Biology subjects

Geranton, S. M.

Publications and source records attributed to Geranton, S. M..

5 recordsLinked to original sources

bioRxiv2025

Stress, Epigenetic Remodeling and FKBP51: Pathways to Chronic Pain Vulnerability

Stress is thought to contribute to the persistence of pain and comorbid anxiety, yet the underlying mechanisms remain unclear. In our pre-clinical model, sub-chronic stress exacerbated subsequently induced inflammatory pain and accelerated the development of comorbid anxiety. DNA methylation analysis of spinal cord tissue after stress exposure revealed hypomethylation in the Fkbp5 promoter site for the canonical FKBP51 transcript and other stress-related genes. However, most epigenetic changes in key regulatory regions did not correlate with changes in gene expression assessed by RNA sequencing, suggesting that stress exposure had remodeled the epigenome without altering gene activity and primed genes for hyper-responsiveness to future challenges. FKBP51 inhibition during stress exposure reduced the exacerbation of inflammatory pain by stress and reversed several stress-induced DNA methylation changes in promoter regions of genes associated with stress and nociception, including Rtn4, Cdk5 and Nrxn1, but not Fkbp5. These results indicate that sub-chronic stress leads to the hypomethylation of Fkbp5 and increased susceptibility to chronic pain driven by FKBP51, but reversing Fkbp5 hypomethylation is not necessary to prevent chronic pain vulnerability, which is likely driven by complex epigenetic regulation of multiple stress-regulated genes.

neuroscience↗

bioRxiv2024

Transcriptional changes across tissue and time provide molecular insights into a therapeutic window of opportunity following traumatic stress exposure

AbstractUnfortunately, survivors of traumatic stress exposure (TSE) frequently develop adverse posttraumatic neuropsychiatric sequelae (APNS) such as chronic pain and stress/depressive symptoms. Increasing evidence indicates that there is a window of opportunity following TSE in which therapeutic interventions are most effective against APNS, yet mechanisms accounting for this observation are poorly understood. Here, we aimed to better understand such mechanisms by generating snapshots of the transcriptional landscape in the early aftermath of TSE across tissues and time. Adult rats were exposed to a TSE model, single prolonged stress (SPS). Then, eight tissues (hypothalamus, left and right hippocampus, amygdala, dorsal root ganglia, spinal cord, heart, and muscle) were isolated from these animals at 2, 24, and 72 hours after SPS and in unexposed controls (n=6 per group). mRNA expression from deep sequencing was used to identify differentially expressed genes (DEGs) and biological pathways enriched over time. In all tissues except the amygdala, the highest number of DEGs was observed 2-hours post-SPS, but DEGs were detected at all timepoints and in all tissues. Some transcripts were differentially expressed in a consistent manner across multiple tissues at a time point (e.g. Fkbp5, 2 hours post-SPS), while others had tissue-or region-specific expression patterns. Stress system pathways were most represented at 2-hours post-SPS, then stress/circadian/inflammatory pathways at 24-hours, and inflammatory pathways at 72-hours. Together these findings provide insights into post-TSE transcriptional landscape dynamics and suggest specific intervention windows of opportunity. Future validation is needed across sex, age, stressor, and cell type.

genomics↗

bioRxiv2024

Acute and early stress axis modulation in joint disease permanently reduces pain and emotional comorbidities

Chronic pain affects 20-30% of the population and imposes a significant socio-economic burden as it is often accompanied by substantial emotional comorbidities such as anxiety and depression. Yet, the mechanisms underlying the interactions between the sensory and emotional aspects of chronic pain remain poorly understood. Here, we investigated the role of FKBP51, a regulator of the stress response, in mediating both sensory and emotional symptoms of chronic pain. Inhibition of FKBP51, via genetic deletion or pharmacological blockade, in persistent joint pain reduced fast-onset sensory, functional and activity-related symptoms, as well as late anxio-depressive comorbidities. FKBP51 inhibition after the establishment of the hypersensitive state provided only temporary symptoms relief, while acute inhibition at disease onset protected from the full development of sensory and anxio-depressive symptoms for up to 6 months. Our results also indicated that early pain symptoms could predict the late sensory and emotional outcomes of chronic pain. RNA sequencing of spinal cord tissue revealed that late FKBP51 inhibition transiently altered nociceptive genes associated with mechanical hypersensitivity. In contrast, early inhibition persistently downregulated the Naaa gene, a key regulator of the transition to chronic pain, and reorganized spinal cilia. Our results indicate that early FKBP51 inhibition after injury can persistently reduce chronic pain and prevent the onset of associated emotional comorbidities by modulating critical spinal neurobiological pathways that play pivotal roles in the transition to chronic pain. Significance statementOur study reveals that early inhibition of FKBP51, a modulator in the stress axis, at the onset of joint damage provides sustained pain relief and significantly delays or prevents emotional comorbidities in a sex-dependent manner. In contrast, FKBP51 inhibition initiated after chronic pain is established results in only temporary symptoms improvement. These findings highlight a critical therapeutic window during which timely intervention can prevent the transition from acute to chronic pain. By establishing a predictive link between early therapeutic response and long-term outcomes, this work has important clinical implications for proactive and personalized chronic pain management.

neuroscience↗

bioRxiv2023

Predicting hypersensitivity and comorbid depressive-like behavior in late stages of joint disease using early weight bearing deficit

Chronic pain is a hallmark of joint diseases and is often accompanied by negative affective symptoms such as low mood, anxiety and memory dysfunction. Whether these may be the results of the more obvious sensory and functional symptoms of joint pain is poorly understood and this likely contributes to the difficulty in adequately managing this condition. Here, we have used two mouse models to address this lack of knowledge. Using a model of ankle inflammation and a model of knee osteoarthritis, we found that these models of joint pain induced weight bearing deficits of different magnitude but relatively similar mechanical allodynia that lasted at least 3 months. However, the models were accompanied by very different affective outcomes, as only the model of knee osteoarthritis, that led to significant early changes in activity and sleep patterns, was accompanied by an increase in negative affective behaviors, including cognitive impairments and depressive-like behavior. The models also had different molecular profiles at both spinal and hippocampal levels. Importantly, the functional outcomes measured in the early stages of the disease stage strongly correlated with sensory and emotional profiles at 3 months, suggesting that early functional measures may be used as predictors of the long-term symptoms associated with persistent joint pain. In conclusion, the predictive value of early measures of functional impact of joint disease could prove useful in the clinics for adapted therapeutic approaches for the prevention of emotional comorbidities and better pain management for patients with joint pain.

neuroscience↗

bioRxiv2022

Using the DNA methylation profile of the stress driver gene FKBP5 for chronic pain diagnosis

Epigenetic changes can bring insight into gene regulatory mechanisms associated with disease pathogenicity, including chronicity and increased vulnerability. To date, we are yet to identify genes sensitive to epigenetic regulation that contribute to the maintenance of chronic pain and with an epigenetic landscape indicative of the susceptibility to persistent pain. Such genes would provide a novel opportunity for better pain management, as their epigenetic profile could be targeted for the treatment of chronic pain or used as an indication of vulnerability for prevention strategies. Here, we investigated the epigenetic profile of the gene FKBP5 for this potential, using targeted bisulphite sequencing in rodent pre-clinical models of chronic and latent hypersensitive states. The FKBP5 promoter DNA methylation (DNAm) signature in the CNS was significantly different between models of persistent pain and there was a significant correlation between CNS and peripheral blood FKBP5 DNAm, indicating that further exploration of FKBP5 promoter DNAm as a biomarker of chronic pain pathogenic origin is warranted. We also found that maternal separation, which promotes the persistency of inflammatory pain in adulthood, was accompanied by long-lasting reduction in FKBP5 DNAm, suggesting that FKPB5 DNAm profile may indicate the increased vulnerability to chronic pain in individuals exposed to trauma in early life. Overall, our data demonstrate that the FKBP5 promoter DNAm landscape brings novel insight into the differing pathogenic origins of chronic pain, may be able to diagnose and stratify patients, and predict the susceptibility to chronic pain.

neuroscience↗