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Neuromechanistic Model of Auditory Bistability.

ABSTRACT: Sequences of higher frequency A and lower frequency B tones repeating in an ABA- triplet pattern are widely used to study auditory streaming. One may experience either an integrated percept, a single ABA-ABA- stream, or a segregated percept, separate but simultaneous streams A-A-A-A- and -B---B--. During minutes-long presentations, subjects may report irregular alternations between these interpretations. We combine neuromechanistic modeling and psychoacoustic experiments to study these persistent alternations and to characterize the effects of manipulating stimulus parameters. Unlike many phenomenological models with abstract, percept-specific competition and fixed inputs, our network model comprises neuronal units with sensory feature dependent inputs that mimic the pulsatile-like A1 responses to tones in the ABA- triplets. It embodies a neuronal computation for percept competition thought to occur beyond primary auditory cortex (A1). Mutual inhibition, adaptation and noise are implemented. We include slow NDMA recurrent excitation for local temporal memory that enables linkage across sound gaps from one triplet to the next. Percepts in our model are identified in the firing patterns of the neuronal units. We predict with the model that manipulations of the frequency difference between tones A and B should affect the dominance durations of the stronger percept, the one dominant a larger fraction of time, more than those of the weaker percept-a property that has been previously established and generalized across several visual bistable paradigms. We confirm the qualitative prediction with our psychoacoustic experiments and use the behavioral data to further constrain and improve the model, achieving quantitative agreement between experimental and modeling results. Our work and model provide a platform that can be extended to consider other stimulus conditions, including the effects of context and volition.

SUBMITTER: Rankin J

PROVIDER: S-EPMC4642990 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: TATA Binding Protein (TBP) is required for transcription initiation by all three eukaryotic RNA polymerases. It participates in transcriptional initiation at the majority of eukaryotic gene promoters, either by direct association to the TATA box upstream of the transcription start site or by indirectly localizing to the promoter through other proteins. TBP exists in solution in a dimeric form but binds to DNA as a monomer. Here, we present the first mathematical model for auto-catalytic TBP expression and use it to study the role of dimerization in maintaining the steady state TBP level. RESULTS: We show that the autogenous regulation of TBP results in a system that is capable of exhibiting three steady states: an unstable low TBP state, one stable state corresponding to a physiological TBP concentration, and another stable steady state corresponding to unviable cells where no TBP is expressed. Our model predicts that a basal level of TBP is required to establish the transcription of the TBP gene, and hence for cell viability. It also predicts that, for the condition corresponding to a typical mammalian cell, the high-TBP state and cell viability is sensitive to variation in DNA binding strength. We use the model to explore the effect of the dimer in buffering the response to changes in TBP levels, and show that for some physiological conditions the dimer is not important in buffering against perturbations. CONCLUSIONS: Results on the necessity of a minimum basal TBP level support the in vivo observations that TBP is maternally inherited, providing the small amount of TBP required to establish its ubiquitous expression. The model shows that the system is sensitive to variations in parameters indicating that it is vulnerable to mutations in TBP. A reduction in TBP-DNA binding constant can lead the system to a regime where the unviable state is the only steady state. Contrary to the current hypotheses, we show that under some physiological conditions the dimer is not very important in restoring the system to steady state. This model demonstrates the use of mathematical modelling to investigate system behaviour and generate hypotheses governing the dynamics of such nonlinear biological systems.

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Neuromechanistic Model of Auditory Bistability.

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