PTSD Understanding and Treatment: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Tehila Cohen.

Memories are a central aspect of our lives, but the mechanisms underlying their formation, consolidation, retrieval, and extinction remain poorly understood.

  • memory
  • transcription
  • RNA
  • microRNA
  • PTSD

1. Synaptic Dynamics in the Memory Modulation Puzzle

1.1. Role of Synaptic Activity in Memory

Synaptic activity plays a crucial role in memory modulation by facilitating the formation and consolidation of memories. The process of memory consolidation involves the transformation of a short-term memory into a long-term memory through the stabilization and strengthening of synaptic connections [18][1]. This process is known to be dependent on the activation of NMDA receptors, which leads to the activation of intracellular signaling pathways and gene expression that ultimately result in synaptic plasticity [19][2]. Additionally, synaptic activity can modulate memory by regulating the encoding and retrieval of memories [20][3]. During encoding, synaptic plasticity allows for the formation of unique and stable connections between neurons that encode a specific memory [21][4]. During retrieval, the reactivation of these connections through synaptic activity is necessary to access and retrieve the stored memory [21][4]. Furthermore, synaptic activity is involved in the process of fear memory extinction, where the association between a previously learned cue and its aversive response is weakened [22][5]. The weakening of this association is thought to occur through the modification of synaptic connections, which ultimately leads to the attenuation of the fear response. To develop effective strategies for targeting memory disorders, it is crucial to understand the molecular mechanisms that modulate memory through synaptic activity. Such an understanding is essential for identifying ways to manipulate these mechanisms and improve memory function in individuals with memory disorders.

1.2. Synaptic Gene Expression and Its Effects on the Stages of Memory Modulation

Previous research on the formation of long-term memories has shown that this process requires changes in the transcription of specific genes at the synapse. The transcription factor CREB and several modulators, including CREB-regulated transcription coactivator-1 (CRTC1), histone deacetylase 4 (HDAC4), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), were found to play critical roles in this process. Genetic enhancement of Creb and Crtc1 activity in the forebrain and HPC of mice, respectively, increases fear memory, while knockdown of Crtc1 leads to decreased fear memory and CREB-mediated gene transcription [23,24,25,26][6][7][8][9]. Interestingly, bioinformatic analysis of experimentally validated database of human transcriptomes [27][10], suggests that miR-34a-5p may regulate the expression of CRTC1 in brain tissue, thus reducing the gene’s expression. It is possible that other miRNAs regulate CRTC1 expression, among other genes related to memory processes. Therefore, the regulation of CRTC1 by miRNAs represents a potential mechanism for modulating fear memory in mice.
Another key player in memory formation is neuronal PAS domain protein 4 (NPAS4). NPAS4 is a transcription factor that plays a crucial role in the formation of contextual memory by inducing the transcription of genes in the cornu ammonis 3 (CA3) region of the HPC [28][11]. It was previously shown that both global and CA3-specific knockout of the Npas4 gene in mice impaired contextual fear conditioning [29][12]. This memory deficit was later corrected with selective expression of Npas4 in the CA3 of the HPC [29][12].
Memory consolidation relies on intricate mechanisms of synaptic activity, too. Recent research has identified a highly connected network of genes involved in vesicle-mediated transport, exocytosis, and neurotransmitter secretion that are crucial for remote-memory-dependent transcriptional programs [30][13]. A study in mice brains found that a significant number of remote-memory-associated differentially expressed genes (DEGs) were related to these functional categories, including syntaxin-1B (STX1B), synaptotagmin-13 (SYT13), vesicle associated membrane protein 2 (VAMP2), N-Ethylmaleimide sensitive factor (NSF), and RAB5A, all linked to the SNARE complex and vesicle exocytosis [30][13]. Serine incorporator 1 (SERINC1) and serine incorporator 3 (SERINC3) were the most highly upregulated genes, potentially promoting vesicle membrane fusion during memory consolidation in mice [30][13]. Experiments using activity-dependent labeling of neurons and single-cell transcriptomics revealed additional evidence for this process [30][13]. These results strengthen the notion that enhanced membrane fusion and vesicle exocytosis may be critical modes of synaptic strengthening during memory consolidation. More specifically, they suggest that a specific set of exocytosis-related genes may be involved in facilitating the formation of highly unique, experience-specific connections. These transcriptional programs appear to be detectable at remote time points, hinting at their possible role in maintaining the memory trace weeks after learning. Thus, these findings indicate that synaptic transcriptional activity plays a key role in memory modulation, shedding light on the molecular mechanisms that could be used to modulate specific memory consolidation [30][13].
Recently published research on synaptic molecular mechanisms of memory consolidation revealed new insights into the role of KH-type splicing regulatory protein (KHSRP) [31][14]. Specifically, the loss of KHSRP was found to increase neuronal growth and synaptic transmission while also altering memory consolidation through RNA stabilization [31][14]. The splicing-regulating protein KHSRP plays a crucial post-transcriptional role in regulating the expression of several target mRNAs involved in neuronal development and function [31][14]. Mice lacking Khsrp (Khsrp−/−) showed alterations in neuronal morphology and function, including increased axon and dendrite growth, and elevated levels of Khsrp-targetted mRNAs [31][14]. Importantly, the loss of Khsrp has also been shown to impair memory consolidation in both the PFC and HPC, demonstrating the critical role of this protein in regulating the processes underlying normal brain function.
Memory recall has also been the center of attention recently for its potential role in memory modification and extinction. According to findings from studies on fear conditioning and recall in mice, fear-associated DEGs were found to be non-overlapping with remote-memory-associated DEGs, indicating that the experience of fear may induce different long-lasting changes in gene expression programs. Furthermore, the recall process appears to induce new transcriptional programs in a separate group of neurons, suggesting a complex interplay between different brain regions and gene expression patterns in the formation and maintenance of remote memories [30][13]. Other transcription factors, such as firkhead box p1 (FOXP1), serum response factor (SRF), and myocyte enhancer factor 2 (MEF2), also affect memory modulation through synaptic activity modulation. Foxp1 knockout impairs spatial memory, while Srf knockdown in the forebrain impairs the formation of immediate memory in response to a novel context [32,33][15][16]. Foxp1 expression can be regulated by miR-6951-3p which could be used to specifically modulate spatial memory in mice [32][15]. Neuronal overexpression of Mef2 restricts dendritic spine growth, impairing spatial and fear memory formation, while decreasing Mef2 levels in the dentate gyrus and amygdala improves memory formation [34][17]. Counterbalancing the negative effect of MEF2 by interfering with AMPA receptor endocytosis improves memory formation [30][13].

2. The Importance of Transcriptional Changes at Specific Times of Memory Modulation

Prior research has already established that gene transcription and protein synthesis are critical for both consolidation and reconsolidation of long-term memories immediately following training or mnemonic trace reactivation [35,36][18][19]. Additionally, some studies have suggested that the consolidation of long-term memories may also require a second wave of gene transcription occurring later. For examples, Cláudio da Silva and Sartori Bonini [37][20] raised the question of whether a similar gene transcription exists for reconsolidation as well; when they blocked late gene expression during a specific time window after training or memory retrieval, long-term spatial memory retention was found to be impaired in the Morris water maze task. The results suggest that the transcription of late genes is necessary for the reconsolidation process in the HPC to stabilize the reactivated mnemonic trace. Interestingly, the transcription inhibitors impaired memory retention only when infused into the dorsal HPC 6 h, but not 9 h, after training [37][20].
A recent study investigated the role of de novo gene transcription in the reconsolidation of alcohol-associated memories in mice [38][21], thus emphasizing the importance of the sensitivity of memory processes to transcriptional programs at specific times in the process. In their study, Goltseker et al. showed that the reconsolidation of alcohol-associated memories requires de novo gene transcription, and that inhibiting said transcription immediately following alcohol memory retrieval disrupts alcohol seeking. The study found that the retrieval of either alcohol- or sucrose-related memories triggered similar increases in mRNA expression of the genes Arc and Egr1, both related to synaptic plasticity functions [38][21]. However, a subset of genes, including Adcy8, Slc8a3, and Neto1, were altered selectively by the retrieval of alcohol, suggesting the likelihood that alcohol-associated memories triggering relapse have unique molecular mechanisms that could be targeted to disrupt them selectively. The study shows that the downregulation of Arc shortly after alcohol memory retrieval disrupts alcohol seeking. These findings suggest a critical role for hippocampal Arc expression in the reconsolidation of alcohol memories. The research also revealed that the “reconsolidation window”, i.e., the timeframe in which memories can be altered, might be narrower than five hours when ARC protein expression upregulation is required for memory reconsolidation. The study suggests that the mPFC is a candidate brain region that regulates alcohol seeking through reconsolidation pathways, given its upregulated ARC protein levels following alcohol memory recall. Finally, the study indicates that the increases in the immediate early genes (IEGs) expression are not unique to the reconsolidation of alcohol-related memories. Instead, ARC and EGR1 were previously implicated in the reconsolidation of several types of memories, including fear memories, recognition memories, and memories associated with different drugs of abuse [38][21].
Taken together, the studies described above suggest a critical relationship between the timing and specificity of transcription in memory consolidation and reconsolidation. Moreover, they emphasize the importance of transcriptional time spans for memory processing and suggest that different types of memories may have unique transcriptional programs. Thus, future research aimed at uncovering the molecular mechanisms underlying the transcriptional regulation of specific types of memories may provide novel therapeutic targets for memory-related disorders.

3. The Transcriptional Activity beyond Neurons

The process of memory modulation is a complex and multi-faceted phenomenon, which involves not only the intricate network of neurons, but also the contribution of non-neuronal cells such as astrocytes and glia cells. Despite the significance of non-neuronal cells, they have often been overlooked in the study of memory modulation. However, recent studies have suggested that these cells play a vital role in many processes, including memory. To fully comprehend the mechanisms of memory modulation and to develop methods to manipulate them, it is essential to understand the role of every player involved.
Recent research has suggested that astrocytes may play a significant role in modulating higher cognitive function, such as working memory (WM), by influencing synaptic transmission. One study employed a computational model to investigate the impact of astrocytes on the stability and duration of working memories [39][22]. Their results indicated that the duration of working memory representations can be influenced by an astrocytic time constant, which defines a “window of vulnerability” during which some memories are tagged for long-term retention while others are terminated. The proportion of memories in the retention and termination groups can be regulated by adjusting the strength of astrocytic feedback or its time constant. These findings suggest that astrocytic signaling may serve as a candidate mechanism for top-down control of working memory representations and their duration [39][22].
Linking this to transcriptional activity, it is worth noting that non-neuronal cells also exhibit changes in transcriptional activity associated with remote memory consolidation. Chen et al. recently showed that non-neuronal cells’ transcriptional activity is distinct from those of neurons, indicating that non-neuronal programs may support the maintenance of the remote fear-memory trace [30][13]. Interestingly, they found that more than 95% of the DEGs were upregulated, suggesting an overall transcriptional activation during consolidation. It is also worth noting that the consolidation of remote memory induces a persistent transcriptional program in astrocytes and microglia. These findings are in line with previous research in Drosophila, which has shown that long-term memory formation requires increases in glial gene expression [40][23]. Together, these observations highlight the role of non-neuronal cells in memory consolidation and suggest that transcriptional changes in these cells may play a crucial role in the formation and maintenance of long-term memory.
In conclusion, the study of memory modulation involves a complex interplay between neurons and non-neuronal cells. While non-neuronal cells have often been overlooked in the past, recent research has highlighted their significant contributions to memory modulation, including the regulation of working memory representations and the transcriptional changes associated with remote memory consolidation. These findings suggest that a comprehensive understanding of memory modulation requires a consideration of all actors involved, including non-neuronal cells, and their underlying mechanisms.

4. Tuning Transcription for Enhanced Memory Control

4.1. Memory Acquisition Suppressor Genes

The molecules of GABAergic inhibitory systems, which are encoded by certain genes, act as suppressors of acquisition [44][24]. The gamma-aminobutyric acid type A (GABAA) receptors, which are activated by the neurotransmitter GABA, function as ligand-gated chloride channels. These channels reduce the ability of neurons to depolarize and fire action potentials, thereby suppressing the acquisition of new memories [45][25]. This suppression occurs through various mechanisms, including the inhibition of the neural representation of stimulus strength, miR-980-mediated inhibition of the A2bp1 gene, regulation of gene expression by stromalin, and reduction in neurotransmitter persistence in the synapse by the transporter SLC22A [46][26]. Specifically, miR-980 limits memory acquisition in mice by decreasing the excitability of neurons. A2bp1 has been identified as a critical mediator of this effect [46][26]. Interestingly, the effects observed on neuronal excitability by miR-980 are similar to those observed when GABA receptor function is reduced [43][27]. In summary, suppressors of acquisition work by limiting the potency of stimuli, capping neuronal excitability, limiting neurotransmitter availability or release, and limiting neurotransmitter persistence/function in the synapse [43][27]. Further research is needed to gain a better understanding of the role of miR-980 in impairing memory acquisition.

4.2. Memory Consolidation Suppressor Genes

A study has identified a suppressor of consolidation associated with CREB function in Aplysia [47][28]. Neutralizing antibodies to Aplysia CREB2, an endogenous CREB inhibitor, when injected into sensory neurons, allow a single pulse of serotonin to produce long-term changes in plasticity. These changes are typically not strong enough to drive such alterations [47][28]. Inhibition of activating transcription factor 4 (ATF4), a homolog of Aplysia CREB2 in mice, enhances spatial memory and long-term potentiation (LTP) [48][29]. It has been well established that CREB-dependent transcription is necessary for long-term memory consolidation. Additionally, it has been found that suppressors of CREB hinder the process of consolidating short-term memory into long-term memory. Several studies have examined the mechanism by which CREB promotes consolidation and how suppressing CREB prevents it. Some of these studies were discussed in previous sections of this review. CREB has been shown to modulate basal neuronal excitability and the development of LTP. Mice lacking CREB display impaired fear and spatial long-term memory, as well as a failure to develop hippocampal LTP [49][30]. On the other hand, overexpression of CREB increases neuronal excitability and long-term memory following suboptimal fear conditioning. In addition, studies suggest that PIWIL1 and PIWIL2 function as redundant memory suppressors in the mouse hippocampus, while miR-182 has been identified as a possible consolidation suppressor in the amygdala [50][31]. Interestingly, CREB1 mRNA levels can be regulated by miR-182-5p in human liver tissue but also by miR-338-3p and miR-495-3p in human brain tissue. Through this targeted process, memory consolidation can be modulated and studied [51][32]. These findings emphasize the significance of CREB-dependent transcription, neuronal excitability, and miRNA regulation in the consolidation of long-term memories and potentially in its modulation.

4.3. Memory Extinction Suppressor Genes

The strength of synaptic connections can be modulated by changes in the levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), which play a crucial role in memory formation and forgetting [52][33]. After learning, the insertion of additional AMPARs into postsynaptic sites increases synaptic strength. Conversely, the internalization of surface AMPARs reduces the functional connection between potentiated synapses and is considered one mechanism for forgetting [53][34]. The GLU2A subunit of AMPAR in the mouse amygdala has been found to have a positive correlation with memory strength after fear conditioning. Additionally, inhibiting the internalization of hippocampal Glu2a following training suppresses the forgetting of episodic memory [54,55][35][36]. Two genes, CASPASE-2 and SYT3, have been identified as regulators of memory stability through the internalization of AMPARs [56,57][37][38]. The general principles learned to date indicate that memory suppressor genes encode molecules that participate in the endocytosis of neurotransmitter receptors. This process helps to reduce excitatory synaptic input. By activating specific dopamine receptors on postsynaptic engram cells, certain dopamine neurons can trigger a signaling cascade. This cascade leads to the activation of small G-proteins and the rearrangement of the cytoskeleton in those cells. Ultimately, this process results in the removal of memories. These mechanisms offer attractive options for reducing the receptive state of engram cells or modifying the structural changes at synapses that occur during memory formation and consolidation. By doing so, they can enhance targeted forgetting.
In conclusion, experiments have shown that changes in gene expression play a critical role in shaping various aspects of memory, from acquisition to consolidation to reconsolidation. The manipulation of the expression of specific genes has profound effects on memory processes. The emerging field of transcriptional regulation and memory control has explored the potential of targeted transcriptional regulation to selectively modulate different aspects of memory processes. Memory suppressor genes have been identified as playing a crucial role in limiting the formation and expression of memories. Harnessing the power of gene expression to regulate memory processes, particularly fear memory pathways, presents exciting possibilities for enhancing cognitive function and addressing memory-related disorders, but what are the implications for PTSD?

5. The Path to Fear Memory Extinction through Molecular Targets in PTSD

Recent studies have begun to shed light on the underlying molecular mechanisms that drive the formation and modulation of memories in PTSD, including on the transcriptional changes that occur in response to traumatic events. Studies of peripheral blood of PTSD patients have shown alterations in the expression of genes that are thought to play a key role in the formation and maintenance of memories [58][39]. For example, the expression of genes such as FK506-binding protein 5 (FKBP5) and BDNF are altered in PTSD patients in the brain and in the peripheral blood, respectively. FKBP5 and BDNF are related to the regulation of stress response and neural plasticity, respectively, and the study showed that changes in these genes’ expression levels may contribute to the development and maintenance of PTSD symptoms [59][40]. Additionally, other previously mentioned experiments indicated that the expression of genes such as protein kinase A (PKA) and CREB, linked to synaptic plasticity and memory consolidation, are altered in PTSD patients [60][41].
Before delving into the transcriptional regulation of memory, particularly fear memory in PTSD, it is important to recognize the crucial role of animal models in uncovering the foundations of most findings in this field. Memory modulation research benefits from the synergy among animal models, clinical studies, and in vitro models. Animal models, especially rodents, offer invaluable insights into the intricate processes of memory formation and modulation. By investigating specific molecular changes, such as alterations in mRNA and microRNA expression, at different stages of memory modulation and within various brain regions, these models provide a comprehensive understanding of the molecular dynamics at play. Moreover, animal models offer distinct advantages for studying memory-related disorders such as PTSD. They provide a level of experimental control that is difficult to achieve in human studies. Furthermore, animal models provide a platform to examine the effects of potential therapeutic interventions. It is important to exercise caution when extrapolating findings from animal models to human conditions. However, these models play a critical role in generating hypotheses and designing subsequent studies involving human subjects. In the context of PTSD, animal models often use stress paradigms that involve single acute stressors such as physical, predator, or social stress. These preclinical models mimic PTSD phenotypes and are assessed using various behavioral tests that measure the expression of PTSD-like symptoms. In summary, the use of animal models in memory modulation research, including fear memory in PTSD, is essential for deciphering the molecular basis of these processes. The controlled experimental conditions, along with behavioral assessments, provide a valuable foundation for investigating the transcriptional changes associated with memory modulation and offer insights into the complexities of PTSD.
The effects of ketamine on fear memory extinction were investigated [61][42]. The research team examined changes in glutamate transmission and dendritic arborization in the PFC of rats subjected to footshock-induced stress. The study found that ketamine administration blocked the acute stress-induced enhancement of glutamate release. This effect was observed 24 or 72 h before or 6 h after the footshock. Furthermore, ketamine administration rescued the retraction of apical dendrites in pyramidal neurons and facilitated the extinction of contextual fear. The study revealed that ketamine has a rapid effect on animals subjected to acute stress. This suggests that there is a mechanism at play involving the restoration of glutamate release and structural remodeling of dendrites. The acute ketamine administration stabilized the dysfunctional release of glutamate induced by stress in animals. The study highlighted that the acute ketamine administration exerted different effects on PFC glutamate release in naïve rats compared to animals subjected to acute foot shock stress [61][42]. These findings suggest a potential mechanism of action for the rapid antidepressant effect of ketamine, which involved the re-establishment of synaptic homeostasis in the PFC. Overall, this offers valuable insights into the immediate effects of ketamine in animals subjected to acute stress. These findings could have significant implications for the development of novel therapeutic strategies for stress-related psychiatric disorders. To date, no study has specifically investigated the transcriptional changes associated with ketamine treatment response in PTSD. However, a study did examine the changes in transcriptional signatures in response to ketamine treatment in depression and focused on the role of glutamate in this process [62][43]. Before administering ketamine, the study identified that two genes associated with glutamate signaling, GRM2 and GRIN2D, were more abundant in ketamine responders compared to non-responders [62][43]. In line with the findings from the ketamine study in PTSD, these suggest that glutamate receptors may be involved in the response to ketamine. Thus, targeting GRM2 could present a potential mechanism for modulating stress-related disorders.
Another established target is modulating the expression of the BDNF gene as a therapeutic approach for fear memory extinction. Impaired fear extinction is a hallmark of PTSD, and BDNF appears to enhance this process [59][40]. A study focused on the role of BDNF on fear memory extinction. BDNF is necessary for the formation of emotional memories in areas of the brain such as the amygdala, HPC, and PFC. Different systems, such as the endocannabinoid system and the hypothalamic–pituitary–adrenal axis, modulate fear extinction through BDNF [59][40]. Exogenous fear extinction enhancers, such as antidepressants and N-methyl D-aspartate agonists, may act through or in concert with the BDNF-TrkB system [63][44]. Genetic manipulations of BDNF and TrkB in mice demonstrate that BDNF and TrkB are essential for CNS development and play a key role in synaptic plasticity and the formation of fear memories [64][45]. Furthermore, there are interesting interactions between the endocannabinoid system and BDNF/TrkB, which would be important for the modulation of fear extinction [65][46]. The generation of conditional knockout mice has shown that fear extinction effects are regionally dependent. While BDNF deletion in the HPC leads to cue-dependent fear extinction deficits, no effect is found in extinction of cue-dependent fear when the BDNF deletion is restricted to the prelimbic cortex (PL). However, BDNF in the PL is necessary for cue-dependent fear acquisition, and the deficit in learned fear is rescued by 7,8-DHF, which mimics endogenous BDNF by activating TrkB receptors [59][40].
Memories are not static entities but rather constantly changing and updating over time. This makes them susceptible to modulation or alteration, which has led research to explore various psychological interventions to modulate memories. One of the main strategies involves targeting the unstable state of memories after retrieval, which can make them more malleable and susceptible to modification. In this approach, memories are temporarily destabilized through retrieval and then modified through various interventions, such as exposure therapy or cognitive reappraisal. This technique has shown promise in treating a range of psychological disorders, including anxiety disorders, PTSD, and addiction. To better grasp the molecular aspect of this phenomenon, a study investigated the mechanisms involved in fear memory reconsolidation and extinction in mice and suggested a transcription factor switch that would determine the memory course after retrieval [68][47]. The authors found that two transcription factors, NF-κB and NFAT, have opposing roles in these processes. NF-κB is required for fear memory reconsolidation, while calcineurin (CaN) phosphatase inhibits NF-κB and induces NFAT nuclear translocation, promoting memory extinction. The inhibition of both calcineurin and NFAT impairs memory extinction, while inhibition of NF-κB enhances memory extinction [68][47]. Interestingly, a study uncovered a noteworthy connection: through the inhibition of miR-142, a pivotal regulator of the fragile mental retardation protein (FMRP), they were able to impede the translocation of NF-κB into neuronal nuclei. This potentially had implications for the shape and structure of neurons. This discovery was part of a broader investigation where the suppression of miR-142 was observed to alleviate PTSD-like behaviors in rats subjected to a stress paradigm. This insight further solidified the link between NF-κB and the regulation of fear memory [69][48]. Additionally, the modulation of PTSD-like behavior in rats following a stress paradigm has been demonstrated by regulating FMRP through other miRNAs, such as miR-132 [70][49].
The report on the transcription factors, NF-κB and NFAT, describes two transcriptional mechanisms that are differentially induced in either reconsolidation or extinction in associative learning. NF-κB is activated in the HPC and is necessary for memory reconsolidation, whereas hippocampal CaN activity is necessary for extinction. Inhibition of both CaN and NFAT in the hippocampus impairs extinction but does not affect reconsolidation. One key downstream target for NFAT in the nucleus is the BDNF promoter [68][47]. This finding is consistent with the previously mentioned study that discusses the role of BDNF on memory extinction, as it has demonstrated that BDNF plays a crucial role in enhancing fear memory extinction. The findings suggest that a restriction of the transcription factor NF-κB is part of the mechanism involved in extinction. Overall, this research shheds light on the intricate and opposing roles of transcription factors in fear memory reconsolidation and extinction. The findings highlight the importance of NF-κB in memory reconsolidation and the inhibitory effects of calcineurin and NFAT in promoting memory extinction.
Many of the studies have shown that memory modulation is associated with transcriptional changes in the brain. However, the question that arises is which symptoms exactly those transcriptional changes have effects on. To better understand how to modulate memories for PTSD, it is important to identify the specific symptoms that these transcriptional changes help alleviate and those that they do not. This knowledge can inform the development of more effective and targeted therapies for PTSD. Interestingly, a relatively recent study focused on the gene expression differences attributed to different PTSD symptoms clusters [71][50]. Using a transcriptome-wide analysis of differential gene expression in peripheral blood, the researchers found that gene expression differences between individuals with PTSD and control participants were mainly attributed to the intrusion symptom cluster. Specifically, ten genes were upregulated in participants with PTSD and high intrusion symptoms at baseline, and interestingly, were downregulated in participants with improved PTSD symptoms following treatment. Among these genes, RBAK, a DNA transcription regulator, was the top upregulated gene associated with PTSD, while C5orf24 was the most downregulated gene associated with symptom improvement [71][50]. Taken together, these findings suggest that specific molecular biomarkers may inform the development of targeted therapies for the precise treatment of PTSD, particularly for individuals with high intrusion symptoms.
Another highly important aspect to consider are the sex-dependent differences, which are particularly significant given the elevated vulnerability of females to PTSD. However, preclinical research has predominantly focused on male rodents. To illuminate stress’s impact on recognition memory, a study investigated sex-dependent shifts in the transcriptional changes of ionotropic glutamate receptor subunits following stress, revealing altered expression of NMDA and AMPA receptor subunits [72][51]. Another investigation delved into the sex-dependent role of the methyl-CpG binding protein 2 (MECP2). Through examining MECP2 mRNA levels in a cohort of 132 participants, including 58 women, a compelling narrative emerged. Among women exposed to trauma and adverse childhood experiences, the downregulation of MECP2 correlated with heightened PTSD symptoms [73][52]. This underscores MECP2′s role in post-trauma pathophysiology and calls for further investigation into its sex-specific implications for the onset and progression of PTSD.
Transcriptional changes are not the only ones prone to sex-dependent influences. Within the realm of epigenetic regulation, the histone variant H2A.Z has emerged as a potent controller of fear memory suppression [74][53]. By utilizing mice with a conditionally inducible H2A.Z knockout (cKO), researchers unveiled nuanced sex-dependent dynamics, revealing a situation where male-specific enhancement of fear memory occurred [74][53]. Notably, H2A.Z cKO elevated non-stress-related memory in both genders, underscoring its dual impact regardless of sex. Due to the distinct vulnerability of females to PTSD, the focus turned towards examining the effects of H2A.Z cKO in a stress-amplified fear learning model. Encouragingly, this manipulation selectively mitigated fear sensitization and pain responses in females, untangling the interconnected influences of sex, task type, and stress history. Consequently, H2A.Z emerges as a potential sex-specific epigenetic factor in PTSD susceptibility, shedding light on avenues for personalized therapeutic strategies. These findings emphasize the importance of integrating gender-specific mechanisms into conversations about stress-induced memory alterations, a pivotal aspect when crafting tailored intervention approaches.

References

  1. McGaugh, J.L. Memory—A Century of Consolidation. Science 2000, 287, 248–251.
  2. Bear, M.F. A synaptic basis for memory storage in the cerebral cortex. Proc. Natl. Acad. Sci. USA 1996, 93, 13453–13459.
  3. Takeuchi, T.; Duszkiewicz, A.J.; Morris, R.G.M. The synaptic plasticity and memory hypothesis: Encoding, storage and persistence. Philos. Trans. R. Soc. B Biol. Sci. 2014, 369, 20130288.
  4. Kastellakis, G.; Poirazi, P. Synaptic Clustering and Memory Formation. Front. Mol. Neurosci. 2019, 12, 300.
  5. Luchkina, N.V.; Bolshakov, V.Y. Mechanisms of fear learning and extinction: Synaptic plasticity–fear memory connection. Psychopharmacology 2018, 236, 163–182.
  6. Suzuki, A.; Fukushima, H.; Mukawa, T.; Toyoda, H.; Wu, L.-J.; Zhao, M.-G.; Xu, H.; Shang, Y.; Endoh, K.; Iwamoto, T.; et al. Upregulation of CREB-Mediated Transcription Enhances Both Short- and Long-Term Memory. J. Neurosci. 2011, 31, 8786–8802.
  7. Sekeres, M.J.; Mercaldo, V.; Richards, B.; Sargin, D.; Mahadevan, V.; Woodin, M.A.; Frankland, P.W.; Josselyn, S.A. Increasing CRTC1 Function in the Dentate Gyrus during Memory Formation or Reactivation Increases Memory Strength without Compromising Memory Quality. J. Neurosci. 2012, 32, 17857–17868.
  8. Nonaka, M.; Kim, R.; Fukushima, H.; Sasaki, K.; Suzuki, K.; Okamura, M.; Ishii, Y.; Kawashima, T.; Kamijo, S.; Takemoto-Kimura, S.; et al. Region-Specific Activation of CRTC1-CREB Signaling Mediates Long-Term Fear Memory. Neuron 2014, 84, 92–106.
  9. Uchida, S.; Shumyatsky, G.P. Synaptically Localized Transcriptional Regulators in Memory Formation. Neuroscience 2018, 370, 4–13.
  10. Boudreau, R.L.; Jiang, P.; Gilmore, B.L.; Spengler, R.M.; Tirabassi, R.; Nelson, J.A.; Ross, C.A.; Xing, Y.; Davidson, B.L. Transcriptome-wide Discovery of microRNA Binding Sites in Human Brain. Neuron 2014, 81, 294–305.
  11. Hegde, A.N.; Smith, S.G. Recent developments in transcriptional and translational regulation underlying long-term synaptic plasticity and memory. Learn. Mem. 2019, 26, 307–317.
  12. Ramamoorthi, K.; Fropf, R.; Belfort, G.M.; Fitzmaurice, H.L.; McKinney, R.M.; Neve, R.L.; Otto, T.; Lin, Y. Npas4 Regulates a Transcriptional Program in CA3 Required for Contextual Memory Formation. Science 2011, 334, 1669–1675.
  13. Chen, M.B.; Jiang, X.; Quake, S.R.; Südhof, T.C. Persistent transcriptional programmes are associated with remote memory. Nature 2020, 587, 437–442.
  14. Olguin, S.L.; Patel, P.; Buchanan, C.N.; Dell’orco, M.; Gardiner, A.S.; Cole, R.; Vaughn, L.S.; Sundararajan, A.; Mudge, J.; Allan, A.M.; et al. KHSRP loss increases neuronal growth and synaptic transmission and alters memory consolidation through RNA stabilization. Commun. Biol. 2022, 5, 672.
  15. Araujo, D.J.; Toriumi, K.; Escamilla, C.O.; Kulkarni, A.; Anderson, A.G.; Harper, M.; Usui, N.; Ellegood, J.; Lerch, J.P.; Birnbaum, S.G.; et al. Foxp1 in Forebrain Pyramidal Neurons Controls Gene Expression Required for Spatial Learning and Synaptic Plasticity. J. Neurosci. 2017, 37, 10917–10931.
  16. Etkin, A.; Alarcón, J.M.; Weisberg, S.P.; Touzani, K.; Huang, Y.Y.; Nordheim, A.; Kandel, E.R. A Role in Learning for SRF: Deletion in the Adult Forebrain Disrupts LTD and the Formation of an Immediate Memory of a Novel Context. Neuron 2006, 50, 127–143.
  17. Cole, C.J.; Mercaldo, V.; Restivo, L.; Yiu, A.P.; Sekeres, M.J.; Han, J.-H.; Vetere, G.; Pekar, T.; Ross, P.J.; Neve, R.L.; et al. MEF2 negatively regulates learning-induced structural plasticity and memory formation. Nat. Neurosci. 2012, 15, 1255–1264.
  18. Alberini, C.M.; Kandel, E.R. The Regulation of Transcription in Memory Consolidation. Cold Spring Harb. Perspect. Biol. 2015, 7, a021741.
  19. von Hertzen, L.S.J.; Giese, K.P. Memory Reconsolidation Engages Only a Subset of Immediate-Early Genes Induced during Consolidation. J. Neurosci. 2005, 25, 1935–1942.
  20. da Silva, W.C.; Bonini, J.S. Inhibition of late mRNA synthesis in the hippocampus impairs consolidation and reconsolidation of spatial memory in male rats. Neurobiol. Learn. Mem. 2022, 195, 107687.
  21. Goltseker, K.; Garay, P.; Bonefas, K.; Iwase, S.; Barak, S. Alcohol-specific transcriptional dynamics of memory reconsolidation and relapse. Transl. Psychiatry 2023, 13, 55.
  22. Becker, S.; Nold, A.; Tchumatchenko, T. Modulation of working memory duration by synaptic and astrocytic mechanisms. PLoS Comput. Biol. 2022, 18, e1010543.
  23. Matsuno, M.; Horiuchi, J.; Ofusa, K.; Masuda, T.; Saitoe, M. Inhibiting Glutamate Activity during Consolidation Suppresses Age-Related Long-Term Memory Impairment in Drosophila. iScience 2019, 15, 55–65.
  24. Liu, X.; Buchanan, M.E.; Han, K.-A.; Davis, R.L. The GABAA Receptor RDL Suppresses the Conditioned Stimulus Pathway for Olfactory Learning. J. Neurosci. 2009, 29, 1573–1579.
  25. Chhatwal, J.P.; Myers, K.M.; Ressler, K.J.; Davis, M. Regulation of Gephyrin and GABAAReceptor Binding within the Amygdala after Fear Acquisition and Extinction. J. Neurosci. 2005, 25, 502–506.
  26. Guven-Ozkan, T.; Busto, G.U.; Schutte, S.S.; Cervantes-Sandoval, I.; O’dowd, D.K.; Davis, R.L. MiR-980 Is a Memory Suppressor MicroRNA that Regulates the Autism-Susceptibility Gene A2bp1. Cell Rep. 2016, 14, 1698–1709.
  27. Noyes, N.C.; Phan, A.; Davis, R.L. Memory suppressor genes: Modulating acquisition, consolidation, and forgetting. Neuron 2021, 109, 3211–3227.
  28. Bartsch, D.; Ghirardi, M.; Skehel, P.A.; Karl, K.A.; Herder, S.P.; Chen, M.; Bailey, C.H.; Kandel, E.R. Aplysia CREB2 represses long-term facilitation: Relief of repression converts transient facilitation into long-term functional and structural change. Cell 1995, 83, 979–992.
  29. Chen, A.; A Muzzio, I.; Malleret, G.; Bartsch, D.; Verbitsky, M.; Pavlidis, P.; Yonan, A.L.; Vronskaya, S.; Grody, M.B.; Cepeda, I.; et al. Inducible Enhancement of Memory Storage and Synaptic Plasticity in Transgenic Mice Expressing an Inhibitor of ATF4 (CREB-2) and C/EBP Proteins. Neuron 2003, 39, 655–669.
  30. Bourtchuladze, R.; Frenguelli, B.; Blendy, J.; Cioffi, D.; Schutz, G.; Silva, A.J. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 1994, 79, 59–68.
  31. Griggs, E.M.; Young, E.J.; Rumbaugh, G.; Miller, C.A. MicroRNA-182 Regulates Amygdala-Dependent Memory Formation. J. Neurosci. 2013, 33, 1734–1740.
  32. Chi, S.W.; Zang, J.B.; Mele, A.; Darnell, R.B. Argonaute HITS-CLIP decodes microRNA–mRNA interaction maps. Nature 2009, 460, 479–486.
  33. Turrigiano, G.G.; Nelson, S.B. Thinking Globally, Acting Locally: AMPA Receptor Turnover and Synaptic Strength. Neuron 1998, 21, 933–935.
  34. Hardt, O.; Nader, K.; Wang, Y.-T. GluA2-dependent AMPA receptor endocytosis and the decay of early and late long-term potentiation: Possible mechanisms for forgetting of short- and long-term memories. Philos. Trans. R. Soc. B Biol. Sci. 2014, 369, 20130141.
  35. Migues, P.V.; Hardt, O.; Wu, D.C.; Gamache, K.; Sacktor, T.C.; Wang, Y.T.; Nader, K. PKMζ maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nat. Neurosci. 2010, 13, 630–634.
  36. Migues, P.V.; Liu, L.; Archbold, G.E.B.; Einarsson, E.; Wong, J.; Bonasia, K.; Ko, S.H.; Wang, Y.T.; Hardt, O. Blocking Synaptic Removal of GluA2-Containing AMPA Receptors Prevents the Natural Forgetting of Long-Term Memories. J. Neurosci. 2016, 36, 3481–3494.
  37. Xu, Z.-X.; Tan, J.-W.; Xu, H.; Hill, C.J.; Ostrovskaya, O.; Martemyanov, K.A.; Xu, B. Caspase-2 promotes AMPA receptor internalization and cognitive flexibility via mTORC2-AKT-GSK3β signaling. Nat. Commun. 2019, 10, 3622.
  38. Awasthi, A.; Ramachandran, B.; Ahmed, S.; Benito, E.; Shinoda, Y.; Nitzan, N.; Heukamp, A.; Rannio, S.; Martens, H.; Barth, J.; et al. Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting. Science 2019, 363, eaav1483.
  39. Banerjee, S.B.; Morrison, F.G.; Ressler, K.J. Genetic approaches for the study of PTSD: Advances and challenges. Neurosci. Lett. 2017, 649, 139–146.
  40. Andero, R.; Ressler, K. Fear extinction and BDNF: Translating animal models of PTSD to the clinic. Genes Brain Behav. 2012, 11, 503–512.
  41. Hauger, R.L.; Olivares-Reyes, J.A.; Dautzenberg, F.M.; Lohr, J.B.; Braun, S.; Oakley, R.H. Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy. Neuropharmacology 2012, 62, 705–714.
  42. Sala, N.; Paoli, C.; Bonifacino, T.; Mingardi, J.; Schiavon, E.; La Via, L.; Milanese, M.; Tornese, P.; Datusalia, A.K.; Rosa, J.; et al. Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along with Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex. Front. Pharmacol. 2022, 13, 759626.
  43. Cathomas, F.; Bevilacqua, L.; Ramakrishnan, A.; Kronman, H.; Costi, S.; Schneider, M.; Chan, K.L.; Li, L.; Nestler, E.J.; Shen, L.; et al. Whole blood transcriptional signatures associated with rapid antidepressant response to ketamine in patients with treatment resistant depression. Transl. Psychiatry 2022, 12, 12.
  44. Peters, J.; Dieppa-Perea, L.M.; Melendez, L.M.; Quirk, G.J. Induction of Fear Extinction with Hippocampal-Infralimbic BDNF. Science 2010, 328, 1288–1290.
  45. Patterson, S.L.; Abel, T.; Deuel, T.A.; Martin, K.C.; Rose, J.C.; Kandel, E.R. Recombinant BDNF Rescues Deficits in Basal Synaptic Transmission and Hippocampal LTP in BDNF Knockout Mice. Neuron 1996, 16, 1137–1145.
  46. D’souza, D.C.; Pittman, B.; Perry, E.; Simen, A. Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans. Psychopharmacology 2008, 202, 569–578.
  47. de la Fuente, V.; Freudenthal, R.; Romano, A. Reconsolidation or Extinction: Transcription Factor Switch in the Determination of Memory Course after Retrieval. J. Neurosci. 2011, 31, 5562–5573.
  48. Nie, P.-Y.; Tong, L.; Li, M.-D.; Fu, C.-H.; Peng, J.-B.; Ji, L.-L. miR-142 downregulation alleviates rat PTSD-like behaviors, reduces the level of inflammatory cytokine expression and apoptosis in hippocampus, and upregulates the expression of fragile X mental retardation protein. J. Neuroinflamm. 2021, 18, 17.
  49. Nie, P.-Y.; Ji, L.-L.; Fu, C.-H.; Peng, J.-B.; Wang, Z.-Y.; Tong, L. miR-132 Regulates PTSD-like Behaviors in Rats Following Single-Prolonged Stress Through Fragile X-Related Protein 1. Cell. Mol. Neurobiol. 2020, 41, 327–340.
  50. Rusch, H.L.; Robinson, J.; Yun, S.; Osier, N.D.; Martin, C.; Brewin, C.R.; Gill, J.M. Gene expression differences in PTSD are uniquely related to the intrusion symptom cluster: A transcriptome-wide analysis in military service members. Brain Behav. Immun. 2019, 80, 904–908.
  51. Torrisi, S.A.; Rizzo, S.; Laudani, S.; Ieraci, A.; Drago, F.; Leggio, G.M. Acute stress alters recognition memory and AMPA/NMDA receptor subunits in a sex-dependent manner. Neurobiol. Stress 2023, 25, 100545.
  52. Cosentino, L.; Witt, S.H.; Dukal, H.; Zidda, F.; Siehl, S.; Flor, H.; De Filippis, B. Methyl-CpG binding protein 2 expression is associated with symptom severity in patients with PTSD in a sex-dependent manner. Transl. Psychiatry 2023, 13, 249.
  53. Ramzan, F.; Creighton, S.D.; Hall, M.; Baumbach, J.; Wahdan, M.; Poulson, S.J.; Michailidis, V.; Stefanelli, G.; Narkaj, K.; Tao, C.S.; et al. Sex-specific effects of the histone variant H2A.Z on fear memory, stress-enhanced fear learning and hypersensitivity to pain. Sci. Rep. 2020, 10, 14331.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback