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- Loera-Valencia, R, et al.
(författare)
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High levels of 27-hydroxycholesterol results in synaptic plasticity alterations in the hippocampus
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 3736-
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Tidskriftsartikel (refereegranskat)abstract
- Alterations in brain cholesterol homeostasis in midlife are correlated with a higher risk of developing Alzheimer’s disease (AD). However, global cholesterol-lowering therapies have yielded mixed results when it comes to slowing down or preventing cognitive decline in AD. We used the transgenic mouse model Cyp27Tg, with systemically high levels of 27-hydroxycholesterol (27-OH) to examine long-term potentiation (LTP) in the hippocampal CA1 region, combined with dendritic spine reconstruction of CA1 pyramidal neurons to detect morphological and functional synaptic alterations induced by 27-OH high levels. Our results show that elevated 27-OH levels lead to enhanced LTP in the Schaffer collateral-CA1 synapses. This increase is correlated with abnormally large dendritic spines in the stratum radiatum. Using immunohistochemistry for synaptopodin (actin-binding protein involved in the recruitment of the spine apparatus), we found a significantly higher density of synaptopodin-positive puncta in CA1 in Cyp27Tg mice. We hypothesize that high 27-OH levels alter synaptic potentiation and could lead to dysfunction of fine-tuned processing of information in hippocampal circuits resulting in cognitive impairment. We suggest that these alterations could be detrimental for synaptic function and cognition later in life, representing a potential mechanism by which hypercholesterolemia could lead to alterations in memory function in neurodegenerative diseases.
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- Mkrtchian, S, et al.
(författare)
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Surgical Trauma in Mice Modifies the Content of Circulating Extracellular Vesicles
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 12, s. 824696-
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Tidskriftsartikel (refereegranskat)abstract
- Surgical interventions rapidly trigger a cascade of molecular, cellular, and neural signaling responses that ultimately reach remote organs, including the brain. Using a mouse model of orthopedic surgery, we have previously demonstrated hippocampal metabolic, structural, and functional changes associated with cognitive impairment. However, the nature of the underlying signals responsible for such periphery-to-brain communication remains hitherto elusive. Here we present the first exploratory study that tests the hypothesis of extracellular vesicles (EVs) as potential mediators carrying information from the injured tissue to the distal organs including the brain. The primary goal was to investigate whether the cargo of circulating EVs after surgery can undergo quantitative changes that could potentially trigger phenotypic modifications in the target tissues. EVs were isolated from the serum of the mice subjected to a tibia surgery after 6, 24, and 72 h, and the proteome and miRNAome were investigated using mass spectrometry and RNA-seq approaches. We found substantial differential expression of proteins and miRNAs starting at 6 h post-surgery and peaking at 24 h. Interestingly, one of the up-regulated proteins at 24 h was α-synuclein, a pathogenic hallmark of certain neurodegenerative syndromes. Analysis of miRNA target mRNA and corresponding biological pathways indicate the potential of post-surgery EVs to modify the extracellular matrix of the recipient cells and regulate metabolic processes including fatty acid metabolism. We conclude that surgery alters the cargo of circulating EVs in the blood, and our results suggest EVs as potential systemic signal carriers mediating remote effects of surgery on the brain.
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- Srivastava, I, et al.
(författare)
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Blocking Astrocytic GABA Restores Synaptic Plasticity in Prefrontal Cortex of Rat Model of Depression
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:7
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Tidskriftsartikel (refereegranskat)abstract
- A decrease in synaptic plasticity and/or a change in excitation/inhibition balance have been suggested as mechanisms underlying major depression disorder. However, given the crucial role of astrocytes in balancing synaptic function, particular attention should be given to the contribution of astrocytes in these mechanisms, especially since previous findings show that astrocytes are affected and exhibit reactive-like features in depression. Moreover, it has been shown that reactive astrocytes increase the synthesis and release of GABA, contributing significantly to tonic GABA inhibition. In this study we found decreased plasticity and increased tonic GABA inhibition in the prelimbic area in acute slices from the medial prefrontal cortex in the Flinders Sensitive Line (FSL) rat model of depression. The tonic inhibition can be reduced by either blocking astrocytic intracellular Ca2+ signaling or by reducing astrocytic GABA through inhibition of the synthesizing enzyme MAO-B with Selegiline. Blocking GABA synthesis also restores the impaired synaptic plasticity in the FSL prefrontal cortex, providing a new antidepressant mechanism of Selegiline.
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- Di Martino, Elena, et al.
(författare)
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Inflammatory, metabolic, and sex-dependent gene-regulatory dynamics of microglia and macrophages in neonatal hippocampus after hypoxia-ischemia
- 2024
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Ingår i: iScience. - : CELL PRESS. - 2589-0042. ; 27:4
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Tidskriftsartikel (refereegranskat)abstract
- Neonatal hypoxia-ischemia (HI) is a major cause of perinatal death and long-term disabilities worldwide. in the hippocampi of mice subjected to HI at postnatal day 9. Using inflammatory pathway and transcripcells isolated from hippocampi showed a partial convergence. Interestingly, microglia-specific genes in but not in females during the experimental time frame. These results highlight the importance of further investigations on metabolic rewiring to pave the way for future interventions in asphyxiated neonates.
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- Qiu, Lin, 2000, et al.
(författare)
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Acute and Long-Term Effects of Brief Sevoflurane Anesthesia During the Early Postnatal Period in Rats
- 2016
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Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 149:1, s. 121-133
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Tidskriftsartikel (refereegranskat)abstract
- The possibility that exposure to general anesthetics during early life results in long-term impairment of neural function attracted considerable interest over the past decade. Extensive laboratory data suggest that administration of these drugs during critical stages of central nervous system development can lead to cell death, impaired neurogenesis, and synaptic growth as well as cognitive deficits. These observations are corroborated by several recent human epidemiological studies arguing that such cognitive impairment might also occur in humans. Despite the potential public health importance of this issue, several important questions remain open. Amongst them, how the duration of anesthesia exposure impact on outcome is as yet not fully elucidated. To gain insight into this question, here we focused on the short- and long-term impact of a 30-min-long exposure to clinically relevant concentrations of sevoflurane in rat pups at 2 functionally distinct stages of the brain growth spurt. We show that this treatment paradigm induced developmental stage-dependent and brain region-specific acute but not lasting changes in dendritic spine densities. Electrophysiological recordings in hippocampal brain slices from adult animals exposed to anesthesia in the early postnatal period revealed larger paired-pulse facilitation but no changes in the long-term potentiation paradigm when compared with nonanesthetized controls. 5-bromo-2-deoxyuridine pulse and pulse-chase experiments demonstrated that neither proliferation nor differentiation and survival of hippocampal progenitors were affected by sevoflurane exposure. In addition, behavioral testing of short- and long-term memory showed no differences between control and sevoflurane-exposed animals. Overall, these results suggest that brief sevoflurane exposure during critical periods of early postnatal development, although it does not seem to exert major long-term effects on brain circuitry development, can induce subtle changes in synaptic plasticity and spine density of which the physiological significance remains to be determined.
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