkit While lncRNA is a primary focus, research into other non-coding species is essential to provide a comprehensive view of how the brain encodes trauma. Identifying how these molecules interact with activity-dependent signaling pathways, such as MAPK and CaMKIIa, will uncover additional therapeutic targets capable of restoring the brain's plasticity and its ability to consolidate safety signals [ 74 ]. 9. Conclusion: An integrated multi-scale model of PTSD The translational crisis in PTSD is a byproduct of the historical disconnect between circuit-level descriptions and the micro-molecular drivers of the disease. While foundations in neuroanatomy remain correct, they are incomplete without a mechanistic understanding of the cellular environment that sustains pathology. By integrating neuroimmunology, the epigenetic regulation of lncRNAs, and human-relevant iPSC technology, the field is moving toward a multi-scale model that identifies actionable drug targets rather than merely describing aberrant activity. Environmental trauma becomes biologically embedded through epigenetic coding, leading to systemic neuroimmune dysfunction and chronic low-grade inflammation. This environment, interacting with inherent genetic and cellular susceptibility, initiates a cycle of C3-mediated synaptic pruning that physically erodes the neural circuits of fear inhibition. The goal is no longer just to manage the symptoms of the traumatized mind, but to actively restore the molecular and cellular foundations of the human brain. CRediT authorship contribution statement Yue Zhang: Writing – original draft, Methodology. Yao Zhang: Writing – review & editing. Yinyin Shu: Formal analysis. Lidong Zhang: Supervision. Qingzhen Liu: Supervision, Conceptualization. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Contributor Information Lidong Zhang, Email: [email protected]. Qingzhen Liu, Email: [email protected]. References 1. Bisson J.I., Cosgrove S., Lewis C., Robert N.P. Post-traumatic stress disorder. Br. Med. J. 2015;351 doi: 10.1136/bmj.h6161. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 2. Stein D.J., McLaughlin K.A., Koenen K.C., Atwoli L., Friedman M.J., Hill E.D., et al. DSM-5 and ICD-11 definitions of posttraumatic stress disorder: investigating “narrow” and “broad” approaches. Depress. Anxiety. 2014;31:494–505. doi: 10.1002/da.22279. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 3. Ressler K.J., Berretta S., Bolshakov V.Y., Rosso I.M., Meloni E.G., Rauch S.L., et al. Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits. Nat. Rev. Neurol. 2022;18:273–288. doi: 10.1038/s41582-022-00635-8. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 4. Milad M.R., Quirk G.J. Fear extinction as a model for translational neuroscience: ten years of progress. Annu. Rev. Psychol. 2012;63:129–151. doi: 10.1146/annurev.psych.121208.131631. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 5. Coventry P.A., Meader N., Melton H., Temple M., Dale H., Wright K., et al. Psychological and pharmacological interventions for posttraumatic stress disorder and comorbid mental health problems following complex traumatic events: systematic review and component network meta-analysis. PLoS Med. 2020;17 doi: 10.1371/journal.pmed.1003262. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 6. Rauch S.L., Shin L.M., Phelps E.A. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research--past, present, and future. Biol. Psychiatry. 2006;60:376–382. doi: 10.1016/j.biopsych.2006.06.004. [ DOI ] [ PubMed ] [ Google Scholar ] 7. Zhang X., Flick K., Rizzo M., Pignatelli M., Tonegawa S. Dopamine induces fear extinction by activating the reward-responding amygdala neurons. Proc. Natl. Acad. Sci. U. S. A. 2025;122 doi: 10.1073/pnas.2501331122. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 8. Chen C., Li S., Zhou Y., Huang H., Lin J.-T., Wu W.-F., et al. Neuronal excitation-inhibition imbalance in the basolateral amygdala is involved in propofol-mediated enhancement of fear memory. Commun. Biol. 2024;7:1408. doi: 10.1038/s42003-024-07105-5. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 9. Whittle N., Fadok J., MacPherson K.P., Nguyen R., Botta P., Wolff S.B.E., et al. Central amygdala micro-circuits mediate fear extinction. Nat. Commun. 2021;12:4156. doi: 10.1038/s41467-021-24068-x. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 10. Campos B., Vinder V., Passos R.B.F., Coutinho E.S.F., Vieira N.C.P., Leal K.B., et al. To BDZ or not to BDZ? That is the question! is there reliable scientific evidence for or against using benzodiazepines in the aftermath of potentially traumatic events for the prevention of PTSD? A systematic review and meta-analysis. J. Psychopharmacol. 2022;36:449–459. doi: 10.1177/02698811221080464. [ DOI ] [ PubMed ] [ Google Scholar ] 11. Gong Q., Lyu H., Kang L., Ma S., Zhang N., Xie X.-H., et al. The genetic relationships between post-traumatic stress disorder and its corresponding neural circuit structures. J. Affect. Disord. 2026;393 doi: 10.1016/j.jad.2025.120323. [ DOI ] [ PubMed ] [ Google Scholar ] 12. Andrewes D.G., Jenkins L.M. The role of the amygdala and the ventromedial prefrontal cortex in emotional regulation: implications for post-traumatic stress disorder. Neuropsychol. Rev. 2019;29:220–243. doi: 10.1007/s11065-019-09398-4. [ DOI ] [ PubMed ] [ Google Scholar ] 13. Binette A.N., Liu J., Bayer H., Crayton K.L., Melissari L., Sweck S.O., et al. Parvalbumin-positive interneurons in the medial prefrontal cortex regulate stress-induced fear extinction impairments in Male and female rats. J. Neurosci. 2023;43:4162–4173. doi: 10.1523/JNEUROSCI.1442-22.2023. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 14. Kühn S., Butler O., Willmund G., Wesemann U., Zimmermann P., Gallinat J. The brain at war: effects of stress on brain structure in soldiers deployed to a war zone. Transl. Psychiatry. 2021;11:247. doi: 10.1038/s41398-021-01356-0. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 15. Webb E.K., Ely T.D., Rowland G.E., Lebois L.A.M., van Rooij S.J.H., Bruce S.E., et al. Neighborhood disadvantage and neural correlates of threat and reward processing in survivors of recent trauma. JAMA Netw. Open. 2023;6 doi: 10.1001/jamanetworkopen.2023.34483. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 16. Zandvakili A., Barredo J., Swearingen H.R., Aiken E.M., Berlow Y.A., Greenberg B.D., et al. Mapping PTSD symptoms to brain networks: a machine learning study. Transl. Psychiatry. 2020;10:195. doi: 10.1038/s41398-020-00879-2. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 17. Bromis K., Calem M., Reinders A.A.T.S., Williams S.C.R., Kempton M.J. Meta-analysis of 89 structural MRI studies in posttraumatic stress disorder and comparison with major depressive disorder. Am. J. Psychiatr. 2018;175:989–998. doi: 10.1176/appi.ajp.2018.17111199. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 18. Gilbertson M.W., Shenton M.E., Ciszewski A., Kasai K., Lasko N.B., Orr S.P., et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat. Neurosci. 2002;5:1242–1247. doi: 10.1038/nn958. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 19. Ben-Zion Z., Korem N., Spiller T.R., Duek O., Keynan J.N., Admon R., et al. Longitudinal volumetric evaluation of hippocampus and amygdala subregions in recent trauma survivors. Mol. Psychiatr. 2023;28:657–667. doi: 10.1038/s41380-022-01842-x. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 20. Misaki M., Mulyana B., Zotev V., Wurfel B.E., Krueger F., Feldner M., et al. Hippocampal volume recovery with real-time functional MRI amygdala neurofeedback emotional training for posttraumatic stress disorder. J. Affect. Disord. 2021;283:229–235. doi: 10.1016/j.jad.2021.01.058. [ DOI ] [ PubMed ] [ Google Scholar ] 21. Zheng Y., Garrett M.E., Sun D., Clarke-Rubright E.K., Haswell C.C., Maihofer A.X., et al. Trauma and posttraumatic stress disorder modulate polygenic predictors of hippocampal and amygdala volume. Transl. Psychiatry. 2021;11:637. doi: 10.1038/s41398-021-01707-x. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 22. Fujikawa R., Ramsaran A.I., Guskjolen A., de la Parra J., Zou Y., Mocle A.J., et al. Neurogenesis-dependent remodeling of hippocampal circuits reduces PTSD-Like behaviors in adult mice. Mol. Psychiatr. 2024;29:3316–3329. doi: 10.1038/s41380-024-02585-7. [ DOI ] [ PubMed ] [ Google Scholar ] 23. Mehta N.D., Stevens J.S., Li Z., Fani N., Gillespie C.F., Ravi M., et al. Inflammation, amygdala-ventromedial prefrontal functional connectivity and symptoms of anxiety and PTSD in African American women recruited from an inner-city hospital: preliminary results. Brain Behav. Immun. 2022;105:122–130. doi: 10.1016/j.bbi.2022.06.013. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 24. Lieberman J.M., Rabellino D., Densmore M., Frewen P.A., Steyrl D., Scharnowski F., et al. Posterior cingulate cortex targeted real-time fMRI neurofeedback recalibrates functional connectivity with the amygdala, posterior insula, and default-mode network in PTSD. Brain Behav. 2023;13 doi: 10.1002/brb3.2883. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 25. Sun D., Gold A.L., Swanson C.A., Haswell C.C., Brown V.M., Stjepanovic D., et al. Threat-induced anxiety during goal pursuit disrupts amygdala-prefrontal cortex connectivity in posttraumatic stress disorder. Transl. Psychiatry. 2020;10:61. doi: 10.1038/s41398-020-0739-4. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 26. Verbitsky A., Dopfel D., Zhang N. Rodent models of post-traumatic stress disorder: behavioral assessment. Transl. Psychiatry. 2020;10:132. doi: 10.1038/s41398-020-0806-x. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 27. Devignes Q., Clancy K.J., Ren B., Pollmann Y., Baker J.T., Rosso I.M. Intrinsic functional connectivity of right dorsolateral prefrontal cortex and hippocampus subregions relates to emotional and sensory-perceptual properties of intrusive trauma memories. Biol. Psychiatry Cogn. Neurosci. Neuroimaging. 2025;S2451–9022(25) doi: 10.1016/j.bpsc.2025.03.004. 00093-X. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 28. Astill Wright L., Horstmann L., Holmes E.A., Bisson J.I. Consolidation/reconsolidation therapies for the prevention and treatment of PTSD and re-experiencing: a systematic review and meta-analysis. Transl. Psychiatry. 2021;11:453. doi: 10.1038/s41398-021-01570-w. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 29. Beckers T., Kindt M. Memory reconsolidation interference as an emerging treatment for emotional disorders: strengths, limitations, challenges, and opportunities. Annu. Rev. Clin. Psychol. 2017;13:99–121. doi: 10.1146/annurev-clinpsy-032816-045209. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 30. Li M., Yang X.-K., Yang J., Li T.-X., Cui C., Peng X., et al. Ketamine ameliorates post-traumatic social avoidance by erasing the traumatic memory encoded in VTA-innervated BLA engram cells. Neuron. 2024;112:3192–3210.e6. doi: 10.1016/j.neuron.2024.06.026. [ DOI ] [ PubMed ] [ Google Scholar ] 31. Monfils M.-H., Cowansage K.K., Klann E., LeDoux J.E. Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science. 2009;324:951–955. doi: 10.1126/science.1167975. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 32. Duek O., Korem N., Li Y., Kelmendi B., Amen S., Gordon C., et al. Long term structural and functional neural changes following a single infusion of ketamine in PTSD. Neuropsychopharmacology. 2023;48:1648–1658. doi: 10.1038/s41386-023-01606-3. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 33. Verma A., Mitra S., Khamaj A., Kant V., Asthana M.K. Preventing fear return in humans: music-based intervention during reactivation-extinction paradigm. PLoS One. 2024;19 doi: 10.1371/journal.pone.0293880. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 34. Mohammadi-Farani A., Limoee M., Shirooie S. Sodium butyrate enhances fear extinction and rescues hippocampal acetylcholinesterase activity in a rat model of posttraumatic stress disorder. Behav. Pharmacol. 2021;32:413–421. doi: 10.1097/FBP.0000000000000633. [ DOI ] [ PubMed ] [ Google Scholar ] 35. Oga K., Fuchikami M., Kobayashi H., Miyagi T., Fujita S., Fujita S., et al. Involvement of dysregulated hippocampal histone H3K9 methylation at the promoter of the BDNF gene in impaired memory extinction. Psychopharmacology (Berl) 2024;241:2363–2374. doi: 10.1007/s00213-024-06640-7. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 36. Török B., Sipos E., Pivac N., Zelena D. Modelling posttraumatic stress disorders in animals. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2019;90:117–133. doi: 10.1016/j.pnpbp.2018.11.013. [ DOI ] [ PubMed ] [ Google Scholar ] 37. Sur B., Lee B. Luteolin reduces fear, anxiety, and depression in rats with post-traumatic stress disorder. Anim. Cell Syst. 2022;26:174–182. doi: 10.1080/19768354.2022.2104925. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 38. Lawrence S., Scofield R.H. Post traumatic stress disorder associated hypothalamic-pituitary-adrenal axis dysregulation and physical illness. Brain Behav Immun Health. 2024;41 doi: 10.1016/j.bbih.2024.100849. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 39. Poupouzas G., Lotsios N.S., Vrettou C.S., Issaris V., Keskinidou C., Papavassiliou K.A., et al. Cell-specific expression and signaling of glucocorticoid receptor isoforms over time in critically ill patients with a low inflammatory response. Crit. Care. 2025;29:390. doi: 10.1186/s13054-025-05628-9. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 40. Raison C.L., Miller A.H. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am. J. Psychiatr. 2003;160:1554–1565. doi: 10.1176/appi.ajp.160.9.1554. [ DOI ] [ PubMed ] [ Google Scholar ] 41. Bourassa K.J., Moffitt T.E., Arseneault L., Barrett-Young A., Danese A., Garrett M.E., et al. PTSD and suPAR: a multicohort investigation of chronic inflammation. Brain Behav. Immun. 2026;131 doi: 10.1016/j.bbi.2025.106159. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 42. Arizanovska D., Bush Iii GF., Dallera C.A., Folorunso O.O., Frye J.B., Doyle K.P., et al. Cognitive loss after brain trauma results from sex-specific activation of synaptic pruning processes. Brain. 2025 doi: 10.1093/brain/awaf293. awaf293. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 43. Hernandez L.M. Mapping the genetic and phenotypic landscape of neonatal C3 and C4 protein concentrations. Cell Genom. 2023;3 doi: 10.1016/j.xgen.2023.100456. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 44. Ebrahimi M., Teymouri K., Chen C.C., Mohiuddin A.G., Pouget J.G., Goncalves V.F., et al. Association study of the complement component C4 gene and suicide risk in schizophrenia. Schizophrenia (Heidelb) 2024;10:14. doi: 10.1038/s41537-024-00440-w. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 45. Tillmon H., Soteros B.M., Shen L., Cong Q., Wollet M., General J., et al. Complement and microglia activation mediate stress-induced synapse loss in layer 2/3 of the medial prefrontal cortex in male mice. Nat. Commun. 2024;15:9803. doi: 10.1038/s41467-024-54007-5. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 46. Aghanouri R. The role of microglial synaptic pruning in amygdala hyperconnectivity and memory impairment in post-traumatic stress disorder (P): a neurobiological perspective on altered neuronal communication. Nat Cell Sci. 2025;3 doi: 10.61474/ncs.2025.00019. [ DOI ] [ Google Scholar ] 47. Sadhukhan T., Rai N., Misiak-Christian M., Hipolito M.M.S., Sadhukhan S., Shelby M., et al. Role of LncRNA in trauma susceptibility and resilience to post-traumatic stress disorder (PTSD): a pilot study in the african American population. Neuropsychiatric Dis. Treat. 2025;21:1469–1479. doi: 10.2147/NDT.S489902. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 48. Li S., Liao Y., Dong Y., Li X., Li J., Cheng Y., et al. Microglial deletion and inhibition alleviate behavior of post-traumatic stress disorder in mice. J. Neuroinflammation. 2021;18:7. doi: 10.1186/s12974-020-02069-9. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 49. Hwang A., Skarica M., Xu S., Coudriet J., Lee C.Y., Lin L., et al. Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD. Nature. 2025;643:744–754. doi: 10.1038/s41586-025-09083-y. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 50. Curci D., Stankovic B., Kotur N., Pugnetti L., Gasic V., Romano M., et al. The long non-coding RNA GAS5 contributes to the suppression of inflammatory responses by inhibiting NF-κB activity. Front. Pharmacol. 2024;15 doi: 10.3389/fphar.2024.1448136. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 51. Deb P., Chini A., Guha P., Rishi A., Bhan A., Brady B., et al. Dynamic regulation of BDNF gene expression by estradiol and lncRNA HOTAIR. Gene. 2024;897 doi: 10.1016/j.gene.2023.148055. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 52. Liau W.-S., Zhao Q., Bademosi A., Gormal R.S., Gong H., Marshall P.R., et al. Fear extinction is regulated by the activity of long noncoding RNAs at the synapse. Nat. Commun. 2023;14:7616. doi: 10.1038/s41467-023-43535-1. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 53. Klimenko A., Nagibin V., Horlova A., Dobropolska Y., Bogovik R., Stroy D., et al. Downregulation of lncRNAs Gomafu, NONMMUT033604.2, and NONMMUT064397.2 in the hippocampus of mice with model of post-traumatic stress disorder. World J. Biol. Psychiatr. 2024;25:283–290. doi: 10.1080/15622975.2024.2342849. [ DOI ] [ PubMed ] [ Google Scholar ] 54. Madugalle S.U., Liau W.-S., Zhao Q., Li X., Gong H., Marshall P.R., et al. Synapse-enriched m6A-modified Malat1 interacts with the novel m6A reader, DPYSL2, and is required for fear-extinction memory. J. Neurosci. 2023;43:7084–7100. doi: 10.1523/JNEUROSCI.0943-23.2023. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 55. Brennand K.J., Simone A., Jou J., Gelboin-Burkhart C., Tran N., Sangar S., et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature. 2011;473:221–225. doi: 10.1038/nature09915. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 56. Wen Z., Nguyen H.N., Guo Z., Lalli M.A., Wang X., Su Y., et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature. 2014;515:414–418. doi: 10.1038/nature13716. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 57. Haridhasapavalan K.K., Raina K., Dey C., Adhikari P., Thummer R.P. An Insight into reprogramming barriers to iPSC generation. Stem Cell Rev. Rep. 2020;16:56–81. doi: 10.1007/s12015-019-09931-1. [ DOI ] [ PubMed ] [ Google Scholar ] 58. Wang A.Y.L., Aviña A.E., Liu Y.-Y., Kao H.-K. Pluripotent stem cells: recent advances and emerging trends. Biomedicines. 2025;13:765. doi: 10.3390/biomedicines13040765. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 59. Seah C., Breen M.S., Rusielewicz T., Bader H.N., Xu C., Hunter C.J., et al. Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression. Nat. Neurosci. 2022;25:1434–1445. doi: 10.1038/s41593-022-01161-y. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 60. Shan X., Zhang A., Rezzonico M.G., Tsai M.-C., Sanchez-Priego C., Zhang Y., et al. Fully defined NGN2 neuron protocol reveals diverse signatures of neuronal maturation. Cell Rep. Methods. 2024;4 doi: 10.1016/j.crmeth.2024.100858. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 61. Maisumu G., Willerth S., Nestor M.W., Waldau B., Schülke S., Nardi F.V., et al. Brain organoids: building higher-order complexity and neural circuitry models. Trends Biotechnol. 2025;43:1583–1598. doi: 10.1016/j.tibtech.2025.02.009. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 62. Patton M.H., Thomas K.T., Bayazitov I.T., Newman K.D., Kurtz N.B., Robinson C.G., et al. Synaptic plasticity in human thalamocortical assembloids. Cell Rep. 2024;43 doi: 10.1016/j.celrep.2024.114503. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 63. Hoffmann A., Ziller M., Spengler D. Progress in iPSC-Based modeling of psychiatric disorders. Int. J. Mol. Sci. 2019;20:4896. doi: 10.3390/ijms20194896. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 64. Schnurr P.P., Hamblen J.L., Wolf J., Coller R., Collie C., Fuller M.A., et al. The management of posttraumatic stress disorder and acute stress disorder: synopsis of the 2023 U.S. department of Veterans affairs and U.S. department of defense clinical practice guideline. Ann. Intern. Med. 2024;177:363–374. doi: 10.7326/M23-2757. [ DOI ] [ PubMed ] [ Google Scholar ] 65. Abdallah C.G., Roache J.D., Gueorguieva R., Averill L.A., Young-McCaughan S., Shiroma P.R., et al. Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology. 2022;47:1574–1581. doi: 10.1038/s41386-022-01266-9. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 66. Asim M., Wang B., Hao B., Wang X. Ketamine for post-traumatic stress disorders and it's possible therapeutic mechanism. Neurochem. Int. 2021;146 doi: 10.1016/j.neuint.2021.105044. [ DOI ] [ PubMed ] [ Google Scholar ] 67. Lai H., Fan P., Zhang P., Zhang M., Li X., Kuang B., et al. Targeting complement C3 with tanshinone I decreases microglia-mediated synaptic engulfment to exert antidepressant effects. Theranostics. 2025;15:8150–8175. doi: 10.7150/thno.115587. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 68. Barker S.J., Thayer M.B., Kim C., Tatarakis D., Simon M.J., Dial R., et al. Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier. Sci. Transl. Med. 2024;16 doi: 10.1126/scitranslmed.adi2245. eadi2245. [ DOI ] [ PubMed ] [ Google Scholar ] 69. Mazur C., Powers B., Zasadny K., Sullivan J.M., Dimant H., Kamme F., et al. Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. JCI Insight. 2019;4 doi: 10.1172/jci.insight.129240. 129240. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 70. Yeoh Y.Q., Amin A., Cuic B., Tomas D., Turner B.J., Shabanpoor F. Efficient systemic CNS delivery of a therapeutic antisense oligonucleotide with a blood-brain barrier-penetrating ApoE-derived peptide. Biomed. Pharmacother. 2024;175 doi: 10.1016/j.biopha.2024.116737. [ DOI ] [ PubMed ] [ Google Scholar ] 71. Shanazz K., Nalloor R., Lucas R., Vazdarjanova A. Neuroinflammation is a susceptibility factor in developing a PTSD-like phenotype. Front. Behav. Neurosci. 2023;17 doi: 10.3389/fnbeh.2023.1112837. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 72. Zervas M., Gage A., Haas M. Bioinformatics-driven identification and prioritization of PTSD targets based on published multi-omic data. Front Drug Discovery. 2025;5 doi: 10.3389/fddsv.2025.1613261. [ DOI ] [ Google Scholar ] 73. Pawlak A., Stefanowicz J., Kotkowska Z., Gabryelska A., Sochal M., Napieraj F., et al. Is it possible to prevent excessive synaptic pruning in schizophrenia? Possibilities and limitations. Front. Synaptic Neurosci. 2025;17 doi: 10.3389/fnsyn.2025.1656232. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 74. Schratt G.M., Tuebing F., Nigh E.A., Kane C.G., Sabatini M.E., Kiebler M., et al. A brain-specific microRNA regulates dendritic spine development. Nature. 2006;439:283–289. doi: 10.1038/nature04367. 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