The Effects of Disruption of Synaptic Signaling on Neuronal Networks

The brain is an organ that acts as the conductor of an orchestra – it governs all vital body functions and assures that all organs operate in harmony. Moreover, it plays a crucial role in various tasks such as memory formation, sensory processing and movement control. The performance of the brain in these tasks requires spatiotemporal patterns formed by the activity of different parts of the brain. The formation of the spatiotemporal patterns in the brain is facilitated by the connections between neurons, also known as synapses. Therefore, transmission failure in synapses may lead to disruption in these patterns and may impair the proper functioning of the brain. The aim of this dissertation is to explore the outcomes when synaptic transmission is disrupted. First, we investigated the universal effect of synaptic failure in neuronal networks having heterogeneous connectivity. Even though human studies on anesthetics claimed that failure in signal transmission in the brain results in loss of coherence in brain activity, we provided evidence that this may not always be true. On the contrary, synaptic failure may facilitate the emergence of coherent neuronal network activity due to more balanced input levels across the neuronal network. The second part of this dissertation focuses on a specific case which arises from disruption in synaptic signaling in the peripheral auditory system, namely hidden hearing loss (HHL). We built a computational model to simulate two mechanisms that give rise to HHL: 1) loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) and 2) myelin defects at the peripheral SGN axons. We concluded that both mechanisms decrease the cumulative SGN activity, whereas only myelin defects desynchronize it, confirming the experimental observations. Finally, we investigated the effect of SGN myelin defects on sound localization, as patients with HHL were shown to have binaural processing deficits. We provided evidence that the activity of the neurons in the downstream cochlear nucleus circuit that is responsible for sound localization is severely impaired as a result of myelin defects in SGN fibers. This result possibly elucidates the mechanism that gives rise to sound localization deficiencies in HHL patients.PHDBiophysicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163002/1/mbudak_1.pd

Synaptic Failure Differentially Affects Pattern Formation in Heterogenous Networks

The communication of neurons is primarily maintained by synapses, which play a crucial role in the functioning of the nervous system. Therefore, synaptic failure may critically impair information processing in the brain and may underlie many neurodegenerative diseases. A number of studies have suggested that synaptic failure may preferentially target neurons with high connectivity (i.e., network hubs). As a result, the activity of these highly connected neurons can be significantly affected. It has been speculated that anesthetics regulate conscious state by affecting synaptic transmission at these network hubs and subsequently reducing overall coherence in the network activity. In addition, hubs in cortical networks are shown to be more vulnerable to amyloid deposition because of their higher activity within the network, causing decrease in coherence patterns and eventually Alzheimer’s disease (AD). Here, we investigate how synaptic failure can affect spatio-temporal dynamics of scale free networks, having a power law scaling of number of connections per neuron – a relatively few neurons (hubs) with a lot of emanating or incoming connections and many cells with low connectivity. We studied two types of synaptic failure: activity-independent and targeted, activity-dependent synaptic failure. We defined scale-free network structures based on the dominating direction of the connections at the hub neurons: incoming and outgoing. We found that the two structures have significantly different dynamical properties. We show that synaptic failure may not only lead to the loss of coherence but unintuitively also can facilitate its emergence. We show that this is because activity-dependent synaptic failure homogenizes the activity levels in the network creating a dynamical substrate for the observed coherence increase. Obtained results may lead to better understanding of changes in large-scale pattern formation during progression of neuro-degenerative diseases targeting synaptic transmission

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Contrasting mechanisms for hidden hearing loss: Synaptopathy vs myelin defects.

Hidden hearing loss (HHL) is an auditory neuropathy characterized by normal hearing thresholds but reduced amplitudes of the sound-evoked auditory nerve compound action potential (CAP). In animal models, HHL can be caused by moderate noise exposure or aging, which induces loss of inner hair cell (IHC) synapses. In contrast, recent evidence has shown that transient loss of cochlear Schwann cells also causes permanent auditory deficits in mice with similarities to HHL. Histological analysis of the cochlea after auditory nerve remyelination showed a permanent disruption of the myelination patterns at the heminode of type I spiral ganglion neuron (SGN) peripheral terminals, suggesting that this defect could be contributing to HHL. To shed light on the mechanisms of different HHL scenarios observed in animals and to test their impact on type I SGN activity, we constructed a reduced biophysical model for a population of SGN peripheral axons whose activity is driven by a well-accepted model of cochlear sound processing. We found that the amplitudes of simulated sound-evoked SGN CAPs are lower and have greater latencies when heminodes are disorganized, i.e. they occur at different distances from the hair cell rather than at the same distance as in the normal cochlea. These results confirm that disruption of heminode positions causes desynchronization of SGN spikes leading to a loss of temporal resolution and reduction of the sound-evoked SGN CAP. Another mechanism resulting in HHL is loss of IHC synapses, i.e., synaptopathy. For comparison, we simulated synaptopathy by removing high threshold IHC-SGN synapses and found that the amplitude of simulated sound-evoked SGN CAPs decreases while latencies remain unchanged, as has been observed in noise exposed animals. Thus, model results illuminate diverse disruptions caused by synaptopathy and demyelination on neural activity in auditory processing that contribute to HHL as observed in animal models and that can contribute to perceptual deficits induced by nerve damage in humans

Correction: Contrasting mechanisms for hidden hearing loss: Synaptopathy vs myelin defects.

[This corrects the article DOI: 10.1371/journal.pcbi.1008499.]

NhaA Na⁺/H⁺ Antiporter Mutants That Hardly React to the Membrane Potential

pH and Na+ homeostasis in all cells requires Na+/H+ antiporters. The crystal structure, obtained at pH 4, of NhaA, the main antiporter of Escherichia coli, has provided general insights into an antiporter mechanism and its unique pH regulation. Here, we describe a general method to select various NhaA mutants from a library of randomly mutagenized NhaA. The selected mutants, A167P and F267C are described in detail. Both mutants are expressed in Escherichia coli EP432 cells at 70–95% of the wild type but grow on selective medium only at neutral pH, A167P on Li+ (0.1 M) and F267C on Na+ (0.6 M). Surprising for an electrogenic secondary transporter, and opposed to wild type NhaA, the rates of A167P and F267C are almost indifferent to membrane potential. Detailed kinetic analysis reveals that in both mutants the rate limiting step of the cation exchange cycle is changed from an electrogenic to an electroneutral reaction

Optimizing tuberculosis treatment efficacy: Comparing the standard regimen with Moxifloxacin-containing regimens.

Tuberculosis (TB) continues to be one of the deadliest infectious diseases in the world, causing ~1.5 million deaths every year. The World Health Organization initiated an End TB Strategy that aims to reduce TB-related deaths in 2035 by 95%. Recent research goals have focused on discovering more effective and more patient-friendly antibiotic drug regimens to increase patient compliance and decrease emergence of resistant TB. Moxifloxacin is one promising antibiotic that may improve the current standard regimen by shortening treatment time. Clinical trials and in vivo mouse studies suggest that regimens containing moxifloxacin have better bactericidal activity. However, testing every possible combination regimen with moxifloxacin either in vivo or clinically is not feasible due to experimental and clinical limitations. To identify better regimens more systematically, we simulated pharmacokinetics/pharmacodynamics of various regimens (with and without moxifloxacin) to evaluate efficacies, and then compared our predictions to both clinical trials and nonhuman primate studies performed herein. We used GranSim, our well-established hybrid agent-based model that simulates granuloma formation and antibiotic treatment, for this task. In addition, we established a multiple-objective optimization pipeline using GranSim to discover optimized regimens based on treatment objectives of interest, i.e., minimizing total drug dosage and lowering time needed to sterilize granulomas. Our approach can efficiently test many regimens and successfully identify optimal regimens to inform pre-clinical studies or clinical trials and ultimately accelerate the TB regimen discovery process