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Cancers Apr 2024So far, the cellular origin of glioblastoma (GBM) needs to be determined, with prevalent theories suggesting emergence from transformed endogenous stem cells. Adult...
So far, the cellular origin of glioblastoma (GBM) needs to be determined, with prevalent theories suggesting emergence from transformed endogenous stem cells. Adult neurogenesis primarily occurs in two brain regions: the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Whether the proximity of GBM to these neurogenic niches affects patient outcome remains uncertain. Previous studies often rely on subjective assessments, limiting the reliability of those results. In this study, we assessed the impact of GBM's relationship with the cortex, SVZ and SGZ on clinical variables using fully automated segmentation methods. In 177 glioblastoma patients, we calculated optimal cutpoints of minimal distances to the SVZ and SGZ to distinguish poor from favorable survival. The impact of tumor contact with neurogenic zones on clinical parameters, such as overall survival, multifocality, MGMT promotor methylation, Ki-67 and KPS score was also examined by multivariable regression analysis, chi-square test and Mann-Whitney-U. The analysis confirmed shorter survival in tumors contacting the SVZ with an optimal cutpoint of 14 mm distance to the SVZ, separating poor from more favorable survival. In contrast, tumor contact with the SGZ did not negatively affect survival. We did not find significant correlations with multifocality or MGMT promotor methylation in tumors contacting the SVZ, as previous studies discussed. These findings suggest that the spatial relationship between GBM and neurogenic niches needs to be assessed differently. Objective measurements disprove prior assumptions, warranting further research on this topic.
PubMed: 38730694
DOI: 10.3390/cancers16091743 -
Journal of Biomedical Science May 2024Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level,...
BACKGROUND
Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level, increased CTSS levels have been associated with the secretion of pro-inflammatory cytokines and disrupted the homeostasis of Ca flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions.
METHODS
We conducted classic Y-maze and Barnes Maze tests to assess the spatial and working memory of Ctss mice, Ctss mice and Ctss mice injected with the CTSS inhibitor (RJW-58). Ex vivo analyses including long-term potentiation (LTP), Golgi staining, immunofluorescence staining of sectioned whole brain tissues obtained from experimental animals were conducted. Furthermore, molecular studies were carried out using cultured HT-22 cell line and primary cortical neurons that treated with RJW-58 to comprehensively assess the gene and protein expressions.
RESULTS
Our findings reported that targeting cathepsin S (CTSS) yields improvements in cognitive function, enhancing both working and spatial memory in behavior models. Ex vivo studies showed elevated levels of long-term potentiation levels and increased synaptic complexity. Microarray analysis demonstrated that brain-derived neurotrophic factor (BDNF) was upregulated when CTSS was knocked down by using siRNA. Moreover, the pharmacological blockade of the CTSS enzymatic activity promoted BDNF expression in a dose- and time-dependent manner. Notably, the inhibition of CTSS was associated with increased neurogenesis in the murine dentate gyrus. These results suggested a promising role of CTSS modulation in cognitive enhancement and neurogenesis.
CONCLUSION
Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS.
Topics: Animals; Male; Mice; Brain-Derived Neurotrophic Factor; Cathepsins; Cognition; Mice, Knockout; Receptor, trkB; Trans-Activators
PubMed: 38725007
DOI: 10.1186/s12929-024-01037-2 -
Scientific Reports May 2024Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus-pituitary-adrenal... (Randomized Controlled Trial)
Randomized Controlled Trial
Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus-pituitary-adrenal (HPA) axis. To examine this in humans, hippocampal volume and hypothalamus (HPA axis) metabolism was quantified in participants with MDD before and after antidepressant treatment. 65 participants (n = 24 males, n = 41 females) with MDD were treated in a double-blind, randomized clinical trial of escitalopram. Participants received simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) before and after treatment. Linear mixed models examined the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism. Chi-squared tests and multivariable logistic regression examined the association between hippocampus/dentate gyrus volume change direction and hypothalamus activity change direction with treatment. Multiple linear regression compared these changes between remitter and non-remitter groups. Covariates included age, sex, and treatment type. No significant linear association was found between hippocampus/dentate gyrus volume and hypothalamus metabolism. 62% (38 of 61) of participants experienced a decrease in hypothalamus metabolism, 43% (27 of 63) of participants demonstrated an increase in hippocampus size (51% [32 of 63] for the dentate gyrus) following treatment. No significant association was found between change in hypothalamus activity and change in hippocampus/dentate gyrus volume, and this association did not vary by sex, medication, or remission status. As this multimodal study, in a cohort of participants on standardized treatment, did not find an association between hypothalamus metabolism and hippocampal volume, it supports a more complex pathway between hippocampus neurogenesis and hypothalamus metabolism changes in response to treatment.
Topics: Humans; Depressive Disorder, Major; Male; Female; Hypothalamus; Adult; Hippocampus; Magnetic Resonance Imaging; Middle Aged; Double-Blind Method; Positron-Emission Tomography; Dentate Gyrus; Citalopram; Hypothalamo-Hypophyseal System; Organ Size
PubMed: 38724691
DOI: 10.1038/s41598-024-61519-z -
Behavioural Brain Research Jun 2024Hippocampus is essential for episodic memory formation, lesion studies demonstrating its role especially in processing spatial and temporal information. Further, adult...
Hippocampus is essential for episodic memory formation, lesion studies demonstrating its role especially in processing spatial and temporal information. Further, adult hippocampal neurogenesis (AHN) in the dentate gyrus (DG) has also been linked to learning. To study hippocampal neuronal activity during events like learning, in vivo calcium imaging has become increasingly popular. It relies on the use of adeno-associated viral (AAV) vectors, which seem to lead to a decrease in AHN when applied on the DG. More notably, imaging requires the implantation of a relatively large lens into the tissue. Here, we examined how injection of an AAV vector and implantation of a 1-mm-diameter lens into the dorsal DG routinely used to image calcium activity impact the behavior of adult male C57BL/6 mice. To this aim, we conducted open-field, object-recognition and object-location tasks at baseline, after AAV vector injection, and after lens implantation. Finally, we determined AHN from hippocampal slices using a doublecortin-antibody. According to our results, the operations needed for in vivo imaging of the dorsal DG did not have adverse effects on behavior, although we noticed a decrease in AHN ipsilaterally to the operations. Thus, our results suggest that in vivo imaging can be safely used to, for example, correlate patterns of calcium activity with learned behavior. One should still keep in mind that the defects on the operated side might be functionally compensated by the (hippocampus in the) contralateral hemisphere.
Topics: Animals; Neurogenesis; Male; Mice, Inbred C57BL; Hippocampus; Mice; Calcium; Behavior, Animal; Recognition, Psychology; Dentate Gyrus; Dependovirus; Genetic Vectors; Functional Laterality
PubMed: 38723676
DOI: 10.1016/j.bbr.2024.115042 -
Pharmacological Reports : PR Jun 2024Synthetic cathinones (SC) constitute the second most frequently abused class of new psychoactive substances. They serve as an alternative to classic psychostimulatory...
BACKGROUND
Synthetic cathinones (SC) constitute the second most frequently abused class of new psychoactive substances. They serve as an alternative to classic psychostimulatory drugs of abuse, such as methamphetamine, cocaine, or 3,4-methylenedioxymethamphetamine (MDMA). Despite the worldwide prevalence of SC, little is known about their long-term impact on the central nervous system. Here, we examined the effects of repeated exposure of mice during infancy, to 3,4-methylenedioxypyrovalerone (MDPV), a SC potently enhancing dopaminergic neurotransmission, on learning and memory in young adult mice.
METHODS
All experiments were performed on C57BL/6J male and female mice. Animals were injected with MDPV (10 or 20 mg/kg) and BrdU (bromodeoxyuridine, 25 mg/kg) during postnatal days 11-20, which is a crucial period for the development of their hippocampus. At the age of 12 weeks, mice underwent an assessment of various types of memory using a battery of behavioral tests. Afterward, their brains were removed for detection of BrdU-positive cells in the dentate gyrus of the hippocampal formation with immunohistochemistry, and for measurement of the expression of synaptic proteins, such as synaptophysin and PSD95, in the hippocampus using Western blot.
RESULTS
Exposure to MDPV resulted in impairment of spatial working memory assessed with Y-maze spontaneous alternation test, and of object recognition memory. However, no deficits in hippocampus-dependent spatial learning and memory were found using the Morris water maze paradigm. Consistently, hippocampal neurogenesis and synaptogenesis were not interrupted. All observed MDPV effects were sex-independent.
CONCLUSIONS
MDPV administered repeatedly to mice during infancy causes learning and memory deficits that persist into adulthood but are not related to aberrant hippocampal development.
Topics: Animals; Benzodioxoles; Synthetic Cathinone; Mice; Female; Male; Mice, Inbred C57BL; Pyrrolidines; Memory Disorders; Hippocampus; Maze Learning; Central Nervous System; Memory
PubMed: 38722542
DOI: 10.1007/s43440-024-00599-0 -
Heliyon May 2024We have recently shown delayed increases in GABA receptor (GABAR) subunit protein levels in the hippocampal dentate gyrus (DG), but not in the pyramidal CA1 and CA3...
We have recently shown delayed increases in GABA receptor (GABAR) subunit protein levels in the hippocampal dentate gyrus (DG), but not in the pyramidal CA1 and CA3 regions, at 15-30 days after the systemic single administration of trimethyltin (TMT) in mice. An attempt was thus made to determine whether the delayed increases return to the control levels found in naive mice afterward. In the DG on hippocampal slices obtained at 90 days after the administration, however, marked increases were still seen in protein levels of both GABAR1 and GABAR2 subunits without significant changes in calbindin and glial fibrillary acidic protein (GFAP) levels on immunoblotting analysis. Fluoro-Jade B staining clearly revealed the absence of degenerated neurons from the DG at 90 days after the administration. Although co-localization was invariably detected between GABAR2 subunit and GFAP in the DG at 30 days on immunohistochemical analysis, GABAR2-positive cells did not merge well with GFAP-positive cells in the DG at 90 days. These results suggest that both GABAR1 and GABAR2 subunits would be tardily and sustainably up-regulated by cells other than neurons and astrocytes in the murine DG at 90 days after a systemic single injection of TMT.
PubMed: 38720739
DOI: 10.1016/j.heliyon.2024.e29713 -
Biochemical Pharmacology Jul 2024Relaxin-family peptide 3 receptor (RXFP3) is activated by relaxin-3 in the brain to influence arousal and related functions, such as feeding and stress responses. Two...
Relaxin-family peptide 3 receptor (RXFP3) is activated by relaxin-3 in the brain to influence arousal and related functions, such as feeding and stress responses. Two transgenic mouse lines have recently been developed that co-express different fluorophores within RXFP3-expressing neurons: either yellow fluorescent protein (YFP; RXFP3-Cre/YFP mice) or tdTomato (RXFP3-Cre/tdTomato mice). To date, the characteristics of neurons that express RXFP3-associated fluorophores in these mice have only been investigated in the bed nucleus of the stria terminalis and the hypothalamic arcuate nucleus. To better determine the utility of these fluorophore-expressing mice for further research, we characterised the neuroanatomical distribution of fluorophores throughout the brain of these mice and compared this to the published distribution of Rxfp3 mRNA (detected by in situ hybridisation) in wildtype mice. Coronal sections of RXFP3-Cre/YFP (n = 8) and RXFP3-Cre/tdTomato (n = 8) mouse brains were imaged, and the density of fluorophore-expressing cells within various brain regions/nuclei was qualitatively assessed. Comparisons with our previously reported RXFP3 mRNA distribution revealed that of 212 brain regions that contained either fluorophore or RXFP3 mRNA, approximately half recorded densities that were within two qualitative measurements of each other (on a 9-point scale), including hippocampal dentate gyrus and amygdala subregions. However, many brain areas with likely non-authentic, false-positive, or false-negative fluorophore expression were also detected, including the cerebellum. Therefore, this study provides a guide to which brain regions should be prioritized for future study of RXFP3 in these mice, to better understand the neuroanatomy and function of this intriguing, neuronal peptide receptor.
Topics: Animals; Mice; Luminescent Proteins; Mice, Transgenic; Brain; Receptors, G-Protein-Coupled; Male; Fluorescent Dyes; Neurons; Integrases; Mice, Inbred C57BL; Red Fluorescent Protein; Bacterial Proteins
PubMed: 38714277
DOI: 10.1016/j.bcp.2024.116265 -
PLoS Biology May 2024Synaptic adhesion molecules (SAMs) are evolutionarily conserved proteins that play an important role in the form and function of neuronal synapses. Teneurins (Tenms) and...
Synaptic adhesion molecules (SAMs) are evolutionarily conserved proteins that play an important role in the form and function of neuronal synapses. Teneurins (Tenms) and latrophilins (Lphns) are well-known cell adhesion molecules that form a transsynaptic complex. Recent studies suggest that Tenm3 and Lphn2 (gene symbol Adgrl2) are involved in hippocampal circuit assembly via their topographical expression. However, it is not known whether other teneurins and latrophilins display similar topographically restricted expression patterns during embryonic and postnatal development. Here, we reveal the cartography of all teneurin (Tenm1-4) and latrophilin (Lphn1-3 [Adgrl1-3]) paralog expression in the mouse hippocampus across prenatal and postnatal development as monitored by large-scale single-molecule RNA in situ hybridization mapping. Our results identify a striking heterogeneity in teneurin and latrophilin expression along the spatiotemporal axis of the hippocampus. Tenm2 and Tenm4 expression levels peak at the neonatal stage when compared to Tenm1 and Tenm3, while Tenm1 expression is restricted to the postnatal pyramidal cell layer. Tenm4 expression in the dentate gyrus (DG) exhibits an opposing topographical expression pattern in the embryonic and neonatal hippocampus. Our findings were validated by analyses of multiple RNA-seq datasets at bulk, single-cell, and spatial levels. Thus, our study presents a comprehensive spatiotemporal map of Tenm and Lphn expression in the hippocampus, showcasing their diverse expression patterns across developmental stages in distinct spatial axes.
Topics: Animals; Hippocampus; Mice; Nerve Tissue Proteins; Receptors, Peptide; Gene Expression Regulation, Developmental; Female; Mice, Inbred C57BL; Male; Tenascin; Receptors, G-Protein-Coupled
PubMed: 38713721
DOI: 10.1371/journal.pbio.3002599 -
Heliyon May 2024Whole brain radiotherapy (WBRT) is used to improve tumor control in patients with primary brain tumors, or brain metastasis from various primary tumors to improve tumor...
Whole brain radiotherapy (WBRT) is used to improve tumor control in patients with primary brain tumors, or brain metastasis from various primary tumors to improve tumor control. However, WBRT can lead to cognitive decline in patients. We assessed whether fractionated WBRT (fWBRT) affects spontaneous behavior of mice in automated home cages and cognition (spatial memory) using the Barnes maze. Male C57Bl/6j mice received bi-lateral fWBRT at a dosage of 4 Gy/day on 5 consecutive days. In line with previous reports, immunohistochemical analysis of doublecortin positive cells in the dentate gyrus showed a profound reduction in immature neurons 4 weeks after fWBRT. Surprisingly, spontaneous behavior as measured in automated home cages was not affected. Moreover, learning and memory measured with Barnes maze, was also not affected 4-6 weeks after fWBRT. At 10-11 weeks after fWBRT a significant difference in escape latency during the learning phase, but not in the probe test of the Barnes maze was observed. In conclusion, although we confirmed the serious adverse effect of fWBRT on neurogenesis 4 weeks after fWBRT, we did not find similar profound effects on spontaneous behavior in the automated home cage nor on learning abilities as measured by the Barnes maze. The relationship between the neurobiological effects of fWBRT and cognition seems more complex than often assumed and the choice of animal model, cognitive tasks, neurobiological parameters, and experimental set-up might be important factors in these types of experiments.
PubMed: 38707355
DOI: 10.1016/j.heliyon.2024.e29947 -
Frontiers in Cellular Neuroscience 2024Retinoic acid (RA), derived from vitamin A (retinol), plays a crucial role in modulating neuroplasticity within the adult brain. Perturbations in RA signaling have been...
Retinoic acid (RA), derived from vitamin A (retinol), plays a crucial role in modulating neuroplasticity within the adult brain. Perturbations in RA signaling have been associated with memory impairments, underscoring the necessity to elucidate RA's influence on neuronal activity, particularly within the hippocampus. In this study, we investigated the cell type and sub-regional distribution of RA-responsive granule cells (GCs) in the mouse hippocampus and delineated their properties. We discovered that RA-responsive GCs tend to exhibit a muted response to environmental novelty, typically remaining inactive. Interestingly, chronic dietary depletion of RA leads to an abnormal increase in GC activation evoked by a novel environment, an effect that is replicated by the localized application of an RA receptor beta (RARβ) antagonist. Furthermore, our study shows that prolonged RA deficiency impairs spatial discrimination-a cognitive function reliant on the hippocampus-with such impairments being reversible with RA replenishment. In summary, our findings significantly contribute to a better understanding of RA's role in regulating adult hippocampal neuroplasticity and cognitive functions.
PubMed: 38694537
DOI: 10.3389/fncel.2024.1379438