Phosphodiesterase 7 inhibitor reduces stress-induced behavioral and cytoarchitectural changes in C57BL/6J mice by activating the BDNF/TrkB pathway.

Background: Phosphodiesterase 7 (PDE7) plays a role in neurological function. Increased expression and activity of PDE7 has been detected in several central nervous system diseases. However, the role of PDE7 in regulating stress levels remains unclear. Thus, this study aimed to determine whether and how PDE7 involved in the stress-induced behavioral and neuron morphological changes. Methods: The single prolonged stress (SPS) was used to build a stress exposure model in C57BL/6 J mice and detected PDE7 activity in hippocampus, amygdala, prefrontal cortex and striatum. Next, three doses (0.2, 1, and 5 mg/kg) of the PDE7 inhibitor BRL-50481 were intraperitoneally administered for 10 days, then behavioral, biochemical, and morphological tests were conducted. Results: PDE7 activity in hippocampus of mice significantly increased at all times after SPS. BRL-50481 significantly attenuated SPS induced anxiety-like behavior and fear response in both context and cue. In addition, BRL-50481 increased the levels of key molecules in the cAMP signaling pathway which were impaired by SPS. Immunofluorescent staining and Sholl analysis demonstrated that BRL-50481 also restored the nucleus/cytoplasm ratio of hippocampal neurons and improved neuronal plasticity. These effects of BRL-50481 were partially blocked by the TrkB inhibitor ANA-12. Conclusion: PDE7 inhibitors attenuate stress-induced behavioral changes by protecting the neuron cytoarchitecture and the neuronal plasticity in hippocampus, which is mediated at least partly through the activation of BDNF/TrkB signaling pathway. These results proved that PDE7 is a potential target for treating stress-induced behavioral and physiological abnormalities.

Epithelial-mesenchymal plasticity in cancer: signaling pathways and therapeutic targets.

Currently, cancer is still a leading cause of human death globally. Tumor deterioration comprises multiple events including metastasis, therapeutic resistance and immune evasion, all of which are tightly related to the phenotypic plasticity especially epithelial-mesenchymal plasticity (EMP). Tumor cells with EMP are manifest in three states as epithelial-mesenchymal transition (EMT), partial EMT, and mesenchymal-epithelial transition, which orchestrate the phenotypic switch and heterogeneity of tumor cells via transcriptional regulation and a series of signaling pathways, including transforming growth factor-ß, Wnt/ß-catenin, and Notch. However, due to the complicated nature of EMP, the diverse process of EMP is still not fully understood. In this review, we systematically conclude the biological background, regulating mechanisms of EMP as well as the role of EMP in therapy response. We also summarize a range of small molecule inhibitors, immune-related therapeutic approaches, and combination therapies that have been developed to target EMP for the outstanding role of EMP-driven tumor deterioration. Additionally, we explore the potential technique for EMP-based tumor mechanistic investigation and therapeutic research, which may burst vigorous prospects. Overall, we elucidate the multifaceted aspects of EMP in tumor progression and suggest a promising direction of cancer treatment based on targeting EMP.

Macrophage plasticity: signaling pathways, tissue repair, and regeneration.

Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt to diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) and alternatively activated (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications orchestrates macrophage polarization, allowing them to respond to various stimuli dynamically. Here, we provide a comprehensive overview of the signaling cascades governing macrophage plasticity, focusing on the roles of Toll-like receptors, signal transducer and activator of transcription proteins, nuclear receptors, and microRNAs. We also discuss the emerging concepts of macrophage metabolic reprogramming and trained immunity, contributing to their functional adaptability. Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases, including chronic wounds, fibrotic disorders, and inflammatory conditions. Ultimately, a deeper understanding of the molecular mechanisms underpinning macrophage plasticity will pave the way for innovative regenerative medicine and tissue engineering approaches.

How obesity affects adipocyte turnover.

Cellular turnover is fundamental for tissue homeostasis and integrity. Adipocyte turnover, accounting for 4% of the total cellular mass turnover in humans, is essential for adipose tissue homeostasis during metabolic stress. In obesity, an altered adipose tissue microenvironment promotes adipocyte death. To clear dead adipocytes, macrophages are recruited and form a distinctive structure known as crown-like structure; subsequently, new adipocytes are generated from adipose stem and progenitor cells in the adipogenic niche to replace dead adipocytes. Accumulating evidence indicates that adipocyte death, clearance, and adipogenesis are sophisticatedly orchestrated during adipocyte turnover. In this Review, we summarize our current understandings of each step in adipocyte turnover, discussing its key players and regulatory mechanisms.

Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex for Phantom Limb Pain.

BACKGROUND: Phantom limb pain (PLP) is a prevalent and distressing occurrence in 60-80% of individuals who have undergone amputations. Recent research underscores the significance of maladaptive cortical plasticity in the genesis of PLP, emphasizing the importance of targeting cortical areas for therapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive tool for cortical stimulation, demonstrates effectiveness in treating various chronic pain conditions of neuropathic origin. Nevertheless, there exists a limited body of research investigating the application of rTMS as a therapeutic intervention specifically for managing PLP. Notably, the dorsolateral prefrontal cortex (DLPFC) plays a crucial role in central pain processing, suggesting its potential as a key therapeutic target in PLP treatment. There is a lack of adequate data regarding the effectiveness of DLPFC-targeting rTMS in alleviating the pain experienced by PLP patients. OBJECTIVE: In this study, our aim was to investigate the impact of 10 sessions of DLPFC-targeting rTMS on the pain status of individuals experiencing PLP. STUDY DESIGN: Randomized controlled trial. SETTING: Traumatic amputees reporting to the tertiary care center with PLP. METHODS: The study was approved by the Institute Ethics Committee (IECPG-299/27.04.2022) and registered in the Clinical Trials Registry of India (CTRI/2022/07/043938). Nineteen patients suffering from PLP were recruited and randomized into real or sham rTMS groups. In the real rTMS group, patients received 10 sessions of rTMS at the DLPFC contralateral to the amputation site. The rTMS, administered at 90% of the resting motor threshold (RMT), was delivered as 8 trains of 150 pulses per train at the rate of one Hz and an inter-train interval of 60 seconds. The total number of pulses per session was 1,200. The sham group received 10 sessions of sham rTMS through the perpendicular placement of an rTMS coil over the DLPFC. These sessions lasted for the same duration and included the same sounds as the real group but involved no active stimulation. The patients' pain status was evaluated using the Visual Analog Scale (VAS) at baseline, at the end of each session of real or sham rTMS and at the 15th, 30th, and 60th day after the the completion of real or sham therapy. RESULTS: A significant decrease in VAS scores was noted after 10 sessions of real rTMS that targeted the DLPFC, in contrast to the sham rTMS group. The real rTMS group's reduction in VAS scores also persisted during the follow-up. LIMITATIONS: A few patients had to drop out due to physical restrictions and financial constraints. Consequently, only a small number of individuals were able to complete the study protocol successfully. CONCLUSION: A regimen of 10 sessions of real rTMS of the DLPFC was associated with significant pain relief in patients with PLP, and the effects were sustained for 2 months. Therefore, the present study shows that rTMS of the DLPFC has potential as an effective therapeutic intervention for sustained pain relief in PLP patients.

The interaction between cannabinoids and long-term synaptic plasticity: A survey on memory formation and underlying mechanisms.

Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), is an essential phenomenon in memory formation as well as maintenance along with many other cognitive functions, such as those needed for coping with external stimuli. Synaptic plasticity consists of gradual changes in the biochemistry and morphology of pre- and postsynaptic neurons, particularly in the hippocampus. Consuming marijuana as a primary source of exocannabinoids immediately impairs attention and working memory-related tasks. Evidence regarding the effects of cannabinoids on LTP and memory is contradictory. While cannabinoids can affect a variety of specific cannabinoid receptors (CBRs) and nonspecific receptors throughout the body and brain, they exert miscellaneous systemic and local cerebral effects. Given the increasing use of cannabis, mainly among the young population, plus its potential adverse long-term effects on learning and memory processes, it could be a future global health challenge. Indeed, the impact of cannabinoids on memory is multifactorial and depends on the dosage, timing, formula, and route of consumption, plus the background complex interaction of the endocannabinoids system with other cerebral networks. Herein, we review how exogenously administrated organic cannabinoids, CBRs agonists or antagonists, and endocannabinoids can affect LTP and synaptic plasticity through various receptors in interaction with other cerebral pathways and primary neurotransmitters.

Corrigendum: Heterogeneity and plasticity of tissue-resident memory T cells in skin diseases and homeostasis: a review.

[This corrects the article DOI: 10.3389/fimmu.2024.1378359.].

Rethinking plasticity: Analysing the concept of "destructive plasticity" in the light of neuroscience definitions.

As a multilevel and multidisciplinary field, neuroscience is designed to interact with various branches of natural and applied sciences as well as with humanities and philosophy. The continental tradition in philosophy, particularly over the past 20 years, tended to establish strong connections with biology and neuroscience findings. This cross fertilization can however be impeded by conceptual intricacies, such as those surrounding the concept of plasticity. The use of this concept has broadened as scientists applied it to explore an ever-growing range of biological phenomena. Here, we examine the consequences of this ambiguity in an interdisciplinary context through the analysis of the concept of "destructive plasticity" in the philosophical writings of Catherine Malabou. The term "destructive plasticity" was coined by Malabou in 2009 to refer to all processes leading to psycho-cognitive and emotional alterations following traumatic or nontraumatic brain injuries or resulting from neurodevelopmental disorders. By comparing it with the neuroscientific definitions of plasticity, we discuss the epistemological obstacles and possibilities related to the integration of this concept into neuroscience. Improving interdisciplinary exchanges requires an advanced and sophisticated manipulation of neurobiological concepts. These concepts are not only intended to guide research programmes within neuroscience but also to organize and frame the dialogue between different theoretical backgrounds.

Knockdown of WISP1/DKK1 restrains phenotypic plasticity in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition and stemness.

OBJECTIVE: Wnt-induced signaling protein 1 (WISP1) and Dickkopf-1 (DKK1) are highly expressed in esophageal squamous cell carcinoma (ESCC), but no direct connection was identified between them. Phenotypic plasticity is a hallmark of ESCC. This research intended to identify the association between WISP1 and DKK1 and their roles in the phenotypic plasticity of ESCC. METHODS: Genes differentially expressed in esophageal carcinoma were analyzed in the GEO database, followed by analyses of GO and KEGG enrichment to screen the hub gene. WISP1 expression and DKK1 secretion was assessed in ESCC tissues and cells. The tumor xenograft and in vivo metastasis models were established by injecting ESCC cells into nude mice. Functional deficiency and rescue experiments were conducted, followed by assays for cell proliferation, migration/invasion, stemness, epithelial-mesenchymal transition (EMT), and apoptosis, as well as tumor volume, weight, proliferation, stemness, and lung metastasis. The binding relationship and co-expression of WISP1 and DKK1 were determined. RESULTS: WISP1 and DKK1 were upregulated in ESCC cells and tissues, and WISP1 was enriched in the cell stemness and Wnt pathways. WISP1 knockdown subdued proliferation, migration/invasion, EMT activity, and stemness but enhanced apoptosis in ESCC cells. WISP1 knockdown restrained ESCC growth, proliferation, stemness, and metastasis in vivo. WISP1 bound to DKK1 in ESCC. DKK1 overexpression abolished the repressive impacts of WISP1 knockdown on the malignant behaviors of ESCC cells in vitro and of ESCC tumor in vivo. CONCLUSION: Knockdown of WISP1/DKK1 restrains the phenotypic plasticity in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition and stemness.

The genetics of phenotypic plasticity. XVIII. Developmental limits restrict adaptive plasticity.

After environmental change, the trait evolution needed to rescue a population depends on the functional form of the plastic change (reaction norm) of that trait. Nearly all previous models of plasticity evolution for continuous traits have assumed that the functional form is linear, i.e., no limits on the range of plasticity. This paper examines the effect of developmental limits, modeled as a sigmoidal reaction norm, on evolutionary rescue after an abrupt environmental change and the subsequent evolution of plasticity, including genetic assimilation. We examined four different scenarios: (1) developmental limits only, (2) developmental limits plus a cost of plasticity, (3) developmental limits with developmental noise, and (4) developmental limits plus environmental variation. The probability of evolutionary rescue increased with an increase in phenotypic variation allowed by plastic development. With a smaller limit to the range of the plastic phenotype, the evolution of adaptive plasticity was limited, meaning the evolution of non-plastic genes was necessary. The addition of developmental constraints to the model did not speed up genetic assimilation, suggesting new theory is needed to understand empirical observations. The modeling framework presented here could be extended to different ecological and evolutionary conditions, alternative reaction norm shapes, the evolution of additional reaction norm parameters such as the range or the location of the inflection point on the environmental axis, or other function-valued traits.

Signatures of Bayesian inference emerge from energy-efficient synapses.

Biological synaptic transmission is unreliable, and this unreliability likely degrades neural circuit performance. While there are biophysical mechanisms that can increase reliability, for instance by increasing vesicle release probability, these mechanisms cost energy. We examined four such mechanisms along with the associated scaling of the energetic costs. We then embedded these energetic costs for reliability in artificial neural networks (ANNs) with trainable stochastic synapses, and trained these networks on standard image classification tasks. The resulting networks revealed a tradeoff between circuit performance and the energetic cost of synaptic reliability. Additionally, the optimised networks exhibited two testable predictions consistent with pre-existing experimental data. Specifically, synapses with lower variability tended to have (1) higher input firing rates and (2) lower learning rates. Surprisingly, these predictions also arise when synapse statistics are inferred through Bayesian inference. Indeed, we were able to find a formal, theoretical link between the performance-reliability cost tradeoff and Bayesian inference. This connection suggests two incompatible possibilities: evolution may have chanced upon a scheme for implementing Bayesian inference by optimising energy efficiency, or alternatively, energy-efficient synapses may display signatures of Bayesian inference without actually using Bayes to reason about uncertainty.

Regulation of neuronal plasticity associated with neuropsychiatric disorders by the orexinergic system.

Orexins are a family of neuropeptides secreted by neurons in the lateral hypothalamus (LH). These peptides act widespreadly across the body by interacting with specific orexin receptors on target cells, which comprise the orexinergic system. Emerging evidence has revealed that the orexinergic system is tightly associated with neuropsychiatric disorders; however, the underlying mechanisms require further exploration. Neuropsychiatric disorders have also been associated with neuroplasticity, while orexins have been shown to play regulatory roles in neuronal plasticity. As such, this review aims to summarize the recent progress of research investigating the roles of the orexinergic system in neuronal plasticity and associated neuropsychiatric disorders, including addiction, depression, and schizophrenia, which may provide novel insights into the mechanism of the orexinergic system in the pathogenesis of these neuropsychiatric disorders.

Epithelial-mesenchymal plasticity (EMP) in wound healing: Exploring EMT mechanisms, regulatory network, and therapeutic opportunities.

Epithelial-to-mesenchymal transition (EMT), a process by which epithelial cells acquire mesenchymal cell characteristics, is well recognized for its critical role in development, wound healing, tissue fibrosis, and cancer progression. During wound healing, keratinocytes undergo a partially reversible EMT process to promote migration and re-epithelialization. In this paper, we review the regulatory roles of key signaling pathways (TGF-ß, Wnt/ß-catenin, Notch) and core transcription factors (Snail, Slug, Twist) in EMT, explore the parallels between re-epithelialization and EMT, and outline recent therapeutic advances and future developments targeting EMT in wound healing. In addition, we call for the adoption of the term "epithelial-mesenchymal plasticity" (EMP) to more accurately describe the dynamic processes that occur during keratinocyte migration and re-epithelialization.

[Effects and mechanisms of electroacupuncture on fear extinction and sleep phase in single prolonged stress mice].

OBJECTIVE: To observe the effects of electroacupuncture (EA) on fear extinction and sleep phase in single prolonged stress (SPS) mice, and explore its mechanism in view of the expression of relevant synaptic proteins. METHODS: Thirty-two C57BL/6J male mice were randomly divided into a control group, a model group, an EA group and a paroxetine (PRX) group, with 8 mice in each one. Modified SPS method was used to establish PTSD model in the model group, the EA group and the PRX group. Seven days after modeling completion, in the EA group, the intervention was delivered at "Baihui" (GV 20) and bilateral "Zusanli" (ST 36), with disperse-dense wave, 3 Hz/15 Hz in frequency and 1 mA in current intensity, for 30 min. In the PRX group, paroxetine solution (2.5 g/L) was administered intragastrically (10 mg/kg). The intervention was given once daily and for consecutive 10 days in the above two groups. The fear conditioning task and the elevated plus-maze test were adopted to evaluate the fear extinction and anxiety of the mice in each group. Using Medusa electroencephalogram (EEG) and electromyography (EMG) recording system from rats and mice, the sleep phase was determined in the mice. With Western blot method adopted, the protein expression of the postsynaptic density protein 95 (PSD95), activity-regulated cytoskeleton-associated protein (ARC), brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartic acid receptor 2A (GluN2A), N-methyl-D-aspartic acid receptor 2B (GluN2B) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor 1 (GluA1) in the hippocampus was detected in the mice. RESULTS: Compared with the control group, the freezing time for the fear re-exposure in 3 min to 15 min and the fear extinction in 0 min to 3 min were prolonged (P<0.05), the fear extinction index decreased (P<0.05), and the open arm time (OT) of the elevated plus-maze was shortened (P<0.05) in the model group. When compared with the model group, in the EA group and the PRX group, the freezing time for the fear re-exposure in 3 min to 6 min and 12 min to 15 min, as well as the fear extinction in 0 min to 3 min was shortened (P<0.05), the fear extinction index increased (P<0.05); the OT in elevated plus-maze was longer in the mice of the EA group (P<0.05). The period of wake (Wake) was prolonged (P<0.05), the non-rapid eye movement period (NREM) and the total sleep time (Sleep) were reduced in the model group (P<0.05) in comparison with the control group. Compared with the model group, the Wake was declined (P<0.05), and the NREM and Sleep increased in the EA group and the PRX group (P<0.05). When compared with the control group, the protein expression of PSD95, ARC, BDNF, GluN2A and GluA1 in the hippocampus decreased (P<0.05), and that of GluN2B increased (P<0.05) in the model group. In the EA group and the PRX group, the protein expression of PSD95, ARC, BDNF, GluN2A and GluA1 in the hippocampus was elevated (P<0.05), and that of GluN2B reduced (P<0.05) when compared with the model group. CONCLUSION: Electroacupuncture at "Baihui" (GV 29) and "Zusanli" (ST 36) can ameliorate anxiety-like behavior, fear extinction disorder and abnormal sleep phase in SPS mice, which may be related to the regulation of synaptic transmission and synaptic plasticity expression in the hippocampus.

The origin of novel traits in cancer.

The traditional view of cancer emphasizes a genes-first process. Novel cancer traits arise by genetic mutations that spread to drive phenotypic change. However, recent data support a phenotypes-first process in which nonheritable cellular variability creates novel traits that later become heritably stabilized by genetic and epigenetic changes. Single-cell measurements reinforce the idea that phenotypes lead genotypes, showing how cancer evolution follows normal developmental plasticity and creates novel traits by recombining parts of different cellular developmental programs. In parallel, studies in evolutionary biology also support a phenotypes-first process driven by developmental plasticity and developmental recombination. These advances in cancer research and evolutionary biology mutually reinforce a revolution in our understanding of how cells and organisms evolve novel traits in response to environmental challenges.

Molecular changes and physiological responses involved in migratory bird fuel management and stopover decisions.

Migratory birds undertake long journeys across continents to reach breeding habitats with abundant resources. These migrations are essential for their survival and are shaped by a complex interplay of physiological adaptations, behavioral cues, and gene expression patterns. Central to migration are stopovers, critical resting points where birds replenish energy stores before continuing their journey. In this study, we integrate physiological measurements, behavioral observations, and molecular data from temporarily caged migrating Garden Warblers (Sylvia borin) to gain insights into their stopover strategies and physiological adaptations after crossing the extended ecological barrier formed by the Sahara Desert and the Mediterranean Sea. Depleted individuals, marked by low body mass and flight muscle mass, showcased remarkable plasticity in recovering and rapidly rebuilding energy stores within a short 5-day stopover. Flight muscle mass increased during this period, highlighting a dynamic trade-off between muscle rebuilding and refuelling. Notably, birds prioritizing muscle rebuilding exhibited a trade-off with the downregulation of genes related to lipid transport and metabolism and at the same time showing evidence of skeletal muscle angiogenesis. Early arrivals were more motivated to depart and exhibited higher levels of physiological stress. Our study highlights the importance of understanding the adaptive responses of birds to changing environmental conditions along their migration routes.

How does climate change impact social bees and bee sociality?

Climatic factors are known to shape the expression of social behaviours. Likewise, variation in social behaviour can dictate climate responses. Understanding interactions between climate and sociality is crucial for forecasting vulnerability and resilience to climate change across animal taxa. These interactions are particularly relevant for taxa like bees that exhibit a broad diversity of social states. An emerging body of literature aims to quantify bee responses to environmental change with respect to variation in key functional traits, including sociality. Additionally, decades of research on environmental drivers of social evolution may prove fruitful for predicting shifts in the costs and benefits of social strategies under climate change. In this review, we explore these findings to ask two interconnected questions: (a) how does sociality mediate vulnerability to climate change, and (b) how might climate change impact social organisation in bees? We highlight traits that intersect with bee sociality that may confer resilience to climate change (e.g. extended activity periods, diet breadth, behavioural thermoregulation) and we generate predictions about the impacts of climate change on the expression and distribution of social phenotypes in bees. The social evolutionary consequences of climate change will be complex and heterogeneous, depending on such factors as local climate and plasticity of social traits. Many contexts will see an increase in the frequency of eusocial nesting as warming temperatures accelerate development and expand the temporal window for rearing a worker brood. More broadly, climate-mediated shifts in the abiotic and biotic selective environments will alter the costs and benefits of social living in different contexts, with cascading impacts at the population, community and ecosystem levels.

Mitochondrial plasticity and synaptic plasticity crosstalk; in health and Alzheimer's disease.

Synaptic plasticity is believed to underlie the cellular and molecular basis of memory formation. Mitochondria are one of the main organelles involved in metabolism and energy maintenance as plastic organelles that change morphologically and functionally in response to cellular needs and regulate synaptic function and plasticity through multiple mechanisms, including ATP generation, calcium homeostasis, and biogenesis. An increased neuronal activity enhances synaptic efficiency, during which mitochondria's spatial distribution and morphology change significantly. These organelles build up in the pre-and postsynaptic zones to produce ATP, which is necessary for several synaptic processes like neurotransmitter release and recycling. Mitochondria also regulate calcium homeostasis by buffering intracellular calcium, which ensures proper synaptic activity. Furthermore, mitochondria in the presynaptic terminal have distinct morphological properties compared to dendritic or postsynaptic mitochondria. This specialization enables precise control of synaptic activity and plasticity. Mitochondrial dysfunction has been linked to synaptic failure in many neurodegenerative disorders, like Alzheimer's disease (AD). In AD, malfunctioning mitochondria cause delays in synaptic vesicle release and recycling, ionic gradient imbalances, and mostly synaptic failure. This review emphasizes mitochondrial plasticity's contribution to synaptic function. It also explores the profound effect of mitochondrial malfunction on neurodegenerative disorders, focusing on AD, and provides an overview of how they sustain cellular health under normal conditions and how their malfunction contributes to neurodegenerative diseases, highlighting their potential as a therapeutic target for such conditions.