Long-lasting Changes Research Articles

Alterations of Excitation-Inhibition Balance and Brain Network Dynamics Support Sensory Deprivation Theory in Presbycusis.

Sensory deprivation theory is an important hypothesis involving potential pathways between hearing loss and cognitive impairment in patients with presbycusis. The theory suggests that prolonged auditory deprivation in presbycusis, including neural deafferentation, cortical reallocation, and atrophy, causes long-lasting changes and reorganization in brain structure and function. However, neurophysiological changes underlying the cognition-ear link have not been explored. In this study, we recruited 98 presbycusis patients and 60 healthy controls and examined the differences between the two groups in gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in bilateral auditory cortex, excitation-inhibition (E/I) balance (Glu/GABA ratio), dynamic functional network connectivity (dFNC), hearing ability and cognitive performance. Then, correlations with each other were investigated and variables with statistical significance were further analyzed using the PROCESS Macro in SPSS. GABA levels in right auditory cortex and Glu levels in bilateral auditory cortex were lower but E/I balance in right auditory cortex were higher in presbycusis patients compared to healthy controls. Hearing assessments and cognitive performance were worse in presbycusis patients. Three recurring connectivity states were identified after dFNC analysis: State 1 (least frequent, middle-high dFNC strength with negative functional connectivity), State 2 (high dFNC strength), and State 3 (most frequent, low dFNC strength). The occurrence and dwell time of State 3 were higher, on the other hand, the dwell time of State 2 decreased in patients with presbycusis compared to healthy controls. In patients with presbycusis, worse hearing assessments and cognition were correlated with decreased GABA levels, increased E/I balance, and aberrant dFNC, decreased GABA levels and increased E/I balance were correlated with decreased occurrence and dwell time in State 3. In the mediation model, the fractional windows, as well as dwell time in State 3, mediated the relationship between the E/I balance in right auditory cortex and episodic memory (Auditory Verbal Learning Test, AVLT) in presbycusis. Moreover, in patients with presbycusis, we found that worse hearing loss contribute to lower GABA levels, higher E/I balance, and further impact aberrant dFNC, which caused lower AVLT scores. Overall, the results suggest that a shift in E/I balance in right auditory cortex plays an important role in cognition-ear link reorganization and provide evidence for sensory deprivation theory, enhancing our understanding the connection between neurophysiological changes and cognitive impairment in presbycusis. In presbycusis patients, E/I balance may serve as a potential neuroimaging marker for exploring and predicting cognitive impairment.

Developing forebrain synapses are uniquely vulnerable to sleep loss

Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood. Importantly, problems with sleep are common in neurodevelopmental disorders including autism spectrum disorder (ASD). Moreover, early life sleep disruption in animal models causes long-lasting changes in adult behavior. Divergent plasticity engaged during sleep necessarily implies that developing and adult synapses will show differential vulnerability to SD. To investigate distinct sleep functions and mechanisms of vulnerability to SD across development, we systematically examined the behavioral and molecular responses to acute SD between juvenile (P21 to P28), adolescent (P42 to P49), and adult (P70 to P100) mice of both sexes. Compared to adults, juveniles lack robust adaptations to SD, precipitating cognitive deficits in the novel object recognition task. Subcellular fractionation, combined with proteome and phosphoproteome analysis revealed the developing synapse is profoundly vulnerable to SD, whereas adults exhibit comparative resilience. SD in juveniles, and not older mice, aberrantly drives induction of synapse potentiation, synaptogenesis, and expression of perineuronal nets. Our analysis further reveals the developing synapse as a putative node of convergence between vulnerability to SD and ASD genetic risk. Together, our systematic analysis supports a distinct developmental function of sleep and reveals how sleep disruption impacts key aspects of brain development, providing insights for ASD susceptibility.

Lasting effects of adolescent social instability stress on dendritic morphology in the nucleus accumbens in female and male Long Evans rats

Social instability stress (SS) in adolescence in rats leads to long-lasting changes in social behaviour and reward-related behaviour relative to control rats. Given the role of the nucleus accumbens (NAc) in such behaviours, we investigated the morphology of medium spiny neurons (MSNs), which are most neurons in the NAc, in adult female and male rats exposed to SS in adolescence. Irrespective of sex, SS rats had increased number of dendritic spines in both the core and shell regions of the NAc (2.3 % and 18.1 % increase, respectively). In the core, SS rats had a 16 % reduction in the total dendritic lengths of MSNs, whereas in the shell, SS rats had a greater dendritic length closer to the soma, and particularly in SS female rats, whereas the opposite was found farther from the soma (SS 10.6 % > CTL overall). Although the extent to which such structural changes may underlie the enduring effects of SS in adolescence requires investigation, the results add to evidence that changes to the social environment in adolescence can determine adult neuronal structural.

CLIMATE CHANGE FORECASTING USING DEEP LEARNING

Climate change is defined as a long-lasting change in the mean weather patterns found on Earth. These changes are either natural, or human made. Since the 19th century, climate change has been on the rise. This is mostly due to igniting fossil fuels like gas, coal, and oil. These can lead to various problems like food and water scarcity, disease, increased flooding, extreme heat, and economic loss. It can also cause the sea levels to rise, and make oceans warmer and more acidic, and escalate human migration. It is referred to as the most significant threat to health on a global scale by the World Health Organization. Even if the efforts made to reduce future warming is successful, some effects will continue for tens of decades. This paper attempts to forecast climate change based on the changes in temperature across the globe from the 19th century onwards. A deep learning-based time series model is built using Recurrent Neural Networks (RNNs) to forecast the average temperature. This model will attempt to predict future values based on historical data. KEYWORDS—Climate change, Deep learning, Recurrent Neural Network

Inflammatory Trajectory of Type 2 Diabetes: Novel Opportunities for Early and Late Treatment.

Low-grade inflammation (LGI) represents a key driver of type 2 diabetes (T2D) and its associated cardiovascular diseases (CVDs). Indeed, inflammatory markers such as hs-CRP and IL-6 predict the development of T2D and its complications, suggesting that LGI already increases before T2D diagnosis and remains elevated even after treatment. Overnutrition, unhealthy diets, physical inactivity, obesity, and aging are all recognized triggers of LGI, promoting insulin resistance and sustaining the pathogenesis of T2D. Once developed, and even before frank appearance, people with T2D undergo a pathological metabolic remodeling, with an alteration of multiple CVD risk factors, i.e., glycemia, lipids, blood pressure, and renal function. In turn, such variables foster a range of inflammatory pathways and mechanisms, e.g., immune cell stimulation, the accrual of senescent cells, long-lasting epigenetic changes, and trained immunity, which are held to chronically fuel LGI at the systemic and tissue levels. Targeting of CVD risk factors partially ameliorates LGI. However, some long-lasting inflammatory pathways are unaffected by common therapies, and LGI burden is still increased in many T2D patients, a phenomenon possibly underlying the residual inflammatory risk (i.e., having hs-CRP > 2 mg/dL despite optimal LDL cholesterol control). On the other hand, selected disease-modifying drugs, e.g., GLP-1RA, seem to also act on the pathogenesis of T2D, curbing the inflammatory trajectory of the disease and possibly preventing it if introduced early. In addition, selected trials demonstrated the potential of canonical anti-inflammatory therapies in reducing the rate of CVDs in patients with this condition or at high risk for it, many of whom had T2D. Since colchicine, an inhibitor of immune cell activation, is now approved for the prevention of CVDs, it might be worth exploring a possible therapeutic paradigm to identify subjects with T2D and an increased LGI burden to treat them with this drug. Upcoming studies will reveal whether disease-modifying drugs reverse early T2D by suppressing sources of LGI and whether colchicine has a broad benefit in people with this condition.

The impact of gravity on perceived object height

Altering posture relative to the direction of gravity, or exposure to microgravity has been shown to affect many aspects of perception, including size perception. Our aims in this study were to investigate whether changes in posture and long-term exposure to microgravity bias the visual perception of object height and to test whether any such biases are accompanied by changes in precision. We also explored the possibility of sex/gender differences. Two cohorts of participants (12 astronauts and 20 controls, 50% women) varied the size of a virtual square in a simulated corridor until it was perceived to match a reference stick held in their hands. Astronauts performed the task before, twice during, and twice after an extended stay onboard the International Space Station. On Earth, they performed the task of sitting upright and lying supine. Earth-bound controls also completed the task five times with test sessions spaced similarly to the astronauts; to simulate the microgravity sessions on the ISS they lay supine. In contrast to earlier studies, we found no immediate effect of microgravity exposure on perceived object height. However, astronauts robustly underestimated the height of the square relative to the haptic reference and these estimates were significantly smaller 60 days or more after their return to Earth. No differences were found in the precision of the astronauts’ judgments. Controls underestimated the height of the square when supine relative to sitting in their first test session (simulating Pre-Flight) but not in later sessions. While these results are largely inconsistent with previous results in the literature, a posture-dependent effect of simulated eye height might provide a unifying explanation. We were unable to make any firm statements related to sex/gender differences. We conclude that no countermeasures are required to mitigate the acute effects of microgravity exposure on object height perception. However, space travelers should be warned about late-emerging and potentially long-lasting changes in this perceptual skill.

Binge ethanol consumption can be attenuated by systemic administration of minocycline and is associated with enhanced neuroinflammation in the central amygdala

Alcohol use disorder (AUD) has a complicated pathophysiology. Binge ethanol intoxication may produce long-lasting changes throughout extended amygdala neurocircuitry including neuroinflammation, often leading to relapse. Therefore, understanding the role of binge drinking induced neuroinflammation on extended amygdala neurocircuitry is critically important for treatment. We sought to understand the role of neuroinflammation in a naturalized form of rodent binge ethanol drinking (Drinking in the Dark (DID)). In a 5-week DID paradigm, we demonstrate that acute intraperitoneal (IP) injection of the anti-inflammatory drug minocycline significantly reduced binge drinking repeatedly in male and female Cx3CR1-GFP and C57BL/6J mice. Importantly, IP administration transiently decreased intermittent access sucrose consumption, was not observed on the second IP injection, but did not significantly alter food or water consumption, suggesting that minocycline may produce initial acute aversive effects and may not alter long-term consumption of natural rewards. Examination of rodent behaviors post ethanol binge drinking reveals no lasting effects of minocycline treatment on locomotion or anxiety-like behavior. To assess neuroinflammation, we developed a novel analysis method using a Matlab image analysis script, which allows for non-biased skeletonization and evaluation of microglia morphology to determine a possible activation state in Cx3CR1-GFP knock-in mice after repeated DID. We observed significant morphological changes of microglia within the CeA, but no differences in the BLA. Taken together, this study demonstrates repeated binge ethanol consumption can produce significant levels of microglia morphology changes within the CeA, and that immunomodulatory therapies may be an intriguing pharmacological candidate for the treatment of AUD.

TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis–induced immune tolerance

Severe and chronic infections, including pneumonia, sepsis, and tuberculosis (TB), induce long-lasting epigenetic changes that are associated with an increase in all-cause postinfectious morbidity and mortality. Oncology studies identified metabolic drivers of the epigenetic landscape, with the tricarboxylic acid (TCA) cycle acting as a central hub. It is unknown if the TCA cycle also regulates epigenetics, specifically DNA methylation, after infection-induced immune tolerance. The following studies demonstrate that lipopolysaccharide and Mycobacterium tuberculosis induce changes in DNA methylation that are mediated by the TCA cycle. Infection-induced DNA hypermethylation is mitigated by inhibitors of cellular metabolism (rapamycin, everolimus, metformin) and the TCA cycle (isocitrate dehydrogenase inhibitors). Conversely, exogenous supplementation with TCA metabolites (succinate and itaconate) induces DNA hypermethylation and immune tolerance. Finally, TB patients who received everolimus have less DNA hypermethylation demonstrating proof of concept that metabolic manipulation can mitigate epigenetic scars.

Socialization causes long-lasting behavioral changes

In modern human societies, social isolation acts as a negative factor for health and life quality. On the other hand, social interaction also has profound effects on animal and human, impacting aggressiveness, feeding and sleep, among many other behaviors. Here, we observe that in the fly Drosophila melanogaster these behavioral changes long-last even after social interaction has ceased, suggesting that the socialization experience triggers behavioral plasticity. These modified behaviors maintain similar levels for 24 h and persist up to 72 h, although showing a progressive decay. We also find that impairing long-term memory mechanisms either genetically or by anesthesia abolishes the expected behavioral changes in response to social interaction. Furthermore, we show that socialization increases CREB-dependent neuronal activity and synaptic plasticity in the mushroom body, the main insect memory center analogous to mammalian hippocampus. We propose that social interaction triggers socialization awareness, understood as long-lasting changes in behavior caused by experience with mechanistic similarities to long-term memory formation.

Inhibition of striatal indirect pathway during second postnatal week leads to long-lasting deficits in motivated behavior.

Schizophrenia is a neuropsychiatric disorder with postulated neurodevelopmental etiology. Genetic and imaging studies have shown enhanced dopamine and D2 receptor occupancy in the striatum of patients with schizophrenia. However, whether alterations in postnatal striatal dopamine can lead to long-lasting changes in brain function and behavior is still unclear. Here, we approximated striatal D2R hyperfunction in mice via designer receptor-mediated activation of inhibitory Gi-protein signaling during a defined postnatal time window. We found that Gi-mediated inhibition of the indirect pathway (IP) during postnatal days 8-15 led to long-lasting decreases in locomotor activity and motivated behavior measured in the adult animal. In vivo photometry further showed that the motivational deficit was associated with an attenuated adaptation of outcome-evoked dopamine levels to changes in effort requirements. These data establish a sensitive time window of D2R-regulated striatal development with long-lasting impacts on neuronal function and behavior.

Maternal diet during pregnancy and adaptive changes in the maternal and fetal pancreas have implications for future metabolic health.

Fetal and neonatal development is a critical period for the establishment of the future metabolic health and disease risk of an individual. Both maternal undernutrition and overnutrition can result in abnormal fetal organ development resulting in inappropriate birth size, child and adult obesity, and increased risk of Type 2 diabetes and cardiovascular diseases. Inappropriate adaptive changes to the maternal pancreas, placental function, and the development of the fetal pancreas in response to nutritional stress during pregnancy are major contributors to a risk trajectory in the offspring. This interconnected maternal-placental-fetal metabolic axis is driven by endocrine signals in response to the availability of nutritional metabolites and can result in cellular stress and premature aging in fetal tissues and the inappropriate expression of key genes involved in metabolic control as a result of long-lasting epigenetic changes. Such changes result is insufficient pancreatic beta-cell mass and function, reduced insulin sensitivity in target tissues such as liver and white adipose and altered development of hypothalamic satiety centres and in basal glucocorticoid levels. Whilst interventions in the obese mother such as dieting and increased exercise, or treatment with insulin or metformin in mothers who develop gestational diabetes, can improve metabolic control and reduce the risk of a large-for-gestational age infant, their effectiveness in changing the adverse metabolic trajectory in the child is as yet unclear.

Differential Impact of Adolescent or Adult Stress on Behavior and Cortical Parvalbumin Interneurons and Perineuronal Nets in Male and Female Mice.

Stress has become a common public health concern, contributing to the rising prevalence of psychiatric disorders. Understanding the impact of stress considering critical variables, such as age, sex, and individual differences, is of the utmost importance for developing effective intervention strategies. Stress effects (daily footshocks for 10 days) during adolescence (postnatal day [PND] 31-40) and adulthood (PND 65-74) were investigated on behavioral outcomes and parvalbumin (PV)-expressing GABAergic interneurons and their associated perineuronal nets (PNNs) in the prefrontal cortex of male and female mice 5 weeks post stress. In adulthood, adolescent stress induced behavioral alterations in male mice, including anxiety-like behaviors, social deficits, cognitive impairments, and altered dopamine system responsivity. Applying integrated behavioral z-score analysis, we identified sex-specific differences in response to adolescent stress, with males displaying greater vulnerability than females. Furthermore, adolescent-stressed male mice showed decreased PV+ and PNN+ cell numbers and PV+/PNN+ colocalization, while in females, adolescent stress reduced prefrontal PV+/PNN+ colocalization in the prefrontal cortex. Further analysis identified distinct behavioral clusters, with certain females demonstrating resilience to adolescent stress-induced deficits in sociability and PV+ cell number. Adult stress in male and female mice did not cause long-lasting changes in behavior and PV+ and PNN+ cell number. Our findings indicate that the timing of stress, sex, and individual variabilities seem to be determinants for the development of behavioral changes associated with psychiatric disorders, particularly in male mice during adolescence.

Starting the pill during adolescence: Age of onset and duration of use influence morphology of the hippocampus and ventromedial prefrontal cortex.

From adolescence, women become more likely to experience fear dysregulation. Oral contraceptives (OCs) can modulate the brain regions involved in fear processes. OCs are generally used for years and often initiated during adolescence, a sensitive period where certain brain regions involved in the fear circuitry are still undergoing important reorganization. It remains unknown whether OC use during adolescence may induce long-lasting changes in the fear circuitry. This study aimed to examine whether age of onset moderated the relationship between duration of use and fear-related brain structures. We collected structural MRI data in 98 healthy adult women (61 current users, 37 past users) and extracted grey matter volumes (GMV) and cortical thickness (CT) of key regions of the fear circuitry. Non-linear multiple regressions revealed interaction effects between age of onset and quadratic duration of use on GMV of the right hippocampus and right ventromedial prefrontal cortex (vmPFC). Among women who initiated OCs earlier in adolescence, a short duration of use was associated with smaller hippocampal GMV and thicker vmPFC compared to a longer duration of use. For both GMV and CT of the right vmPFC, women with an early OC onset had more grey matter at a short duration of use than those with a later onset. Our results suggest that OC use earlier in adolescence may induce lasting effects on structural correlates of fear learning and its regulation. These findings support further investigation into the timing of OC use to better comprehend how OCs could disrupt normal brain development processes.

Input specificity of NMDA-dependent GABAergic plasticity in the hippocampus

Sensory experiences and learning induce long-lasting changes in both excitatory and inhibitory synapses, thereby providing a crucial substrate for memory. However, the co-tuning of excitatory long-term potentiation (eLTP) or depression (eLTD) with the simultaneous changes at inhibitory synapses (iLTP/iLTD) remains unclear. Herein, we investigated the co-expression of NMDA-induced synaptic plasticity at excitatory and inhibitory synapses in hippocampal CA1 pyramidal cells (PCs) using a combination of electrophysiological, optogenetic, and pharmacological approaches. We found that inhibitory inputs from somatostatin (SST) and parvalbumin (PV)-positive interneurons onto CA1 PCs display input-specific long-term plastic changes following transient NMDA receptor activation. Notably, synapses from SST-positive interneurons consistently exhibited iLTP, irrespective of the direction of excitatory plasticity, whereas synapses from PV-positive interneurons predominantly showed iLTP concurrent with eLTP, rather than eLTD. As neuroplasticity is known to depend on the extracellular matrix, we tested the impact of metalloproteinases (MMP) inhibition. MMP3 blockade interfered with GABAergic plasticity for all inhibitory inputs, whereas MMP9 inhibition selectively blocked eLTP and iLTP in SST-CA1PC synapses co-occurring with eLTP but not eLTD. These findings demonstrate the dissociation of excitatory and inhibitory plasticity co-expression. We propose that these mechanisms of plasticity co-expression may be involved in maintaining excitation-inhibition balance and modulating neuronal integration modes.

Enduring Neurobiological Consequences of Early-Life Stress: Insights from Rodent Behavioral Paradigms.

Stress profoundly affects physical and mental health, particularly when experienced early in life. Early-life stress (ELS) encompasses adverse childhood experiences such as abuse, neglect, violence, or chronic poverty. These stressors can induce long-lasting changes in brain structure and function, impacting areas involved in emotion regulation, cognition, and stress response. Consequently, individuals exposed to high levels of ELS are at an increased risk for mental health disorders like depression, anxiety, and post-traumatic stress disorders, as well as physical health issues, including metabolic disorders, cardiovascular disease, and cancer. This review explores the biological and psychological consequences of early-life adversity paradigms in rodents, such as maternal separation or deprivation and limited bedding or nesting. The study of these experimental models have revealed that the organism's response to ELS is complex, involving genetic and epigenetic mechanisms, and is associated with the dysregulation of physiological systems like the nervous, neuroendocrine, and immune systems, in a sex-dependent fashion. Understanding the impact of ELS is crucial for developing effective interventions and preventive strategies in humans exposed to stressful or traumatic experiences in childhood.

Promoting long-lasting changes in student well-being through a pharmacy general education course: A pilot study

Objective Colleges and universities need effective strategies to help students develop medication-use behaviors that positively support their well-being. This pilot study evaluated the utility of Fink’s Taxonomy of Significant Learning (FTSL), an evidence-based instructional strategy, to create long-lasting changes in students’ well-being during a pharmacy general education course. Participants and methods Using a mixed methods survey design, we assessed 84 undergraduate students’ changes in self-reported well-being at three different time points (pre-intervention, post-intervention, and 6-month follow-up) through five variables (safe medication practices, general healthcare behaviors, healthcare self-efficacy, safe medication storage, and safe medication disposal). Results The results of multiple repeated-measures ANCOVAs, four McNemar chi-square tests, and qualitative thematic analysis showed significant positive changes in several variables over time. Conclusions This pilot study demonstrated that intentional integration of FTSL during the course design process helped students develop long-lasting general healthcare and safe medication-use behavior intentions. We discuss holistic approaches for promoting student well-being.

Analysis of Electrooculogram in Detecting Eye Movements Associated with Brain Injury

Electrooculogram (EOG) has been a valuable clinical neurophysiology tool in the past five decades of the twentieth century. It facilitated understanding more about eye movement, which is clinically useful in identifying the neural substrate disrupted due to brain injuries. This is vital since accurate measurement of neural injuries has a direct bearing on a patient’s life. A number of neurological investigations, including neurological assessment and diagnosis, are done based on measuring eye movements. This essay focuses on using EOG technology and its benefits in identifying limitations of using physiological indices in individuals because of measurable ocular pathophysiological parameters. In the current essay, the major objective will be to discuss the EOG features, the EOG record in healthy individuals, and the relationship of EOG recordings to affected individuals following a neurological event. The eye-integrated EOG recorded from the front part of the face measures eye position change and shows an exponential decay of voltage due to its design, eye physiology, and the removal of corneal function slowly from the corneal electrode. This makes it the best choice to provide an eye position record with high accuracy that can be made available easily for clinicians. The rapid recordings obtained using transcranial electromagnetic stimulation could demonstrate that EOG has the potential to provide high pre-surgical planning utilities for brain tumor removal. This technology is also best for identifying physiological variability within an individual; the same concept can be extended to study brain injuries that trigger physiological changes in eye muscles. In effect, it potentially becomes a tool for personalized care wherein severity estimation for brain injuries would be based on measuring ocular function rather than the nature of the injury. Given its clinical potential, the present essay will review EOG technologies to assess eye pixel movement, its potential for clinical evaluation, physiological basis, and the research evidence regarding changes in EOG in affected individuals with brain injury. In this essay, the long-lasting and short-lasting EOG changes are presented as case studies of individuals diagnosed with PTA, hence demonstrating its clinical utility.

Competitive processes shape multi-synapse plasticity along dendritic segments

Neurons receive thousands of inputs onto their dendritic arbour, where individual synapses undergo activity-dependent plasticity. Long-lasting changes in postsynaptic strengths correlate with changes in spine head volume. The magnitude and direction of such structural plasticity - potentiation (sLTP) and depression (sLTD) - depend upon the number and spatial distribution of stimulated synapses. However, how neurons allocate resources to implement synaptic strength changes across space and time amongst neighbouring synapses remains unclear. Here we combined experimental and modelling approaches to explore the elementary processes underlying multi-spine plasticity. We used glutamate uncaging to induce sLTP at varying number of synapses sharing the same dendritic branch, and we built a model incorporating a dual role Ca2+-dependent component that induces spine growth or shrinkage. Our results suggest that competition among spines for molecular resources is a key driver of multi-spine plasticity and that spatial distance between simultaneously stimulated spines impacts the resulting spine dynamics.

Dendritic Cells Trained Immunity: A Revolutionary Therapy in Genitourinary Tract infections

Genitourinary Tract infections (GTI), including both vulvovaginal candidiasis (VVC) and urinary tract infections (UTIs), represent a significant burden on public health, affecting millions of women worldwide. These conditions not only impact the quality of life of patients but also incur high healthcare costs due to the need for recurrent treatment and management of complications. The mainstay of treatment for these conditions has traditionally been antibiotics and antifungals. However, overuse of these medications is linked to antibiotic resistance and adverse effects. Dendritic cell trained immunity is an innovative, state-of-the-art reprogramming therapy that offers a revolutionary approach, especially when conventional vaccines are unavailable or for individuals experiencing recurrent infections. Novel studies have demonstrated that these glycoconjugates induce long-lasting epigenetic changes in dendritic cells (DCs), initiating a trained immunity effect that extends protection against subsequent microbial exposures. The aim of this study is to present the latest evidence on the treatment of recurrent genitourinary tract infections, highlighting the potential of dendritic cell trained immunity as a significant breakthrough in gynecological care. This innovative approach not only represents a shift from traditional treatment methods but also offers hope for more effective and sustainable management of recurrent infections, ultimately improving patient outcomes and reducing the burden on healthcare systems.

RORα negatively regulates BCG-induced trained immunity

Trained immunity is a long-lasting change in the responsiveness of innate immune cells, leading to a stronger response upon an unrelated secondary challenge. Epigenetic, transcriptional, and metabolic reprogramming contribute to the development of trained immunity. By investigating the impact of gene variants on trained immunity responses after Bacillus Calmette–Guérin (BCG) vaccination, we identified a strong association between polymorphisms in the RORA gene and BCG-induced trained immunity in PBMCs isolated from healthy human donors. RORα, encoded by the RORA gene in humans, is a nuclear receptor and a transcription factor, regulating genes involved in circadian rhythm, inflammation, cholesterol, and lipid metabolism. We found that natural RORα agonists in the circulation negatively correlate with the strength of trained immunity responses after BCG vaccination. Moreover, pharmacological inhibition of RORα in human PBMCs led to higher cytokine production capacity and boosted trained immunity induction by BCG. Blocking RORα activity also resulted in morphological changes and increased ROS and lactate production of BCG-trained cells. Blocking lactate dehydrogenase A (LDHA) and glycolysis with sodium oxamate reduced the cytokine production capacity of cells trained with a combination of BCG and the RORα agonist. In conclusion, this study highlights the potential role of RORα in trained immunity, and its impact on human vaccination and diseases should be further investigated.