Meaney, D. F. | bioRxiv Science

bioRxiv2019

A multilayer network model of neuron-astrocyte populations in vitro reveals mGluR5 inhibition is protective following traumatic injury

Astrocytes communicate bidirectionally with neurons, enhancing synaptic plasticity and promoting the synchronization of neuronal microcircuits. Despite recent advances in understanding neuron-astrocyte signaling, little is known about astrocytic modulation of neuronal activity at the population level, particularly in disease or following injury. We used high-speed calcium imaging of mixed cortical cultures in vitro to determine how population activity changes after disruption of glutamatergic signaling and mechanical injury. We constructed a multilayer network model of neuron-astrocyte connectivity, which captured distinct topology and response behavior from single cell type networks. mGluR5 inhibition decreased neuronal activity, but did not on its own disrupt functional connectivity or network topology. In contrast, injury increased the strength, clustering, and efficiency of neuronal but not astrocytic networks, an effect that was not observed in networks pre-treated with mGluR5 inhibition. Comparison of spatial and functional connectivity revealed that functional connectivity is largely independent of spatial proximity at the microscale, but mechanical injury increased the spatial-functional correlation. Finally, we found that astrocyte segments of the same cell often belong to separate functional communities based on neuronal connectivity, suggesting that astrocyte segments function as independent entities. Our findings demonstrate the utility of multilayer network models for characterizing the multiscale connectivity of two distinct but functionally dependent cell populations. AUTHOR SUMMARYAstrocytes communicate bidirectionally with neurons, enhancing synaptic plasticity and promoting the synchronization of neuronal microcircuits. We constructed a multilayer network model of neuron-astrocyte connectivity based on calcium activity in mixed cortical cultures, and used this model to evaluate the effect of glutamatergic inhibition and mechanical injury on network topology. We found that injury increased the strength, clustering, and efficiency of neuronal but not astrocytic networks, an effect that was not observed in injured networks pre-treated with a glutamate receptor antagonist. Our findings demonstrate the utility of multilayer network models for characterizing the multiscale connectivity of two distinct but functionally dependent cell populations.

neuroscience↗

bioRxiv2019

Neurodegeneration exposes firing rate dependent effects on oscillation dynamics in computational neural networks

Traumatic brain injury (TBI) can lead to neurodegeneration in the injured circuitry, either through primary structural damage to the neuron or secondary effects that disrupt key cellular processes. Moreover, traumatic injuries can preferentially impact subpopulations of neurons, but the functional network effects of these targeted degeneration profiles remain unclear. Although isolating the consequences of complex injury dynamics and long-term recovery of the circuit can be difficult to control experimentally, computational networks can be a powerful tool to analyze the consequences of injury. Here, we use the Izhikevich spiking neuron model to create networks representative of cortical tissue. After an initial settling period with spike-timing-dependent plasticity (STDP), networks developed rhythmic oscillations similar to those seen in vivo. As neurons were sequentially removed from the network, population activity rate and oscillation dynamics were significantly reduced. In a successive period of network restructuring with STDP, network activity levels were returned to baseline for some injury levels and oscillation dynamics significantly improved. We next explored the role that specific neurons have in the creation and termination of oscillation dynamics. We determined that oscillations initiate from activation of low firing rate neurons with limited structural inputs. To terminate oscillations, high activity excitatory neurons with strong input connectivity activate downstream inhibitory circuitry. Finally, we confirm the excitatory neuron population role through targeted neurodegeneration. These results suggest targeted neurodegeneration can play a key role in the oscillation dynamics after injury.\n\nAuthor SummaryIn this study, we study the impact of neuronal degeneration - a process that commonly occurs after traumatic injury and neurodegenerative disease - on the neuronal dynamics in a cortical network. We create computational models of neural networks and include spike timing plasticity to alter the synaptic strength among connections as networks remodel after simulated injury. We find that spike-timing dependent plasticity helps recover the neural dynamics of an injured microcircuit, but it frequently cannot recover the original oscillation dynamics in an uninjured network. In addition, we find that selectively injuring excitatory neurons with the highest firing rate reduced the neuronal oscillations in a circuit much more than either random deletion or the removing neurons with the lowest firing rate. In all, these data suggest (a) plasticity reduces the consequences of neurodegeneration and (b) losing the most active neurons in the network has the most adverse effect on neural oscillations.

bioengineering↗