The Functional Role of Inhibition in the Sound Evoked Goldfish Startle Behavior

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DESCRIPTION (provided by applicant): The causes of many neuorological and psychiatric illnesses remain unknown despite their widespread prevelance and cost to families and society. Electrical recordings from human and primate brains have demonstrated the sophisticated capacities of single neurons to process information and make decisions, i.e. compute. It is possible that many neurological and psychiatric diseases are caused by neurons that perform computations incorrectly. The long-term objective of the proposed project is to understand how synaptic mechanisms define the computational capacities of a single neuron. To address this question I study an identifiable neuron whose activity correlates with a stereotypic behavior. The two goldfish Mauthner (M-) cells receive auditory input, process this input, and the all-or-none result is translated in to an escape response, the C-start. Thus the M-cell(s) must deduce, from a continuous stream of sensory information, whether or not a stimulus merits the initiation of an escape, the precise timing of the escape, the initial direction of the escape, which is reflected in whether the left or right M-cell is activated. Since the M-cell soma and lateral dendrite are accessible to intracellular recordings in vivo I intend to describe how these functions are carried out by the sub-threshold interactions between sound evoked synaptic excitation and inhibition. Auditory afferents make excitatory chemical and electrical synapses on the M-cell while glycinergic feed-forward inhibitory interneurons chemically and ephaptically inhibit the M-cell. Published data indicates that the timing of sound evoked excitatory electrotonic postsynaptic potentials (PSPs) are phase locked to the sound stimulus. Aim 1 will test whether the timing of the glycinergic inhibitory PSPs are also phase locked and investigate how excitation and inhibition are integrated. Aim 2 will determine whether the phase locking of the sound evoked synaptic activity is necessary for unambiguously determining the location of a sound source underwater and Aim 3 will determine if the strength of glycinergic inhibition of the M-cell governs the probability that a stimulus will elicit a C-start. Paired intracellular recordings will be performed in immobilized fish in air, and these results will be correlated with underwater studies in behaving fish monitored with high speed video, EMG, and extracellular chronic electrodes. Strychnine applied by intramuscular injection and locally by electroporesis will disrupt glycinergic inhibition and simulate hyperekplexia, a hereditary disease resulting in spasticity and associated with mutations in the glycine receptor. The results of these experiments will clarify if glycinergic inhibition disrupted in the spinal cord or brain stem induces hyperekplexia and identify pharmacological approaches that can reduce spasticity.