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Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect. The DG contains a unique population of multipotent neural stem cells (NSCs) that give rise to adult newborn neurons, but oligodendrogenic potential has not been demonstrated in vivo. We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo. Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR). Together, these results suggest a novel model in which stress may alter hippocampal function by promoting oligodendrogenesis, thereby altering the cellular composition and white matter structure.

Electrophysiology has been largely used to investigate internal organs' activities and pathologies. The organs which have been investigated are the ones which base their function on electrical activity, such as heart (ECG), brain (EEG) or eye (EOG). It has been ignored that there are other electrical parameters to be taken into consideration, besides the electrical potential. In this study we examined the electrical activity of one of the less excitable organ, the liver, measuring its electrical resistance. The aim of the study was to compare the electrical resistance of the normal rat liver with the one of the intoxicated rat liver. Ten male Wistar rats were used, five of which were intoxicated with carbon tetrachloride, and five made up the control group. For measurements, we used an electrical generator of variable frequencies, three digital multimeters and two electrodes. The intensity of the electrical current was measured and, according to Ohm's law, we calculated the electrical resistance at the source's known voltage. Microsoft Excel, GraphPad and Statistica were used for statistical analysis. A pathological analysis of the rat liver has been performed; blood proteins and hepatic transaminases were also measured. The data obtained from the two groups were significantly different, corresponding to the normal and intoxicated rat livers, respectively, according to the pathological and biochemical results. Knowing the electrical behavior of normal and pathological tissues opens a path to fast and accurate intraoperatory diagnosis, ahead of the pathological biopsy result. [ABSTRACT FROM AUTHOR]

Dissection of small fetuses (less than 10 weeks of pregnancy) can be a very difficult task for the general pathologist. We propose a dissection method based on performing axial sections of the three main cavities of the body (skull, thorax and abdominal cavity), preserving most of the relations between organs. Also, this method proved to outline some elements and tissues difficult to highlight through classical autopsy, like the spinal cord or cerebral aqueducts. [ABSTRACT FROM AUTHOR]

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (tripartite motif family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2911-919, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "regulatory loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL influences LRRK2's association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 modulates LRRK2's interaction with Rab29 and prevents upregulation of LRRK2 kinase activity by Rab29 in an E3-ligase-dependent manner. Finally, TRIM1 rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, controlling its degradation, localization, binding partners, kinase activity, and cytotoxicity., (© 2022 Stormo et al.)

The in vivo distribution of 50 nm clusters of polyethylene glycol-conjugated superparamagnetic iron oxide nanoparticles (SPIONs-PEG) was conducted in this study. SPIONs-PEG were synthesized de novo, and their structure and paramagnetic behaviors were analyzed by specific methods (TEM, DLS, XRD, VSM). Wistar rats were treated with 10 mg Fe/kg body weight SPIONs-PEG and their organs and blood were examined at two intervals for short-term (15, 30, 60, 180 min) and long-term (6, 12, 24 h) exposure evaluation. Most exposed organs were investigated through light and transmission electron microscopy, and blood and urine samples were examined through fluorescence spectrophotometry. SPIONs-PEG clusters entered the bloodstream after intraperitoneal and intravenous administrations and ended up in the urine, with the highest clearance at 12 h. The skin and spleen were within normal histological parameters, while the liver, kidney, brain, and lungs showed signs of transient local anoxia or other transient pathological affections. This study shows that once internalized, the synthesized SPIONs-PEG disperse well through the bloodstream with minor to nil induced tissue damage, are biocompatible, have good clearance, and are suited for biomedical applications.

Aims: To present our initial experience and results of MRI-TRUS fusion guided prostate biopsy and assess the role of contralateral lobe systematic biopsy., Material and Method: A number of 119 patients with clinical or biochemical suspicion for prostate cancer (PCa) were included. All patients harbored at least one PIRADS score ≥ 3 lesion and underwent MRI-TRUS fusion guided biopsy, as well as a concurrent systematic biopsy. The biopsy was performed by the same operator, using a rigidregistration software system., Results: The mean age of the patients was 62.2 years. The mean pre-biopsy PSA was 9.15 ng/dl. The diagnosis rate of MRI-TRUS fusion guided biopsy was 47% for overall PCa and 29.4% for clinically significant (cs) PCa. A higher PIRADS score was significantly associated with the presence of overall and csPCa. MRI-TRUS fusion guided biopsy had a higher percentage of positive biopsy cores (51% vs 29%), higher likelihood of csPCa (OR 5.36, p=0.008) and upgrading (14.8%) in comparison with systematic biopsy but missed 6.7% csPCa. The contralateral lobe systematic biopsy could have been avoided without losing the PCa diagnosis all patients with PIRADS score 5, both in initial and repeat biopsy setting. Anterior and transitional lesions were more likely to be diagnosed only by targeted cores., Conclusion: MRI-TRUS guided prostate biopsy improves the detection of PCa, but systematic biopsy is still essential. In selected cases (PIRADS 5), contralateral lobe systematic biopsy can safely be avoided. Pre-biopsy mpMRI might reduce the number of biopsy sessions in patients with anterior and transitional lesions.

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease with pathological hallmarks including the formation of extracellular aggregates of amyloid-beta (Aβ) known as plaques and intracellular tau tangles. Coincident with the formation of Aβ plaques is recruitment and activation of glial cells to the plaque forming a plaque niche. In addition to histological data showing the formation of the niche, AD genetic studies have added to the growing appreciation of how dysfunctional glia pathways drive neuropathology, with emphasis on microglia pathways. Genomic approaches enable comparisons of human disease profiles between different mouse models informing on their utility to evaluate secondary changes to triggers such as Aβ deposition., Methods: In this study, we utilized two animal models of AD to examine and characterize the AD-associated pathology: the Tg2576 Swedish APP (KM670/671NL) and TgCRND8 Swedish plus Indiana APP (KM670/671NL + V717F) lines. We used laser capture microscopy (LCM) to isolate samples surrounding Thio-S positive plaques from distal non-plaque tissue. These samples were then analyzed using RNA sequencing., Results: We determined age-associated transcriptomic differences between two similar yet distinct APP transgenic mouse models, known to differ in proportional amyloidogenic species and plaque deposition rates. In Tg2576, human AD gene signatures were not observed despite profiling mice out to 15 months of age. TgCRND8 mice however showed progressive and robust induction of lysomal, neuroimmune, and ITIM/ITAM-associated gene signatures overlapping with prior human AD brain transcriptomic studies. Notably, RNAseq analyses highlighted the vast majority of transcriptional changes observed in aging TgCRND8 cortical brain homogenates were in fact specifically enriched within the plaque niche samples. Data uncovered plaque-associated enrichment of microglia-related genes such as ITIM/ITAM-associated genes and pathway markers of phagocytosis., Conclusion: This work may help guide improved translational value of APP mouse models of AD, particularly for strategies aimed at targeting neuroimmune and neurodegenerative pathways, by demonstrating that TgCRND8 more closely recapitulates specific human AD-associated transcriptional responses.

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.

A rare neuroendocrine tumor, the pheochromocytoma (PCC) raises problems due both the limited experience of the researchers in this field and its pathogenic mechanisms, still not fully elucidated. The malignant potential of this tumor cannot be predicted based on its macro- or microscopic aspects, but on the presence of metastases. The aims of this study were: (1) the reevaluation of data for a pertinent and complete tumor diagnostic and prognostic pattern; (2) the statistical correlation of all investigated parameters with the malignant form and the survival rate in order to obtain a possible predictor of malignancy; (3) the potential identification of initially diagnosed benign tumors that become malignant in time. The retrospective study was conducted on 17 patients diagnosed with pheochromocytoma. We investigated: the personal data, the associated neuroendocrine syndromes, the clinical, the laboratory, the macro- and microscopic data [location, size, Hematoxylin-Eosin (HE) pheochromocytoma of the adrenal gland scaled score (PASS score), and immunohistochemical aspects] and the survival rate (analyzed by Kaplan-Meier method and Log-Rank test). The influence of diagnostic parameters on malignancy was calculated taking into consideration the survival rate. By reevaluation of the 17 cases, we tried to emphasize the value of a complex diagnosis pattern for PCCs, based on the correlation between clinical data, laboratory findings and microscopic features. A significant statistical difference between benign and malignant forms was not registered, but there were parameters as age, association with neuroendocrine syndromes, PASS score and specifically Ki-67 mitotic index that had a powerful impact on the survival rate and could be consider as possible predictors of malignancy. The potential of PCC malignant transformation was revealed in our study, by two cases that have metastasized in time.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of familial and sporadic Parkinson's disease (PD). That the most prevalent mutation, G2019S, leads to increased kinase activity has led to a concerted effort to identify LRRK2 kinase inhibitors as a potential disease-modifying therapy for PD. An internal medicinal chemistry effort identified several potent and highly selective compounds with favorable drug-like properties. Here, we characterize the pharmacological properties of cis-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine (MLi-2), a structurally novel, highly potent, and selective LRRK2 kinase inhibitor with central nervous system activity. MLi-2 exhibits exceptional potency in a purified LRRK2 kinase assay in vitro (IC50 = 0.76 nM), a cellular assay monitoring dephosphorylation of LRRK2 pSer935 LRRK2 (IC50 = 1.4 nM), and a radioligand competition binding assay (IC50 = 3.4 nM). MLi-2 has greater than 295-fold selectivity for over 300 kinases in addition to a diverse panel of receptors and ion channels. Acute oral and subchronic dosing in MLi-2 mice resulted in dose-dependent central and peripheral target inhibition over a 24-hour period as measured by dephosphorylation of pSer935 LRRK2. Treatment of MitoPark mice with MLi-2 was well tolerated over a 15-week period at brain and plasma exposures >100× the in vivo plasma IC50 for LRRK2 kinase inhibition as measured by pSer935 dephosphorylation. Morphologic changes in the lung, consistent with enlarged type II pneumocytes, were observed in MLi-2-treated MitoPark mice. These data demonstrate the suitability of MLi-2 as a compound to explore LRRK2 biology in cellular and animal models., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Motherhood is accompanied by alterations in numerous nonreproductive behaviors, including learning and memory, as well as anxiety and stress regulation. These functions have been linked to adult neurogenesis in the hippocampus, but the effect of maternal experience on this brain region has not been completely explored. To determine whether the production of new hippocampal granule cells is altered during the postpartum period, we examined the number of proliferating cells and their progeny in the dentate gyrus of primiparous female rats at various time points during the postpartum period while they were caring for their offspring, as well as after weaning. Additionally, we investigated whether cell proliferation in the postpartum female is affected by the presence of offspring and nursing-induced increases in glucocorticoids. Analysis of the number of BrdU-labeled cells revealed that cell proliferation in the dentate gyrus was suppressed in lactating postpartum females until the time of weaning. This effect was temporary; a difference was detectable at 1 week after BrdU-labeling, when the majority of cells expressed a marker of immature and mature granule neurons (TuJ1) but not at 2 weeks, when most cells expressed a marker of mature neurons (NeuN). The decrease in cell proliferation was dependent on elevated basal glucocorticoid levels associated with lactation; removal of nursing pups reduced basal corticosterone levels and prevented the decrease in the number of BrdU-labeled cells. Moreover, preventing increased basal corticosterone levels by means of adrenalectomy and low-dose corticosterone replacement eliminated the reduction in cell proliferation. These findings indicate that offspring interactions inhibit adult neurogenesis through changes in adrenal steroids, and further suggest a potential mechanism for alterations in hippocampal function during the postpartum period., ((c) 2007 Wiley-Liss, Inc.)

Prolonged sleep deprivation is stressful and has been associated with adverse consequences for health and cognitive performance. Here, we show that sleep deprivation inhibits adult neurogenesis at a time when circulating levels of corticosterone are elevated. Moreover, clamping levels of this hormone prevents the sleep deprivation-induced reduction of cell proliferation. The recovery of normal levels of adult neurogenesis after chronic sleep deprivation occurs over a 2-wk period and involves a temporary increase in new neuron formation. This compensatory increase is dissociated from glucocorticoid levels as well as from the restoration of normal sleep patterns. Collectively, these findings suggest that, although sleep deprivation inhibits adult neurogenesis by acting as a stressor, its compensatory aftereffects involve glucocorticoid-independent factors.

Stress hormones have potent growth-inhibiting effects on a variety of peripheral tissues. Consistent with this general function, stress has been shown to inhibit cell proliferation and, ultimately, neurogenesis in the hippocampus. This effect appears to be common across mammalian species, life stages, and most types of stressors. Although some evidence points to a role for glucocorticoids in mediating this effect, contradictory data exist. This review considers the growing literature on this subject with specific emphasis on paradoxical findings and the role of glucocorticoids in modulating adult neurogenesis., ((c) 2006 Wiley-Liss, Inc.)

Maternal deprivation produces persistent abnormalities in behavioral and neuroendocrine functions associated with the hippocampus, a brain region that shows considerable structural change in response to experience throughout life. Here we show that adverse experience early in life affects the regulation of adult neurogenesis in the hippocampus. More specifically, a decrease in cell proliferation and immature neuron production are observed in the dentate gyrus of adult rats that are maternally separated as pups. Although maternally separated rats show normal basal levels of corticosterone, the suppression of cell proliferation in these rats can be reversed by lowering corticosterone below the control value. In addition, normal stress-induced suppression of cell proliferation and neurogenesis, despite normal activation of the hypothalamic pituitary adrenal (HPA) axis, is not observed in maternally separated rats. Our results suggest that early adverse experience inhibits structural plasticity via hypersensitivity to glucocorticoids and diminishes the ability of the hippocampus to respond to stress in adulthood.

St. John's wort is widely used as an herbal remedy for depression. Although its mechanism of action remains unknown, some evidence suggests that St. John's wort might act via brain serotonin (e.g., as a serotonin reuptake inhibitor). To determine whether St. John's wort affects the central serotonergic system, we monitored the discharge rate of serotonin-containing neurons in the dorsal raphe nucleus of awake cats following systemic administration of two clinical preparations of St. John's wort, Jarsin 300 (15-600 mg/kg, p.o.) and Hyperforat (0.5-4.0 ml, i.v.). Both preparations were found to have no effect on neuronal activity. This contrasts sharply with the action of fluoxetine and sertraline (2 mg/kg, p.o.), two selective serotonin reuptake inhibitors (SSRIs), which markedly depressed neuronal activity by increasing the synaptic availability of serotonin at inhibitory somatodendritic 5-HT(1A) autoreceptors. The failure of St. John's wort to depress neuronal activity cannot be attributed to an impairment of the 5-HT(1A) autoreceptor mechanism, since pretreatment with Jarsin 300 (300 mg/kg, p.o.) did not alter the responsiveness of serotonergic neurons to the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (10 microg/kg, i.v.). Overall, these findings indicate that the mode of action of St. John's wort is different from that of conventional antidepressant drugs, which elevate brain serotonin and evoke negative feedback control of serotonergic neurons.