A distinguishing characteristic of the dorsal cochlear nucleus (DCN) is that it is the first site in the ascending auditory pathway that integrates acoustic information relayed by the auditory nerve with multimodal inputs from several brain regions that convey somatosensory information important for sound source discrimination and localization. These two independent streams converge upon distinct dendritic regions of fusiform cells, principal neurons that provide the main output of the DCN. We are investigating the cellular and synaptic mechanisms underlying fusiform cell responses to sounds, and how these responses can be influenced by somatosensory stimuli. To address these questions we combine in-vivo recordings with brain-slice electrophysiology and cellular imaging techniques. Our progress in the past year is outlined below. 1. First, we have developed techniques to record in-vivo sound-evoked responses from individual neurons in the mouse DCN. Determining how the different classes of neurons in the mouse DCN respond to sounds is a critical first step in developing hypotheses about the underlying synaptic mechanisms in this circuit. Our initial study (Ma and Brenowitz, 2012) was published earlier this year. Currently our primary goal with regard to in vivo studies is to perform whole-cell recordings which will permit more detailed understanding of the underlying circuit mechanisms that generate the observed responses of fusiform cells and other elements of the cochlear nucleus circuit. 2. We have continued to investigate the role of neuromodulatory pathways that influence DCN function. Endocannabinoids act as retrograde messengers that are released from postsynaptic neurons and regulate synaptic transmission at synapses in many brain regions, including auditory synapses, but their role in auditory function is not known. We have demonstrated a novel mechanism of activity- and calcium-dependent endocannabinoid release from DCN cartwheel cells, glycinergic neurons that suppress fusiform cell activity. This work was published earlier this year (Sedlacek et al., 2011). We have also extended this work to investigate the role of NMDA receptors in regulating spike-timing dependent short term plasticity mediated by endocannabinoid release from cartwheel cells. This work will be presented at the fall Society for Neuroscience meeting and is in preparation for publication. 3. We have been working to identify cellular processes that regulate synaptic transmission in the cochlear nucleus at the level of single dendritic spines, structures that are difficult to study because of their small size which are close to the resolution limit of light microscopy. We have identified an interesting and novel interaction between large-conductance (BK) calcium-activated potassium channels and voltage-gated calcium channels that serves as a negative feedback loop, regulating the strength of synaptic potentials and the size of synaptically-evoked calcium transients. This work was presented at the 2012 Gordon Research Conference on Synaptic Transmission and a manuscript is in preparation. 4. We are investigating the extent to which sensory input is required for normal development of synaptic transmission in the cochlear nucleus. Therefore, we are studying how hearing loss affects synaptic mechanisms in the DCN, by investigating synaptic and biophysical mechanisms that control firing properties of fusiform cells during normal development and after sensory deprivation caused by deafness. By providing insight into basic synaptic mechanisms in the DCN we hope our work can contribute to the understanding and treatment of human hearing disorders and can have implications for cochlear implantation.

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Project End
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Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$916,670
Indirect Cost
Name
National Institute on Deafness and Other Communication Disorders
Department
Type
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He, Shan; Wang, Ya-Xian; Petralia, Ronald S et al. (2014) Cholinergic modulation of large-conductance calcium-activated potassium channels regulates synaptic strength and spine calcium in cartwheel cells of the dorsal cochlear nucleus. J Neurosci 34:5261-72
Brenowitz, Stephan D; Regehr, Wade G (2014) Presynaptic calcium measurements using bulk loading of acetoxymethyl indicators. Cold Spring Harb Protoc 2014:750-7
Sedlacek, Miloslav; Brenowitz, Stephan D (2014) Cell-type specific short-term plasticity at auditory nerve synapses controls feed-forward inhibition in the dorsal cochlear nucleus. Front Neural Circuits 8:78
Wang, Philip Y; Petralia, Ronald S; Wang, Ya-Xian et al. (2011) Functional NMDA receptors at axonal growth cones of young hippocampal neurons. J Neurosci 31:9289-97