CRCNS: Mechanistic Modeling and Inference of Neuronal Synaptic Transmission

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Action potential-triggered transmitter release forms a hallmark of interneuronal communication. The release is critically impacted by diverse noise mechanisms, such as random arrival of action potentials, probabilistic vesicle release, and random replenishment of vesicle pools. How these noise mechanisms combine to impact fidelity of interneuronal communication is an intriguing fundamental problem. A key focus of this project is to use the mathematical formalism of Stochastic Hybrid Systems (SHS) that combine continuous dynamics with discrete random events for modeling synaptic transmission. The SHS-based formalism will be used to derive analytical results connecting synaptic noise mechanisms to randomness in the neurotransmitter levels, and its impact on temporal precision of the responses in the postsynaptic neuron. The project will also develop novel inference methods for inferring neurotransmission parameters from whole-cell patch-clamp recordings in acute brain slices of juvenile mice. Integration of mathematical models with experimental data on long-lasting high-frequency activation of input neurons will be used to characterize neurotransmission at various auditory and non-auditory synapse types. This interdisciplinary approach--coupled with genetic and pharmacological manipulation of neurotransmitter release, re-uptake, and vesicle replenishment--will systematically uncover the role of these processes in information processing at the single-cell level and how auditory brainstem synapses achieve exquisitely high fidelity during prolonged stimulation. Altogether, the project will reveal the extraordinary capabilities of auditory synapses and thus form a basis for a better understanding of central auditory processing disorders. RELEVANCE (See instructions): Hearing impairment is the most prevalent sensory deficit, with major socioeconomic impact. In order to understand how hearing happens, we must obtain a comprehensive knowledge about neuronal information processing in the central auditory system. The project will thoroughly address synaptic processes involved in sound localization by combining empirical work with computational modeling, and we will achieve hitherto unreached synergistic effects towards our goal.