Single-cell computation in auditory brainstem and its impact on cortical coding and behavior

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Project Abstract Understanding how neuronal computations build up a perception of the external world is fundamental to our understanding of how the brain works. This is particularly relevant to sensory systems, where heterogenous inputs representing distinct sensory features must be re-assembled to generate a perception. How individual neurons in early stages of sensory circuits process parallel inputs, and how these circuit elements later contribute to cortical computations that bind the inputs together is completely unknown. Studies have demonstrated that the timing, position and strength of a given input along the dendrite of a given neuron is a critical strategy used by the brain to encode sensory features. However, how such dendritic integrations of inputs in single neurons contribute to an animal's overall perception is not understood. To re-assemble diverse features from the same initial stimulus, the brain needs to determine which features occurred at the same time. Currently, little is known about how or where this timing information might be encoded. The auditory system offers an ideal system to tackle this question based on its tractability to interdisciplinary methods and its known ability to encode even miniscule differences in timing. Specifically, we will take advantage of a unique cell type in the auditory cochlear nucleus, called octopus cells, as a model to investigate the question of how small cell classes contribute to behavioral and perceptual circuits. Octopus cells are prominent in all mammalian species and are well known to encode temporal inputs with submillisecond precision through integration of primary sensory inputs along their large and extensive dendrites. We propose to carry out a multi- lab, integrated analysis of the molecular and biophysical properties of octopus cells and to track how these single cell computations are transformed along the auditory pathway to contribute to an animal's final auditory percept and hence behavior. Using the mouse as a model system, we will apply new sequencing methods together with high resolution brain imaging and single cell reconstructions to create a comprehensive wiring diagram of octopus cells and their auditory inputs. By generating mouse strains for selective access to octopus cells, we will be ideally positioned to investigate the in vitro and in vivo physiology of octopus cells and therefore bridge experimental and computational models for how timing information is encoded at the single cell level. Lastly, we will study how timing information propagates to higher auditory centers by recording from large populations of neurons in the midbrain, thalamus, and cortex and then assessing the functional relevance of temporal coding for auditory behavior. By leveraging molecular, biophysical, electrophysiological, behavioral, and computational approaches toward the study of this model cell type, these studies will allow us to extract general principles of single cell computations and their effects on systems-level circuit function, with broad implications for understanding how parallel streams of information are integrated to generate sensory perception.