Inhibitory interneurons are essential to shaping the output of neuronal circuits. Different circuits perform different computations, and so it follows that the way in which inhibition is expressed and regulated varies accordingly. In feedforward inhibition, the interneuron and the principal cell it contacts are activated by the same afferent fibers, and thus the principal cell experiences inhibition following a brief excitation However, this inhibition also acts on other, unrelated excitatory inputs to the cell. This principle forms the basis for circuits that integrate information across sensory modalities, in which signals from one modality can gate on and off the passage of information from another. This proposal focuses on control of inhibitory neurons in the gating of signals in the dorsal cochlear nucleus (DCN), a cerebellar-like structure unique to mammals. The DCN is believed to play a key role in orientation toward significant sounds. DCN fusiform neurons receive input from auditory nerve and from a system of parallel fibers carrying multimodal input, including proprioceptive signals encoding the position of the head and ears. DCN parallel fibers also activate inhibitory glycinergic cartwheel cells, which provide feedforward inhibition to fusiform cells capable of virtually shutting down auditory signals to higher regions. This relatively simple circuit, and the unusual properties of synapses made by parallel fibers and cartwheel cells, provide an opportunity to understand how sensory signals may be gated in the mammalian brain. We will investigate how cartwheel cells contribute to this function through the kinetics and plasticity of their synaptic contacts. Patch-clamp techniques will be combined with imaging methods and photolysis-based mapping methods to identify circuits formed by cartwheel cells, and work out mechanisms and function of short term plasticity mediated by endocannabinoid signaling, and a novel spike-timing dependent long-term plasticity. The results will provide new information regarding the function of this and related circuits. Moreover, this work may lend new clues to the treatment of tinnitus, a condition thought to be maintained by long-term plasticity in this brain region.
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