The dorsal cochlear nucleus is a relatively complex neural region whose function may be to provide rapid and early processing of complex acoustic stimuli, and to form associations between auditory and non-auditory events. The proposed experiments investigate the cellular mechanisms of information processing in the circuitry of the molecular layer of this nucleus. This circuitry consists of an obligatory set of interneurons, the granule cells, which receive input from diverse mossy fiber afferents and in turn form excitatory parallel fibers that innervate two major targets: a set of inhibitory neurons, the cartwheel cells, and the principal projection neurons of the nucleus, the pyramidal cells.
The aims of this proposal trace the transformations that take place at 3 key points in this circuit: at the mossy-fiber granule cell synapse, at the synapses between parallel fibers and their postsynaptic targets, and in the dendrites of cells postsynaptic to the parallel fibers. In the first aim, synaptic integration at the mossy-fiber granule cell synapse will be examined. They hypothesize that granule cells act as coincidence detectors, and require near-simultaneous activation of at least two mossy fiber inputs in order to discharge action potentials. They will also examine the intrinsic discharge of the granule cells, and the role of Golgi-cell inhibition in regulating the transmission through these cells. In the second aim, we hypothesize that the parallel fiber synapses on cartwheel cells and pyramidal cells are a site of synaptic plasticity, and we will investigate the specific requirements for calcium elevation, activation of neurotransmitter receptors, and activation of protein kinase C that may underlie long term changes in synaptic function. In the third aim, we will investigate the way in which postsynaptic potentials are integrated in the dendritic trees of pyramidal and cartwheel cells. The investigators hypothesize that the different patterns of dendritic branching in these cells, and the presence of active voltadependent channels in their dendrites, will be associated with different characteristics of synaptic integration of activity from their shared source, the parallel fibers. They will determine the sites and types of conductances present in the dendritic trees using optical imaging techniques, and will compare features of synaptic integration in the two cell types using focal activation of one and two discrete clusters of parallel fibers inputs to the dendritic tree under different conditions. All of these experiments utilize tight-seal recording of visualized and identified neurons in brain slices from young rats, and some experiments also utilize time domain imaging of single cells loaded with fluorescent ion-sensitive dyes. The results of these experiments will help us to understand key cellular mechanisms involved in neural integration of information in the inputs that are relayed into the cochlear nucleus through the granule cell system. The results derived from these studies will have an impact on our understanding of information processing in the dorsal cochlear nucleus and its dynamic characteristics, and may suggest new functions for this primary auditory center. These studies may also lead to new knowledge about the general rules of information processing in the dendrites of neurons throughout the brain.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
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Special Emphasis Panel (ZRG1-CMS (01))
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Johns Hopkins University
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Campagnola, Luke; Kratz, Megan B; Manis, Paul B (2014) ACQ4: an open-source software platform for data acquisition and analysis in neurophysiology research. Front Neuroinform 8:3
Koehler, Seth D; Pradhan, Shashwati; Manis, Paul B et al. (2011) Somatosensory inputs modify auditory spike timing in dorsal cochlear nucleus principal cells. Eur J Neurosci 33:409-20
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Basura, Gregory J; Abbas, Atheir I; O'Donohue, Heather et al. (2008) Ontogeny of serotonin and serotonin2A receptors in rat auditory cortex. Hear Res 244:45-50
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Kanold, Patrick O; Manis, Paul B (2005) Encoding the timing of inhibitory inputs. J Neurophysiol 93:2887-97
Molitor, Scott C; Manis, Paul B (2003) Dendritic Ca2+ transients evoked by action potentials in rat dorsal cochlear nucleus pyramidal and cartwheel neurons. J Neurophysiol 89:2225-37

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