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Auer, N.

Publications and source records attributed to Auer, N..

4 recordsLinked to original sources

Population sparseness determines strength of Hebbian plasticity for maximal memory lifetime in associative networks

The brain can efficiently learn and form memories based on limited exposure to stimuli. One key factor believed to support this ability is sparse coding, which can reduce overlap between representations and minimize interference. It is well known that increased sparseness can enhance memory capacity, yet its impact on the speed of learning remains poorly understood. Here we analyze the relationship between population sparseness and learning speed -- specifically, how the learning speed that maximizes memory capacity depends on the sparseness of the neural code, and how this in turn affects the networks maximal capacity. To this end, we study a feedforward network with Hebbian and homeostatic plasticity and a two-state synapse model. The network learns to associate binary input-output pattern pairs, where sparseness corresponds to a small fraction of active neurons per pattern. The learning speed is modeled as the probability of synaptic changes during learning. The results presented in this manuscript are based on both network simulations and an analytical theory that predicts expected memory capacity and optimal learning speed. For both perfect and noisy retrieval cues, we find that the optimal learning speed indeed increases with increasing pattern sparseness -- an effect that is more pronounced for input sparseness than for output sparseness. Interestingly, the optimal learning speed stays the same across different network sizes if the number of active units in an input pattern is kept constant. While the capacity obtained at optimal learning speed increases monotonically with output sparseness, its dependence on input sparseness is non-monotonic. Overall, we provide the first detailed investigation of the interactions between population sparseness, learning speed, and storage capacity. Our findings propose that differences in population sparseness across brain regions may underlie observed differences in how quickly those regions adapt and learn. Author summaryThe brain can efficiently learn and form memories based on limited exposure to stimuli. One key factor believed to support this ability is the way neural circuits encode and organize information about the external world. Population sparseness refers to the phenomenon in which, in many brain regions, only a small subset of neurons is active at any given time or in response to a particular stimulus. Sparse codes are believed to reduce overlap between representations and minimize interference and can thus enhance the storage capacity of a network. Here we investigate the effect of population sparseness on the speed of learning input-output associations in a network model with Hebbian learning. We find that the learning speed that yields the maximal capacity increases with increasing sparseness. The maximal capacity increases for sparser input and output representations but in the first case only up to a certain point before sparseness becomes destructive. These findings could contribute to explaining why some brain regions learn faster than others.

neuroscience↗

LOSS OF ROR2 TYROSINE KINASE RECEPTOR IS ASSOCIATED WITH ENDOTHELIAL DYSFUNCTION IN PAH VIA INAPPROPRIATE INTEGRIN BETA 1 ACTIVATION

RationaleEndothelial dysfunction is a key feature of pulmonary arterial hypertension (PAH). We previously identified Wnt7a, a ligand of the Wnt planar cell polarity (PCP) pathway, as essential for pulmonary angiogenesis, with its loss linked to PAH. Given the importance of Wnt/PCP to lung endothelial function and angiogenesis, our goal is to elucidate how Wnt/PCP regulates angiogenic responses in pulmonary microvascular endothelial cells (PMVECs). ROR2, a tyrosine kinase receptor specific to Wnt/PCP, is crucial for cardiovascular development, but its role in PAH is unclear. We hypothesized that ROR2 supports endothelial homeostasis, and its loss would impair angiogenesis, contributing to PAH. MethodsEndothelial-specific ROR2 knockout (ROR2 ECKO) and wild-type (WT) mice were studied under normoxia and chronic hypoxia using echocardiography, hemodynamics, and lung morphometry. PMVECs from healthy and PAH lungs were transfected with ROR2 siRNA/constructs for functional and molecular studies. Focal adhesion (FA) activation and force generation were assessed via FRET-based methods. Bulk and single-cell transcriptomic analyses were performed on siROR2 PMVECs and ROR2 ECKO lungs. ResultsROR2 ECKO mice exhibited worsened pulmonary hypertension, right ventricular remodeling, microvascular loss, and muscularization in hypoxia. Single-cell RNA sequencing of lung endothelial cells showed dysregulation of pathways involved in barrier formation and angiogenesis. Evans blue dye extravasation confirmed reduced endothelial barrier integrity in ROR2 ECKO mice. ROR2-deficient PAH PMVECs displayed increased adhesion, permeability, and FA numbers, with reduced VE-cadherin at cell junctions. Confocal imaging revealed ROR2 localization in FAs, interacting with integrin {beta}1 (ITGB1). FRET analysis showed that ITGB1 remained in an active, adhesion-promoting state in ROR2-deficient cells. Restoring ROR2 in PAH PMVECs normalized adhesion, barrier function, and FA abundance. Transcriptomic analysis identified Rab12 as a key mediator of ROR2-ITGB1 crosstalk, with Rab12 knockdown mimicking ROR2 deficiency in PMVECs. ConclusionsROR2 regulates pulmonary angiogenesis by maintaining endothelial barrier integrity and facilitating integrin recycling. Restoring ROR2 signaling could be a potential therapeutic approach for PAH.

cell biology↗

CES1 DEFICIENCY IS ASSOCIATED WITH METABOLIC REPROGRAMING AND ENDOTHELIAL DYSFUNCTION IN PULMONARY ARTERIAL HYPERTENSION

BackgroundPulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary microvascular loss and obliterative remodeling, driven by metabolic reprogramming, oxidative stress, and endothelial dysfunction. While BMPR2 mutations contribute to metabolic shifts in pulmonary microvascular endothelial cells (PMVECs), their low penetrance suggests additional genetic modifiers play a role. A genetic screen of PAH PMVECs identified carboxylesterase 1 (CES1)--an endoplasmic reticulum (ER) enzyme involved in lipid metabolism and detoxification--as a candidate regulator of endothelial metabolism and angiogenesis. We hypothesize that CES1 loss promotes endothelial dysfunction via metabolic reprogramming, lipotoxicity, and oxidative stress. MethodsPAH and healthy PMVECs and lung tissues were obtained from transplant donors and commercial sources. CES1 expression was modulated in PMVECs using siRNA knockdown and plasmid overexpression. Mitochondrial and ER function were assessed via confocal microscopy and proteomics. CES1 heterozygous knockout (HET KO) and endothelial-specific knockout (ECKO) mice were exposed to normoxia or hypoxia, with lung tissues analyzed by single-cell RNA sequencing (scRNA-seq) and histopathology. ResultsCES1 expression was significantly reduced in PAH PMVECs and vascular lesions. CES1-deficient PMVECs exhibited increased apoptosis, reactive oxygen species (ROS) production, mitochondrial fragmentation, ER stress, and impaired angiogenesis. Confocal imaging and metabolic studies revealed lipid droplet accumulation, reduced fatty acid oxidation, and a glycolytic shift-- phenotypes reversed by CES1 restoration. Mechanistically, CES1 transcription was induced by BMPR2 via NRF2 activation, a key regulator of redox and metabolic homeostasis. In vivo, CES1-deficient mice developed severe pulmonary hypertension (PH) under hypoxia, with extensive vascular remodeling, right ventricular dysfunction, and dysregulated angiogenesis and lipid metabolism pathways, as confirmed by lung scRNA-seq. ConclusionsCES1 is essential for pulmonary endothelial homeostasis and serves as a critical modifier of BMPR2 signaling. Given the limited efficacy of current PAH therapies in reversing endothelial dysfunction and small-vessel loss, restoring CES1 expression represents a promising therapeutic strategy.

biochemistry↗

Quantitative modeling of the emergence of macroscopic grid-like representations

Grid cells are neurons in the entorhinal cortex that are thought to perform neural computations in support of spatial navigation. When subjects navigate through spatial environments, grid cells exhibit firing fields that are arranged in a triangular grid pattern. As direct recordings of grid cells from the human brain are only rarely possible, functional magnetic resonance imaging (fMRI) studies proposed and described an indirect measure of entorhinal grid-cell activity, which is quantified as a hexadirectional modulation of fMRI activity as a function of the subjects movement direction. However, it still remains unclear how the activity of a population of grid cells may exhibit hexadirectional modulation and thus provides the basis for the hexadirectional modulation of entorhinal cortex activity measured with fMRI. Here, we thus performed numerical simulations and analytical calculations to better understand how the aggregated activity of many grid cells may be hexadirectionally modulated. Our simulations implemented three different hypotheses proposing that the hexadirectional modulation occurs because grid cells show head-direction tuning aligned with the grid axes; are subjected to repetition suppression; or exhibit a bias towards a particular grid phase offset. Our simulations suggest that hexadirectional modulation is best explained by the conjunctive grid by head-direction cell hypothesis, which can produce the strongest and most robust hexasymmetry. In contrast, our simulations including previously observed biological properties of grid cells do not provide clear support for the structure-function mapping hypothesis. Our observations on hexadirectional modulation generated by grid-cell adaptation effects and the available data on adaptation properties of grid cells are insufficient to substantiate or refute the repetition suppression hypothesis. Furthermore, we found that the magnitude of the hexadirectional modulation depends considerably on the subjects navigation pattern. Our results thus indicate that future fMRI studies could be designed to test which of the three hypotheses most likely accounts for the fMRI measure of grid cells. These findings also underline the importance of quantifying the biological properties of single grid cells in humans to further elucidate how hexadirectional modulations of fMRI activity may emerge.

neuroscience↗