Cell Proliferation In Brain Research Articles

Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish: unveiling the role of vascular endothelial growth factor signaling and microglia.

After brain damage, regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals, suggesting a close link between these processes. However, the mechanisms by which these processes interact are not well understood. In this work, we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury. To this end, we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms. First, using the Tg(fli1:EGFP × mpeg1.1:mCherry) zebrafish line, which enables visualization of blood vessels and microglia respectively, we analyzed regenerative angiogenesis from 1 to 21 days post-lesion. In parallel, we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry. We found that after brain damage, the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor (vegfaa and vegfbb) were increased. At the same time, neural stem cell proliferation was also increased, peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis, along with the recruitment of microglia. Then, through pharmacological manipulation by injecting an anti-angiogenic drug (Tivozanib) or Vegf at the lesion site, we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes, as well as microglial recruitment. Finally, we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis, as previously described, as well as injury-induced angiogenesis. In conclusion, we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process. In addition, we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes. This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.

Mechanisms of Glioblastoma Replication: Ca2+ Flares and Cl- Currents.

Glioblastoma (GBM) is amongst the deadliest types of cancers, with no resolutive cure currently available. GBM cell proliferation in the patient's brain is a complex phenomenon controlled by multiple mechanisms. The aim of this study was to determine whether the ionic fluxes controlling cell duplication could represent a target for GBM therapy. In this work, we combined multi-channel Ca2+ and Cl- imaging, optical tweezers, electrophysiology, and immunohistochemistry to describe the role of ion fluxes in mediating the cell volume changes that accompany mitosis of U87 GBM cells. We identified three main steps: (i) in round GBM cells undergoing mitosis, during the transition from anaphase to telophase and cytokinesis, large Ca2+ flares occur, reaching values of 0.5 to 1 μmol/L; (ii) these Ca2+ flares activate Ca2+-dependent Cl- channels, allowing the entry of Cl- ions; and (iii) to maintain osmotic balance, GBM cells swell to complete mitosis. This sequence of steps was validated by electrophysiological experiments showing that Cl- channels are activated either directly or indirectly by Ca2+, and by additional live-cell imaging experiments. Cl- channel blockers with different molecular structures, such as niflumic acid and carbenoxolone, blocked GBM replication by arresting GBM cells in a round configuration. These results describe the central role of Ca2+ flares and Cl- fluxes during mitosis and show that inhibition of Ca2+-activated Cl- channels blocks GBM replication, opening the way to new approaches for the clinical treatment of GBM. Implications: Our work identifies ionic fluxes occurring during cell division as targets for devising novel therapies for glioblastoma treatment.

Enhancing neurogenesis after traumatic brain injury: The role of adenosine kinase inhibition in promoting neuronal survival and differentiation

Traumatic brain injury (TBI) presents a significant public health challenge, necessitating innovative interventions for effective treatment. Recent studies have challenged conventional perspectives on neurogenesis, unveiling endogenous repair mechanisms within the adult brain following injury. However, the intricate mechanisms governing post-TBI neurogenesis remain unclear. The microenvironment of an injured brain, characterized by astrogliosis, neuroinflammation, and excessive cell death, significantly influences the fate of newly generated neurons. Adenosine kinase (ADK), the key metabolic regulator of adenosine, emerges as a crucial factor in brain development and cell proliferation after TBI. This study investigates the hypothesis that targeting ADK could enhance brain repair, promote neuronal survival, and facilitate differentiation. In a TBI model induced by controlled cortical impact, C57BL/6 male mice received intraperitoneal injections of the small molecule ADK inhibitor 5-iodotubercidin (ITU) for three days following TBI. To trace the fate of TBI-associated proliferative cells, animals received intraperitoneal injections of BrdU for seven days, beginning immediately after TBI. Our results show that ADK inhibition by ITU improved brain repair 14 days after injury as evidenced by a diminished injury size. Additionally, the number of mature neurons generated after TBI was increased in ITU-treated mice. Remarkably, the TBI-associated pathological events including astrogliosis, neuroinflammation, and cell death were arrested in ITU-treated mice. Finally, ADK inhibition modulated cell death by regulating the PERK signaling pathway. Together, these findings demonstrate a novel therapeutic approach to target multiple pathological mechanisms involved in TBI. This research contributes valuable insights into the intricate molecular mechanisms underlying neurogenesis and gliosis after TBT.

11β-Hydroxysteroid dehydrogenase type 2 may mediate the stress-specific effects of cortisol on brain cell proliferation in adult zebrafish (Danio rerio).

Stress-induced increases in cortisol can stimulate or inhibit brain cell proliferation, but the mechanisms behind these opposing effects are unknown. We tested the hypothesis that 11β-hydroxysteroid dehydrogenase type 2 (Hsd11b2), a glucocorticoid-inactivating enzyme expressed in neurogenic regions of the adult zebrafish brain, mitigates cortisol-induced changes to brain cell proliferation, using one of three stress regimes: a single 1min air exposure (acute stress), two air exposures spaced 24 h apart (repeat acute stress) or social subordination (chronic stress). Plasma cortisol was significantly elevated 15 min after air exposure and recovered within 24 h after acute and repeat acute stress, whereas subordinate fish exhibited significant and sustained elevations relative to dominant fish for 24 h. Following acute stress, brain hsd11b2 transcript abundance was elevated up to 6 h after a single air exposure but was unchanged by repeat acute stress or social subordination. A sustained increase in brain Hsd11b2 protein levels occurred after acute stress, but not after repeat or chronic stress. Following acute and repeat acute stress, brain pcna transcript abundance (a marker of cell proliferation) exhibited a prolonged elevation, but was unaffected by social subordination. Interestingly, the number of telencephalic BrdU+ cells increased in fish after a single air exposure but was unchanged by repeat acute stress. Following acute and repeat acute stress, fish expressed lower brain glucocorticoid and mineralocorticoid receptor (gr and mr) transcript abundance while subordinate fish exhibited no changes. Taken together, these results demonstrate stressor-specific regulation of Hsd11b2 in the zebrafish brain that could modulate rates of cortisol catabolism contributing to observed differences in brain cell proliferation.

Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer’s disease

BackgroundNeural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimer’s disease (AD) pathology. Addressing these impairments by using neurotrophic factors is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations.MethodsHere, we use a combination of mouse and human stem cell models for comprehensive in-vitro characterization of a novel neurogenic compound, focusing on the brain-derived neurotrophic factor (BDNF) pathway. The ability of ENT-A011, a steroidal dehydroepiandrosterone derivative, to activate the tyrosine receptor kinase B (TrkB) receptor was tested through western blotting in NIH-3T3 cells and its neurogenic and neuroprotective action were assessed through proliferation, cell death and Amyloid-β (Aβ) toxicity assays in mouse primary adult hippocampal NSCs, mouse embryonic cortical NSCs and neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. RNA-seq profiling was used to assess if the compound acts through the same gene network as BDNF in human NPCs.ResultsENT-A011 was able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Aβ-induced cell death, acting selectively through TrkB activation. The compound was able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from Αβ toxicity and prevent synapse loss after Aβ treatment. ENT-A011 successfully induces proliferation and prevents cell death after Aβ toxicity in human NPCs, acting through a core gene network shared with BDNF as shown through RNA-seq.ConclusionsOur work characterizes a novel BDNF mimetic with preferable pharmacological properties and neurogenic and neuroprotective actions in Alzheimer’s disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing.

SETDB1 regulates short interspersed nuclear elements and chromatin loop organization in mouse neural precursor cells

BackgroundTransposable elements play a critical role in maintaining genome architecture during neurodevelopment. Short Interspersed Nuclear Elements (SINEs), a major subtype of transposable elements, are known to harbor binding sites for the CCCTC-binding factor (CTCF) and pivotal in orchestrating chromatin organization. However, the regulatory mechanisms controlling the activity of SINEs in the developing brain remains elusive.ResultsIn our study, we conduct a comprehensive genome-wide epigenetic analysis in mouse neural precursor cells using ATAC-seq, ChIP-seq, whole genome bisulfite sequencing, in situ Hi-C, and RNA-seq. Our findings reveal that the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-mediated H3K9me3, in conjunction with DNA methylation, restricts chromatin accessibility on a selective subset of SINEs in neural precursor cells. Mechanistically, loss of Setdb1 increases CTCF access to these SINE elements and contributes to chromatin loop reorganization. Moreover, de novo loop formation contributes to differential gene expression, including the dysregulation of genes enriched in mitotic pathways. This leads to the disruptions of cell proliferation in the embryonic brain after genetic ablation of Setdb1 both in vitro and in vivo.ConclusionsIn summary, our study sheds light on the epigenetic regulation of SINEs in mouse neural precursor cells, suggesting their role in maintaining chromatin organization and cell proliferation during neurodevelopment.

DEEP LEARNING ANALYSIS OF 3D VOLUME OF BRAIN ANOTOMY USING MRI

Developing machines that behave in a manner just like humans is the intention of artificial intelligence (AI). Further to sample recognition, making plans, and problem-fixing, laptop sports with synthetic intelligence embody special sports activities. A set of algorithms known as "deep learning" is applied in system learning. With the help of magnetic resonance imaging (MRI), experts use advanced techniques to develop models that can detect and classify brain tumors. This results in the fast and easy identification of such tumors, enabling doctors to provide timely and effective treatment to patients. Thought issues are through and massive as the result of aberrant brain cell proliferation, which could harm the structure of the brain and in the long run, bring about malignant brain maximum cancers. The early identification of brain tumors and the following appropriate remedy may additionally lower the loss of life fee. On this advise generative adversarial community (GAN) architecture for the inexperienced identification of brain tumors through the usage of MRI images. This project discusses numerous methods which include resnet-50, vgg16, and inception v3, and evaluates the proposed structure and those models. To investigate the general performance of the models, we took into consideration unique metrics that incorporate the accuracy, don't forget, loss, and vicinity below the curve (AUC). Due to reading distinct methods with our proposed version and the usage of those metrics, we concluded that the proposed version did better than the others. We may additionally infer that the proposed model is dependable for the early detection of diffusion of thought tumors after evaluating it with the other models. In this project we need to apply extra datasets from 2022. In this architecture will be done by using information collection, Pre-manner with resize and filtering of median, segmentation through thresholding or clustering, and finally using an algorithm with GAN for training and augmentation of the dataset to get more accuracy.

Food for Thought: The Effects of Feeding on Neurogenesis in the Ball Python, Python regius

Introduction: Pythons are a well-studied model of postprandial physiological plasticity. Consuming a meal evokes a suite of physiological changes in pythons including one of the largest documented increases in post-feeding metabolic rates relative to resting values. However, little is known about how this plasticity manifests in the brain. Previous work has shown that cell proliferation in the python brain increases 6 days following meal consumption. This study aimed to confirm these findings and build on them in the long term by tracking the survival and maturation of these newly created cells across a 2-month period. Methods: We investigated differences in neural cell proliferation in ball pythons 6 days after a meal with immunofluorescence using the cell-birth marker 5-bromo-12′-deoxyuridine (BrdU). We investigated differences in neural cell maturation in ball pythons 2 months after a meal using double immunofluorescence for BrdU and a reptilian ortholog of the neuronal marker Fox3. Results: We did not find significantly greater rates of cell proliferation in snakes 6 days after feeding, but we did observe more new cells in neurogenic regions in fed snakes 2 months after the meal. Feeding was not associated with higher rates of neurogenesis, but snakes that received a meal had higher numbers of newly created nonneuronal cells than fasted controls. We documented particularly high cell survival rates in the olfactory bulbs and lateral cortex. Conclusion: Consuming a meal stimulates cell proliferation in the brains of ball pythons after digestion is complete, although this effect emerged at a later time point in this study than expected. Higher rates of proliferation partially account for greater numbers of newly created non-neuronal cells in the brains of fed snakes 2 months after the meal, but our results also suggest that feeding may have a mild neuroprotective effect. We captured a slight trend toward higher cell survival rates in fed snakes, and survival rates were particularly high in brain regions associated with olfactory perception and processing. These findings shed light on the relationship between energy balance and the creation of new neural cells in the brains of ball pythons.

The effects of nutrient-induced quiescence on neural stem cell proliferation in the Drosophila central brain

In the fruit fly, neural stem cells (neuroblasts) residing within a specialized brain niche divide throughout development to produce the adult CNS. Neuroblasts normally transition between a proliferative or quiescent state during development, and this balance is critical for proper tissue growth and neuron production. NBs enter quiescence at the end of embryogenesis when maternal nutrient stores are depleted and reactivate proliferation soon after freshly hatched larvae consume their first meal. This reactivation is regulated by a nutritional checkpoint that requires dietary amino acids. Neuroblasts in larvae maintained on a diet lacking amino acids halt proliferation and production of neurons for extended periods of time, and this state is reversible after reintroduction of amino acids to their diet. Presumably this developmental plasticity is an adaptation that allows mobile larvae to secure another nutrient source, but the extent to which such a delay affects the structure and function of the adult CNS has not been investigated. We used our previously established nutrient deprivation model to halt neuroblast proliferation in larvae for a prolonged period. Using confocal microscopy, we measured the effect of this treatment on both the number of mitotic neuroblasts and how many daughter cells they produced. Both measures of neuroblast proliferation were reduced in delayed larvae compared to controls, despite having access to dietary nutrients for the same amount of time. These results elucidate an uninvestigated aspect of plasticity in the developing CNS and lay the foundation for further functional study of adult brains.

Influence of Graphene-Based Nanocomposites in Neurogenesis and Neuritogenesis: A Brief Summary.

Graphene is a prospective candidate for various biomedical applications, including drug transporters, bioimaging agents, and scaffolds for tissue engineering, thanks to its superior electrical conductivity and biocompatibility. The clinical issue of nerve regeneration and rehabilitation still has a major influence on people's lives. Nanomaterials based on graphene have been exploited extensively to promote nerve cell differentiation and proliferation. Their high electrical conductivity and mechanical robustness make them appropriate for nerve tissue engineering. Combining graphene with other substances, such as biopolymers, may transmit biochemical signals that support brain cell division, proliferation, and regeneration. The utilization of nanocomposites based on graphene in neurogenesis and neuritogenesis is the primary emphasis of this review. Here are some examples of the many synthetic strategies used. For neuritogenesis and neurogenesis, it has also been explored to combine electrical stimulation with graphene-based materials.

Molecular pathways underlying lung-brain axis signaling in asthma: Relevance for psychopathology and neuroinflammation

Accumulating evidence indicates that asthma has systemic effects and affects brain function. Although airway inflammation is proposed to initiate afferent communications with the brain, the signaling pathways have not been established. We sought to identify the cellular and molecular pathways involved in afferent lung-brain communication during airway inflammation in asthma. In 23 adults with mild asthma, segmental bronchial provocation with allergen (SBP-Ag) was used to provoke airway inflammation and retrieve bronchoalveolar lavage fluid for targeted protein analysis and RNA sequencing to determine gene expression profiles. Neural responses to emotional cues in nodes of the salience network were assessed with functional magnetic resonance imaging at baseline and 48 hours after SBP-Ag. Cell deconvolution and gene coexpression network analysis identified 11 cell-associated gene modules that changed in response to SBP-Ag. SBP-Ag increased bronchoalveolar lavage eosinophils and expression of an eosinophil-associated module enriched for genes related to TH17-type inflammation (eg, IL17A), as well as cell proliferation in lung and brain (eg, NOTCH1, VEGFA, and LIF). Increased expression of genes in this module, as well as several TH17-type inflammation-related proteins, was associated with an increase from baseline in salience network reactivity. Our results identify a specific inflammatory pathway linking asthma-related airway inflammation and emotion-related neural function. Systemically, TH17-type inflammation has been implicated in both depression and neuroinflammation, with impacts on long-term brain health. Thus, our data emphasize that inflammation in the lung in asthma may have profound effects outside of the lung that may be targetable with novel therapeutic approaches.

M2 Microglia Extracellular Vesicle miR-124 Regulates Neural Stem Cell Differentiation in Ischemic Stroke via AAK1/NOTCH.

Small extracellular vesicles (sEVs) derived from M2 microglia (M2-microglia-derived small extracellular vesicles [M2-sEVs]) contribute to central nervous system repair, although the underlying mechanism remains unknown. In this study, we aimed to identify the mechanism through which microRNA-124 (miR-124) carried in sEVs promotes neural stem cell (NSC) proliferation and neuronal differentiation in the ischemic mouse brain. M2-sEVs with or without miR-124 knockdown were injected intravenously for 7 consecutive days after transient middle cerebral artery occlusion surgery. The atrophy volume, neurological score, and degree of neurogenesis were examined at different time points after ischemic attack. NSCs treated with different sEVs were subjected to proteomic analysis. Target protein concentrations were quantified, and subsequent bioinformatic analysis was conducted to explore the key signaling pathways. M2-sEV transplantation promoted functional neurological recovery following transient middle cerebral artery occlusion injury. M2-sEV treatment decreased the brain atrophy volume, neurological score, and mortality rate. The effect was reserved by knockdown of miR-124 in M2-sEVs. M2-sEVs promoted proliferation and differentiation of mature neuronal NSCs in vivo. Proteomic analysis of NSC samples treated with M2-sEVs with and without miR-124 knockdown revealed that AAK1 (adaptor-associated protein kinase 1) was the key responding protein in NSCs. The binding of AAK1 to Notch promoted the differentiation of NSCs into neurons rather than astrocytes. Our data suggest that AAK1/Notch is the key pathway in NSCs that responds to the miR-124 carried within M2-sEVs in the ischemic brain. M2-sEVs carrying ample quantities of miR-124 promote functional recovery after ischemic stroke by enhancing NSC proliferation and differentiation. Targeting of M2-sEVs could represent a potential therapeutic strategy for brain recovery.

Extract from the paralyzed spinal cord of rats enhances neural stem cell proliferation in the neonatal rat brain by upregulating the Notch1/Hes1 pathway.

Extract from the paralyzed spinal cord of rats enhances neural stem cell proliferation in the neonatal rat brain by upregulating the Notch1/Hes1 pathway.

A Deep Analysis of Brain Tumor Detection from MR Images Using Deep Learning Networks

Creating machines that behave and work in a way similar to humans is the objective of artificial intelligence (AI). In addition to pattern recognition, planning, and problem-solving, computer activities with artificial intelligence include other activities. A group of algorithms called “deep learning” is used in machine learning. With the aid of magnetic resonance imaging (MRI), deep learning is utilized to create models for the detection and categorization of brain tumors. This allows for the quick and simple identification of brain tumors. Brain disorders are mostly the result of aberrant brain cell proliferation, which can harm the structure of the brain and ultimately result in malignant brain cancer. The early identification of brain tumors and the subsequent appropriate treatment may lower the death rate. In this study, we suggest a convolutional neural network (CNN) architecture for the efficient identification of brain tumors using MR images. This paper also discusses various models such as ResNet-50, VGG16, and Inception V3 and conducts a comparison between the proposed architecture and these models. To analyze the performance of the models, we considered different metrics such as the accuracy, recall, loss, and area under the curve (AUC). As a result of analyzing different models with our proposed model using these metrics, we concluded that the proposed model performed better than the others. Using a dataset of 3264 MR images, we found that the CNN model had an accuracy of 93.3%, an AUC of 98.43%, a recall of 91.19%, and a loss of 0.25. We may infer that the proposed model is reliable for the early detection of a variety of brain tumors after comparing it to the other models.

Cell proliferation and neurogenesis in the adult telencephalon of the newt Cynops pyrrhogaster.

Urodele amphibians have the ability to regenerate several organs, including the brain. For this reason, the research on neurogenesis in these species after ablation of some parts of the brain has markedly progressed. However, detailed information on the characteristics and fate of proliferated cells as well as the function of newly generated neurons under normal conditions is still limited. In this study, we focused on investigating the proliferative and neurogenic zones as well as the fate of proliferated cells in the adult brain of the Japanese red-bellied newt to clarify the significance of neurogenesis in adulthood. We found that the proximal region of the lateral ventricles in the telencephalon and the preoptic area in the diencephalon were the main sites for continuous cell proliferation in the adult brain. Furthermore, we characterized proliferative cells and analyzed neurogenesis through a combination of 5-ethynyl-2'-deoxyuridine (EdU) labeling and immunohistochemistry using antibodies against the stem cell marker Sox2 and neuronal marker NeuN. Twenty-four hoursafter EdU injection, most of the EdU-positive cells were Sox2-immunopositive, whereas, EdU-positive signals and NeuN-immunoreactivities were not colocalized. Two months after EdU injection, the colocalization ratio of EdU-positive signals with Sox2-immunoreactivities decreased to approximately 10%, whereas the ratio of colocalization of EdU-positive signals with NeuN-immunoreactivities increased to approximately 60%. Furthermore, a portion of the EdU-incorporated cells developed into γ-aminobutyric acid-producing cells, which are assumed to function as interneurons. On the basis of these results, the significance of newly generated neurons was discussed with special reference to their reproductive behavior.

Physical and social enrichment influences the adaptability-related behaviors of black rockfish Sebastes schlegelii: An effect mediated by social behaviors, HPI axis and neurogenesis

Environmental enrichment is a promising method to increase fish ecological fitness in hatchery release and to improve fish welfare in the aquaculture industry. However, little is known about the effects of physical and social enrichment on fish behavioral development and the relevant regulatory mechanisms. To address this knowledge gap, a typical aquaculture fish, black rockfish Sebastes schlegelii, was exposed to contrasting environments (i.e., physically enriched environment vs. barren environment, and socially low-density environment vs. high-density environment) for six weeks. Subsequently, the adaptability-related behaviors and social interactions during the captive period were determined, and stress-related physiological parameters and neurogenesis-related gene markers were measured. In general, the fish from an enriched environment expressed significantly higher sheltering propensity and anti-predator ability while less risk-taking frequency than the fish from a barren environment. And meanwhile, the fish from a low-density environment presented significantly less risk-taking behavior and more anti-predator responses than high-density fish. A structurally barren environment significantly increased fish aggressive frequency and locomotor activity compared with an enriched environment, whereas the social environment did not affect fish social interactions. For physiological status, the hypothalamus-pituitary-interrenal (HPI) axis and corticosteroid receptor system activities of barren fish were significantly higher than those of enriched fish, and meanwhile, the high-density fish also presented significantly higher physiological stress than low-density fish. For neurogenesis processes, an enriched environment did not affect fish brain cell proliferation but increased telencephalon neuronal differentiation ratio and immature neuron number. In contrast, a low-density environment significantly stimulated cell proliferating activity in telencephalon but did not affect brain neuronal differentiation activity. These novel results verified the conspicuous effects of physical and social environments on the adaptability-related behaviors in aquaculture fish, and finally, we proposed a novel regulatory pathway for fish behavioral plasticity, i.e., environmental stimuli - social interactions - HPI axis - corticosteroid receptor system - neurogenesis - adaptability-related behaviors. These results may lay the foundations for restoring fishery resources and for improving fish welfare, add novel knowledge to fish biology and environmental enrichment framework, and help deeply understand the mechanisms of environmental effects on marine animal behaviors.

Social Enhancement of Adult Neurogenesis in Zebrafish is Not Regulated by Cortisol

In Mammals adult neurogenesis is influenced by environmental conditions, and the glucocorticoid hormones (GC) play a major role in this regulation. In contrast in fish, the study of the effects of cortisol on the regulation of environmental driven adult neurogenesis has produced conflicting results. While in some species elevated cortisol levels impair cell proliferation, in others, it promotes cell proliferation and differentiation. This lack of consistency may be explained by methodological differences across studies, namely in the stimuli and/or cortisol treatments used. Here, we tested the effects of the social environment on adult neurogenesis, considering a positive and a negative social context, and different durations of cortisol exposure. We hypothesise that there is an interaction between the valence of the social environment and cortisol, such that elevated acute cortisol experienced during social interactions only have a detrimental effect on neurogenesis in negative social contexts. Therefore, fish were exposed to a positive (conspecific shoal) or negative (predator) social experience, and the interaction between the valence of the social context and cortisol exposure (acute and chronic) was tested. Our results indicate that adult neurogenesis is modulated by the social environment, with the number of newly generated cells being dependent on the valence of the social information (positive > negative). These effects were independent of cortisol, either for acute or chronic exposure, highlighting the social environment as a key factor in the modulation of cell proliferation in the adult zebrafish brain, and rejecting a role for cortisol in this modulation.

Using AI-Based Evolutionary Algorithms to Elucidate Adult Brain Tumor (Glioma) Etiology Associated with IDH1 for Therapeutic Target Identification.

Adult brain tumors (glioma) represent a cancer of unmet need where standard-of-care is non-curative; thus, new therapies are urgently needed. It is unclear whether isocitrate dehydrogenases (IDH1/2) when not mutated have any role in gliomagenesis or tumor growth. Nevertheless, IDH1 is overexpressed in glioblastoma (GBM), which could impact upon cellular metabolism and epigenetic reprogramming. This study characterizes IDH1 expression and associated genes and pathways. A novel biomarker discovery pipeline using artificial intelligence (evolutionary algorithms) was employed to analyze IDH-wildtype adult gliomas from the TCGA LGG-GBM cohort. Ninety genes whose expression correlated with IDH1 expression were identified from: (1) All gliomas, (2) primary GBM, and (3) recurrent GBM tumors. Genes were overrepresented in ubiquitin-mediated proteolysis, focal adhesion, mTOR signaling, and pyruvate metabolism pathways. Other non-enriched pathways included O-glycan biosynthesis, notch signaling, and signaling regulating stem cell pluripotency (PCGF3). Potential prognostic (TSPYL2, JAKMIP1, CIT, TMTC1) and two diagnostic (MINK1, PLEKHM3) biomarkers were downregulated in GBM. Their gene expression and methylation were negatively and positively correlated with IDH1 expression, respectively. Two diagnostic biomarkers (BZW1, RCF2) showed the opposite trend. Prognostic genes were not impacted by high frequencies of molecular alterations and only one (TMTC1) could be validated in another cohort. Genes with mechanistic links to IDH1 were involved in brain neuronal development, cell proliferation, cytokinesis, and O-mannosylation as well as tumor suppression and anaplerosis. Results highlight metabolic vulnerabilities and therapeutic targets for use in future clinical trials.

Contraceptive drug, Nestorone, enhances stem cell-mediated remodeling of the stroke brain by dampening inflammation and rescuing mitochondria

Ischemic stroke remains a significant unmet need causing massive mortality and morbidity due to few treatment options with limited therapeutic window. The progestin Nestorone® (segesterone acetate) displays high affinity for the progesterone receptor in exerting its potent birth control and hormone replacement therapy. Accumulating evidence implicates a new utility of Nestorone in affording neuroprotection in a variety of central nervous system diseases, including stroke. However, the mechanism of action mediating Nestorone's neuroprotection in stroke remains unknown. Here, we showed that stand-alone treatments of Nestorone or human amniotic fluid-derived stem cells (hAFSc), but more pronounced with their combined treatment, led to significant improvements in behavioral function and reductions in infarction and peri-infarct cell loss in adult rats with ischemic stroke. We detected significantly lower levels of pro-inflammatory signals (OX6 and IBA1) coupled with enhanced levels of stem cell proliferation (Ki67) and differentiation (DCX and MAP2) in both brain and spleen of stroke rats that received stand-alone or combined treatments of Nestorone and hAFSc. In concert, the in vitro oxygen-glucose deprivation stroke model revealed that neural stem cells treated with Nestorone exhibited increased stem cell proliferation and differentiation that was accompanied by rescue of the mitochondrial respiratory activity characterized by reduced mitochondrial reactive oxygen species, increased ATP, elevated mitochondrial deacetylase Sirtuin 3 (SIRT3), and a normalized ratio of acetyl-superoxide dismutase 2 (Ac-SOD2)/SOD2, suggesting the key role of mitochondrial metabolism and oxidative protection in Nestorone's therapeutic effects in stroke.

Tetrabromobisphenol A Disturbs Brain Development in Both Thyroid Hormone-Dependent and -Independent Manners in Xenopus laevis.

Although tetrabromobisphenol A (TBBPA) has been well proven to disturb TH signaling in both in vitro and in vivo assays, it is still unclear whether TBBPA can affect brain development due to TH signaling disruption. Here, we employed the T3-induced Xenopus metamorphosis assay (TIXMA) and the spontaneous metamorphosis assay to address this issue. In the TIXMA, 5–500 nmol/L TBBPA affected T3-induced TH-response gene expression and T3-induced brain development (brain morphological changes, cell proliferation, and neurodifferentiation) at premetamorphic stages in a complicated biphasic concentration-response manner. Notably, 500 nmol/L TBBPA treatment alone exerted a stimulatory effect on tadpole growth and brain development at these stages, in parallel with a lack of TH signaling activation, suggesting the involvement of other signaling pathways. As expected, at the metamorphic climax, we observed inhibitory effects of 50–500 nmol/L TBBPA on metamorphic development and brain development, which was in agreement with the antagonistic effects of higher concentrations on T3-induced brain development at premetamorphic stages. Taken together, all results demonstrate that TBBPA can disturb TH signaling and subsequently interfere with TH-dependent brain development in Xenopus; meanwhile, other signaling pathways besides TH signaling could be involved in this process. Our study improves the understanding of the effects of TBBPA on vertebrate brain development.