Biology subjects

Uysal, B.

Publications and source records attributed to Uysal, B..

3 recordsLinked to original sources

bioRxiv2024

Effective excitability captures network dynamics across development and phenotypes

Neuronal cultures in vitro are a versatile system for studying the fundamental properties of individual neurons and neuronal networks. Recently, this approach has gained attention as a precision medicine tool. Mature neuronal cultures in vitro exhibit synchronized collective dynamics called network bursting. If analyzed appropriately, this activity could offer insights into the networks properties, such as its composition, topology, and developmental and pathological processes. A promising method for investigating the collective dynamics of neuronal networks is to map them onto simplified dynamical systems. This approach allows the study of dynamical regimes and the characteristics of the parameters that lead to data-consistent activity. We designed a simple biophysically inspired dynamical system and used Bayesian inference to fit it to a large number of recordings of in vitro population activity. Even with a small number of parameters, the model showed strong inter-parameter dependencies leading to invariant bursting dynamics for many parameter combinations. We further validated this observation in our analytical solution. We found that in vitro bursting can be well characterized by each of three dynamical regimes: oscillatory, bistable, and excitable. The probability of finding a data-consistent match in a particular regime changes with network composition and development. The more informative way to describe the in vitro network bursting is the effective excitability, which we analytically show to be related to the parameter-invariance of the models dynamics. We establish that the effective excitability can be estimated directly from the experimentally recorded data. Finally, we demonstrate that effective excitability reliably detects the differences between cultures of cortical, hippocampal, and human pluripotent stem cell-derived neurons, allowing us to map their developmental trajectories. Our results open a new avenue for the model-based description of in vitro network phenotypes emerging across different experimental conditions.

neuroscience↗

bioRxiv2019

PINK1 Regulates Dopamine and Lipids at Mitochondria to Maintain Synapses and Neuronal Function

Mitochondrial dysfunction contributes to the pathogenesis of Parkinsons disease but it is not clear why inherent mitochondrial defects lead specifically to the death of dopaminergic neurons of the mid brain. PINK1 is mitochondrial kinase and PINK1 mutations cause early onset Parkinsons disease.\n\nWe found that in neuronal progenitors, PINK1 regulates mitochondrial morphology, mitochondrial contact to the endoplasmic reticulum (ER) and the phosphorylation of Miro1. A compensatory metabolic shift towards lipid synthesis provides mitochondria with the components needed for membrane renewal and oxidative phosphorylation, maintaining the mitochondrial network once mature.\n\nCholesterol is increased by loss of PINK1, promoting overall membrane rigidity. This alters the distribution of phosphorylated DAT at synapses and impairs dopamine uptake. PINK1 is required for the phosphorylation of tyrosine hydroxylase at Ser19, dopamine and calcium homeostasis and dopaminergic pacemaking.\n\nWe suggest a novel mechanism for PINK1 pathogenicity in Parkinsons disease in addition to but not exclusive of mitophagy. We also provide a basis for potential therapeutics by showing that low doses of the cholesterol depleting drug {beta}-cyclodextrin reverse PINK1-specific phenotypes.

neuroscience↗

bioRxiv2019

Human cerebrospinal fluid induce neuronal excitability changes in resected human neocortical and hippocampal brain slices

Human cerebrospinal fluid (hCSF) have proven advantageous over conventional medium when culturing both rodent and human brain tissue. Increased excitability and synchronicity, similar to the active state exclusively recorded in vivo, reported in rodent slice and cell-cultures with hCSF as recording medium, indicates properties of the hCSF not matched by the artificial cerebrospinal fluid (aCSF) commonly used for electrophysiological recording. To evaluate the possible importance of using hCSF as electrophysiological recording medium of human brain tissue, we compared the general excitability in ex vivo human brain tissue slice cultures during perfusion with hCSF and aCSF. For measuring the general activity from a majority of neurons within neocortical and hippocampal human ex vivo slices we used a microelectrode array (MEA) recording technique with 252 electrodes covering an area of 3.2 x 3.2 mm2 and a second CMOS-based MEA with 4225 electrodes on a 2 x 2 mm2 area for detailed mapping of action potential waveforms. We found that hCSF increase the number of active neurons and the firing rate of the neurons in the slices as well as increasing the numbers of bursts while leaving the duration of the bursts unchanged. Interestingly, not only an increase in the overall activity in the slices was observed, but a reconfiguration of the network functionality could be detected with specific activation and inactivation of subpopulations of neuronal ensembles. In conclusion, hCSF is an important component to consider for future human tissue studies, especially for experiments designed to mimic the in vivo situation.

neuroscience↗