Astrocytic gliotransmission as a pathway for stable stimulation of post-synaptic spiking: Implications for working memory

The brain consists not only of neurons but also of non-neuronal cells, including astrocytes. Recent discoveries in neuroscience suggest that astrocytes directly regulate neuronal activity by releasing gliotransmitters such as glutamate. In this paper, we consider a biologically plausible mathematical model of a tripartite neuron-astrocyte network. We study the stability of the nonlinear astrocyte dynamics, as well as its role in regulating the firing rate of the post-synaptic neuron. We show that astrocytes enable storing neuronal information temporarily. Motivated by recent findings on the role of astrocytes in explaining mechanisms of working memory, we numerically verify the utility of our analysis in showing the possibility of two competing theories of persistent and sparse neuronal activity of working memory.Comment: IFAC World Congress (2023

From multiscale biophysics to digital twins of tissues and organs: future opportunities for in silico pharmacology

With many advancements in in silico biology in recent years, the paramount challenge is to translate the accumulated knowledge into exciting industry partnerships and clinical applications. Achieving models that characterize the link of molecular interactions to the activity and structure of a whole organ are termed multiscale biophysics. Historically, the pharmaceutical industry has worked well with in silico models by leveraging their prediction capabilities for drug testing. However, the needed higher fidelity and higher resolution of models for efficient prediction of pharmacological phenomenon dictates that in silico approaches must account for the verifiable multiscale biophysical phenomena, as a spatial and temporal dimension variation for different processes and models. The collection of different multiscale models for different tissues and organs can compose digital twin solutions towards becoming a service for researchers, clinicians, and drug developers. Our paper has two main goals: 1) To clarify to what extent detailed single- and multiscale modeling has been accomplished thus far, we provide a review on this topic focusing on the biophysics of epithelial, cardiac, and brain tissues; 2) To discuss the present and future role of multiscale biophysics in in silico pharmacology as a digital twin solution by defining a roadmap from simple biophysical models to powerful prediction tools. Digital twins have the potential to pave the way for extensive clinical and pharmaceutical usage of multiscale models and our paper shows the basic fundamentals and opportunities towards their accurate development enabling the quantum leaps of future precise and personalized medical software.Comment: 30 pages, 10 figures, 1 tabl

Larger Connection Radius Increases Hub Astrocyte Number in a 3D Neuron-Astrocyte Network Model

Astrocytes – a prominent glial cell type in the brain – form networks that tightly interact with the brain’s neuronal circuits. Thus, it is essential to study the modes of such interaction if we aim to understand how neural circuits process information. Thereby, calcium elevations, the primary signal in astrocytes, propagate to the adjacent neighboring cells and directly regulate neuronal communication. It is mostly unknown how the astrocyte network topology influences neuronal activity. Here, we used a computational model to simulate planar and 3D neuron-astrocyte networks with varying topologies. We investigated the number of active nodes, the shortest path, and the mean degree. Furthermore, we applied a graph coloring analysis that highlights the network organization between different network structures. With the increase of the maximum distance between two connected astrocytes, the information flow is more centralized to the most connected cells. Our results suggest that activity-dependent plasticity and the topology of brain areas might alter the amount of astrocyte controlled synapses

Astrocytes in modulating subcellular, cellular and intercellular molecular neuronal communication

Astrocytes are one of the most abundant cell types in our brain. They modulate the brain homeostasis and play a role in the synaptic signalling and thus the molecular propagation inside the brain. Moreover, they form communication networks that co-localise with the neuronal networks with comparable topological complexity. There is an increasing piece of evidence that astrocytes are important in plasticity and learning from the level of the single synapse to the entire network. Moreover, several diseases are molecular communications on different scales from the synaptic to network level.acceptedVersionPeer reviewe

Astrocytic control in in vitro and simulated neuron-astrocyte networks

acceptedVersionPeer reviewe

Astrocytes Exhibit a Protective Role in Neuronal Firing Patterns under Chemically Induced Seizures in Neuron-Astrocyte Co-Cultures.

Astrocytes and neurons respond to each other by releasing transmitters, such as γ-aminobutyric acid (GABA) and glutamate, that modulate the synaptic transmission and electrochemical behavior of both cell types. Astrocytes also maintain neuronal homeostasis by clearing neurotransmitters from the extracellular space. These astrocytic actions are altered in diseases involving malfunction of neurons, e.g., in epilepsy, Alzheimer's disease, and Parkinson's disease. Convulsant drugs such as 4-aminopyridine (4-AP) and gabazine are commonly used to study epilepsy in vitro. In this study, we aim to assess the modulatory roles of astrocytes during epileptic-like conditions and in compensating drug-elicited hyperactivity. We plated rat cortical neurons and astrocytes with different ratios on microelectrode arrays, induced seizures with 4-AP and gabazine, and recorded the evoked neuronal activity. Our results indicated that astrocytes effectively counteracted the effect of 4-AP during stimulation. Gabazine, instead, induced neuronal hyperactivity and synchronicity in all cultures. Furthermore, our results showed that the response time to the drugs increased with an increasing number of astrocytes in the co-cultures. To the best of our knowledge, our study is the first that shows the critical modulatory role of astrocytes in 4-AP and gabazine-induced discharges and highlights the importance of considering different proportions of cells in the cultures

Simulation of developing human neuronal cell networks

BACKGROUND: Microelectrode array (MEA) is a widely used technique to study for example the functional properties of neuronal networks derived from human embryonic stem cells (hESC-NN). With hESC-NN, we can investigate the earliest developmental stages of neuronal network formation in the human brain. METHODS: In this paper, we propose an in silico model of maturating hESC-NNs based on a phenomenological model called INEX. We focus on simulations of the development of bursts in hESC-NNs, which are the main feature of neuronal activation patterns. The model was developed with data from developing hESC-NN recordings on MEAs which showed increase in the neuronal activity during the investigated six measurement time points in the experimental and simulated data. RESULTS: Our simulations suggest that the maturation process of hESC-NN, resulting in the formation of bursts, can be explained by the development of synapses. Moreover, spike and burst rate both decreased at the last measurement time point suggesting a pruning of synapses as the weak ones are removed. CONCLUSIONS: To conclude, our model reflects the assumption that the interaction between excitatory and inhibitory neurons during the maturation of a neuronal network and the spontaneous emergence of bursts are due to increased connectivity caused by the forming of new synapses.BioMed Central open acces

From Multiscale Biophysics to Digital Twins of Tissues and Organs: Future Opportunities for in-silico Pharmacology

With many advancements in in silico multiscale biology in recent years, the paramount challenge is to translate the accumulated knowledge into exciting industry partnerships and clinical applications. Historically, the pharmaceutical industry has worked well with in silico models by leveraging their prediction capabilities for drug testing. However, the needed higher fidelity and higher resolution of models for efficient prediction of pharmacological phenomenon dictates that in silico approaches must account for the verifiable multiscale biophysical phenomena, as a spatial and temporal dimension variation for different processes and models. Our paper has two main goals: 1) To clarify to what extent detailed single-and multiscale modeling has been accomplished thus far, we provide a review on this topic focusing on the biophysics of epithelial, cardiac, and brain tissues; 2) To discuss the present and future role of multiscale biophysics in in silico pharmacology as a digital twin solution by defining a roadmap from simple biophysical models to powerful prediction tools. Digital twins have the potential to pave the way for extensive clinical and pharmaceutical usage of multiscale models, and our paper shows the fundamentals and opportunities for their accurate development, enabling the quantum leaps of future precise and personalized medical software

Combined Experimental and System-Level Analyses Reveal the Complex Regulatory Network of miR-124 during Human Neurogenesis

Non-coding RNAs regulate many biological processes including neurogenesis. The brain-enriched miR-124 has been assigned as a key player of neuronal differentiation via its complex but little understood regulation of thousands of annotated targets. To systematically chart its regulatory functions, we used CRISPR/Cas9 gene editing to disrupt all six miR-124 alleles in human induced pluripotent stem cells. Upon neuronal induction, miR-124-deleted cells underwent neurogenesis and became functional neurons, albeit with altered morphology and neurotransmitter specification. Using RNA-induced-silencing-complex precipitation, we identified 98 high-confidence miR-124 targets, of which some directly led to decreased viability. By performing advanced transcription-factor-network analysis, we identified indirect miR-124 effects on apoptosis, neuronal subtype differentiation, and the regulation of previously uncharacterized zinc finger transcription factors. Our data emphasize the need for combined experimental- and system-level analyses to comprehensively disentangle and reveal miRNA functions, including their involvement in the neurogenesis of diverse neuronal cell types found in the human brain