Biology subjects

Albers, E.

Publications and source records attributed to Albers, E..

6 recordsLinked to original sources

bioRxiv2025

Influence of STDP rule choice and network connectivity on polychronous groups and cell ensembles in spiking neural networks

Spike-timing dependent plasticity plays an important role in how biological neural networks modify themselves with experience. However, the relationship between STDP and memory is not fully understood. Previously, an important advancement in understanding the relationship between spike-timing dependent plasticity (STDP) and memory was made through cortical simulations. The proposed memory items, polychronous groups (PGs), combined the network anatomy with precise spike-timing relationships between the connected cells of the network. However, there are some challenges with this previous work. It is unclear how different STDP rules would impact the PG results and if the PG results are complementary with purely spike-pattern defined memory items called cell ensembles (CEs). Lastly, it is unclear how these results are affected by changes in network connectivity. We address these challenges by comparing the PGs and CEs detected in spiking neural network simulations of cortical and hippocampal CA1 networks with two different STDP rule implementations. We show that the PG and CE results differ greatly for the two different STDP rules and for the cortical and CA1 networks. Our results show an important disconnect between anatomically defined and spike-pattern defined memories in spiking neural network simulations illustrating that care must be taken when drawing conclusions on the relationship between STDP and memory in simulation studies.

neuroscience↗

bioRxiv2025

Using Information Geometry to Characterize Higher-Order Interactions in EEG

In neuroscience, methods from information geometry (IG) have been successfully applied in the modelling of binary vectors from spike train data, using the orthogonal decomposition of the Kullback-Leibler divergence and mutual information to isolate different orders of interaction between neurons. While spike train data is well-approximated with a binary model, here we apply these IG methods to data from electroencephalography (EEG), a continuous signal requiring appropriate discretization strategies. We developed and compared three different binarization methods and used them to identify third-order interactions in an experiment involving imagined motor movements. The statistical significance of these interactions was assessed using phase-randomized surrogate data that eliminated higher-order dependencies while preserving the spectral characteristics of the original signals. We validated our approach by implementing known second- and third-order dependencies in a forward model and quantified information attenuation at different steps of the analysis. This revealed that the greatest loss in information occurred when going from the idealized binary case to enforcing these dependencies using oscillatory signals. When applied to the real EEG dataset, our analysis detected statistically significant third-order interactions during the task condition despite the relatively sparse data (45 trials per condition). This work demonstrates that IG methods can successfully extract genuine higher-order dependencies from continuous neural recordings when paired with appropriate binarization schemes.

neuroscience↗

bioRxiv2024

Human iPSC-derived brain pericytes exhibit differences in inflammatory activation compared to primary human brain pericytes

BackgroundiPSC-derived cells are increasingly used to model complex diseases in vitro because they can be patient derived and can differentiate into any cell in the adult human body. Recent studies have demonstrated the generation of brain pericytes using a neural crest-based differentiation protocol. However, the inflammatory response of these iPSC-derived brain pericytes has not been investigated. We aimed to investigate the response of iPSC-derived brain pericytes to common inflammatory stimuli, thereby assessing the suitability of these cells to study inflammatory disease. MethodsBrain pericytes were differentiated from iPSCs for 42 days. The expression of brain pericyte markers was assessed by RT-qPCR and immunofluorescent staining at days 0, 15, 21, and 42 of differentiation to validate the brain pericyte-like phenotype. Nuclear localisation of NF{kappa}B and STAT1 was assessed by immunofluorescence following IL-1{beta}- and TNF-treatment in day 21 and day 42 iPSC-derived pericytes, and primary human pericytes. Cytometric bead array assessed the concentration of secreted inflammatory factors in the cell medium and phagocytosis was investigated using fluorescent carboxylated beads and flow cytometry. ResultsAt day 42 of differentiation, but not at day 21, cells expressed brain pericyte markers. Generally, iPSC-derived pericytes lacked consistent responses to inflammatory treatment compared to primary human pericytes. Day 21 and 42 iPSC-derived pericytes exhibited a NF{kappa}B response to IL-1{beta} treatment comparable to primary human pericytes. Day 21 iPSC-derived pericytes exhibited a STAT1 response with IL-1{beta} treatment which was absent in day 42 cells, but present in a subset of primary human pericytes. TNF treatment presented similar NF{kappa}B responses between day 21 and 42 iPSC-derived and primary human pericytes, but a STAT1 response was again present in a subset of primary human pericytes which was absent in both day 21 and day 42 iPSC-derived pericytes. Numerous differences were observed in the secretion of cytokines and chemokines following treatment of iPSC-derived and primary human pericytes with IL-1{beta} and TNF. iPSC-derived pericytes exhibited greater rates of phagocytosis than primary human pericytes. ConclusionsWith the increase in iPSC-derived cells in research, labs should undertake validation of lineage specificity when adapting an iPSC-derived differentiation protocol. In our hands, the inflammatory response of iPSC-derived pericytes was different to that of primary human pericytes, raising concern regarding the use of iPSC-derived pericytes to study neuroinflammatory disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/613375v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1e3612eorg.highwire.dtl.DTLVardef@1014537org.highwire.dtl.DTLVardef@6729adorg.highwire.dtl.DTLVardef@e14825_HPS_FORMAT_FIGEXP M_FIG C_FIG Brain pericytes can be generated from iPSCs. The work presented here shows the generation of phenotypically distinct pericytes from the original protocol, demonstrating the significant variability present within some iPSC differentiation protocols. Furthermore, functional differences are demonstrated between iPSC-derived brain pericytes and primary brain pericytes, revealing limitations in the use of iPSC-derived brain pericytes to model brain pericyte biology. Key PointsO_ST_ABSWhat is already known about this topic?C_ST_ABSBrain pericyte-like cells can be generated from induced pluripotent stem cells, however their responses to inflammatory stimuli has not been assessed. What does this study add?iPSC-derived brain pericytes exhibit different inflammatory responses compared to primary brain pericytes, showing that some iPSC-derived cell models are not appropriate for modelling all aspects of a cells biology. Furthermore, the iPSC-derived pericytes generated here were markedly different to those generated from the original article. It is therefore important for each lab to optimise the generation of iPSC-derived cell in their own hands to account for potential inter-lab variability.

cell biology↗

bioRxiv2024

Screening activity of brain cancer-derived factors on primary human brain pericytes

Brain cancers offer poor prognoses to patients accompanied by symptoms that drastically impact the patient and their family. Brain tumours recruit local non-transformed cells to provide trophic support and immunosuppression within the tumour microenvironment, supporting tumour progression. Given the localization and supportive role of pericytes at the brain vasculature, we explored the potential for brain pericytes to contribute to the brain cancer microenvironment. To investigate this, primary brain pericytes were treated with factors commonly upregulated in brain cancers. Changes to brain pericyte cell signalling, inflammatory secretion, and phagocytosis were investigated. The TGF{beta} superfamily cytokines TGF{beta} and GDF-15 activated SMAD2/3 and inhibited C/EBP-{delta}, revealing a potential mechanism behind the pleiotropic action of TGF{beta} on brain pericytes. IL-17 induced secretion of IL-6 without activating NF{kappa}B, STAT1, SMAD2/3, or C/EBP-{delta} signalling pathways. IL-27 and IFN{gamma} induced STAT1 signalling and significantly reduced pericyte phagocytosis. The remaining brain cancer-derived factors did not induce a measured response, indicating that these factors may act on other cell types or require co-stimulation with other factors to produce significant effects. Together, these findings show potential mechanisms by which brain pericytes contribute to aspects of inflammation and starts to uncover the supportive role brain pericytes may play in brain cancers.

cancer biology↗

bioRxiv2020

Supraphysiological protection from replication stress does not extend mammalian lifespan

Replication Stress (RS) is a type of DNA damage generated at the replication fork, characterized by single-stranded DNA (ssDNA) accumulation, and which can be caused by a variety of factors. Previous studies have reported elevated RS levels in aged cells. In addition, mouse models with a deficient RS response show accelerated aging. However, the relevance of endogenous or physiological RS, compared to other sources of genomic instability, for the normal onset of aging is unknown. We have performed long term survival studies of transgenic mice with extra copies of the Chk1 and/or Rrm2 genes, which we previously showed extend the lifespan of a progeroid ATR-hypomorphic model suffering from high levels of RS. In contrast to their effect in the context of progeria, the lifespan of Chk1, Rrm2 and Chk1/Rrm2 transgenic mice was similar to WT littermates in physiological settings. Most mice studied died due to tumors -mainly lymphomas-irrespective of their genetic background. Interestingly, a slightly higher percentage of transgenic mice developed tumors compared to WT mice. Our results indicate that supraphysiological protection from RS does not extend lifespan, indicating that RS may not be a relevant source of genomic instability on the onset of "normal" aging.

cancer biology↗

bioRxiv2020

ATR expands embryonic stem cell fate potential in response to replication stress

Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood. Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in ESCs that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated by Dux, a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) and Zscan4. This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GSRF1 dependent post-transcriptional regulation of Dux mRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extra{-}embryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS.

cell biology↗