Synaptic and intrinsic plasticity during sound offset encoding

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This proposal will reveal brain mechanisms which mediate the capacity of the brain to wire and rewire itself during early development and in response to changes in auditory experience. Correct wiring and appropriate activity patterns result in the ability to detect and respond quickly to changes in the environment, e.g. the appearance or disappearance of an object such as sound. The encoding of sound in terms of onset and offset is highly developed; onset timing and accuracy is well characterized, but the ionic mechanism of offset-encoding in the Superior Paraolivary Nucleus (SPN) has only recently been described (by myself and my collaborators). These neurons convert powerful inhibition during sound into precise action potential firing upon sound termination. I have preliminary evidence that this circuit (and component proteins) is under activity-dependent control. However, it is not yet understood how the inhibition leading to offset-encoding is affected by experience-dependent changes in the acoustic environment during normal ontogeny or following an acoustic insult. In this proposal my lab will explore how changes in the brainstem inhibitory constraint affect the phasic offset response and (as indicated by preliminary data) enables aberrant, continuous rhythmic firing. Such an experience-dependent switch from phasic to continuous firing suggests a loss of function in the SPN, so that sound offset detection is compromised. Two approaches will be used to investigate the inhibitory constraint: 1) optogenetic silencing of MNTB neurons and 2) sound over-exposure to induce an acoustic trauma, so that plasticity changes in the MNTB/SPN microcircuit can be explored. Complementary use of slice and in vivo electrophysiology will provide insights into the molecular mechanisms controlling firing patterns in the SPN; while whole animal recording will provide the physiological mechanisms for processing of realistic sensory stimuli on a systems level. Uncovering the relationship between inhibitory input strength and a switch from phasic offset-encoding to continuous rhythmic firing will provide general understanding of experience-dependent learning and plasticity. And in the age of the iPod, with the huge potential for personal exposure to extreme sound levels and the according risk of damage, this project will provide mechanistic insights into both, short- and long term changes to the auditory pathway in response to acoustic over-exposure and will contribute to the development of treatments that can protect or restore the sensory capacity.