Mamiko Niwa - US grants

[unreadable] DESCRIPTION (provided by applicant): How does single neuron activity relate to perception? How do single neurons process temporally varying information, and how is this information encoded by their temporal firing pattern? The proposed study aims to address these fundamental questions. The auditory system is exceptional to study the union of these questions because of its unique design to analyze temporal structure in the acoustic environment. Amplitude-modulated (AM) sound provides temporal variation in sound intensity to which auditory neurons phase-lock. This straightforward relationship between temporal stimulus structure and temporal response properties provides an excellent framework to investigate temporal codes in the brain. We will record single-units responses in the primary auditory cortex (A1) and the middle-lateral field of the auditory cortex (ML) of non-human subjects while they actively discriminate AM. We will characterize temporal phase- locking of single neuron responses to AM with vector strength (VS). We will also measure spike-counts in response to AM. With analytical techniques derived from signal detection theory, we will determine behavioral AM sensitivity and neural AM sensitivity based on both VS and spike-count. By simultaneously recording behavior and neural activity and comparing them with analogous statistical measures, the design of this study allows us to directly link neural activity to behavior. Here, we aim to address three specific questions; 1) whether, temporal or rate codes, can better account for AM discrimination ability; 2) whether active engagement in AM discrimination improves the temporal precision of neural firing as well as rate coding of AM in A1 and ML; 3) whether some neurons' activities in A1 and ML are closely associated with the animal's decisions. Comparative study of A1 and ML will add to the understanding of parallel and hierarchical processing of temporal sound properties in the auditory cortex and how this processing is modulated by behavioral state. In addition, the study will take the first step to understand the degree of synchrony of activity across nearby neurons, which is critical to derive models of how neural sensitivity can be accounted for by a population of neurons. This study will add to the understanding of how speech is processed, as speech is rich with AM. This will also add to the understanding of temporal processing which has been linked to several learning impairments. Additionally, cochlear implants transmit amplitude and temporal information of sound as principal cues, and the understanding of how temporal information is processed upstream in auditory system should help in the design of these prostheses to improve the hearing of the impaired. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): One astonishing feature of the auditory system is its broad dynamic range - the auditory system detects sounds from a water droplet to jet engine without causing damage. At the first neural processing stage of the auditory system, different groups of spiral ganglion neurons (SGNs) are thought to represent distinct dynamic ranges. Given that the dynamic range of inner hair cells is thought to be largely homogeneous, how afferent fibers acquire such heterogeneous dynamic ranges remains to be resolved. Recent studies provide evidence that the difference in dynamic range among afferent fibers originates, at least partially, at IHC/afferent synapses. Here, the proposed study hypothesizes an additional contributor to dynamic range by action potential (AP) generation mechanisms. In Specific Aim 1, we will determine whether the size of injected current required to fire an AP is variable among afferent fibers, thus testing for differences in postsynaptic threshold as a means of establishing dynamic range. For this, we will perform a current-clamp recording on single afferent fiber's bouton, and measure the minimum current injection required to fire an AP. A broad distribution of current threshold for AP firing would support that synaptic current may be differently propagated and integrated to fire AP among afferent fibers. In Specific Aim 2, we will determine whether AP generation mechanisms indeed contribute in creating heterogeneous dynamic range among afferent fiber. For this, excitatory post- synaptic currents (EPSCs) as well as APs from a single afferent fiber will be recorded while depolarizing the IHC contacted by the recorded fiber to a sequence of voltages. This experiment allows us to determine the afferent fiber's dynamic range at the level of EPSCs (output of pre- and post-synaptic mechanisms) as well as its dynamic range at the level of SGN output, AP firing rate. By comparing the lower and upper bounds of dynamic ranges by EPSC with those by AP firing rate, we will determine the respective contributions of synaptic and AP generation mechanisms in creating heterogeneous dynamic range among afferent fibers. In Specific Aim 3, we will determine whether there are variations in molecular profiles among afferent fibers. We are particularly interested in what specific molecules are involved in AP generation mechanisms that play a role in establishing heterogeneous dynamic range of SGNs. We will examine mRNA expression of candidate molecules at single-cell level by qRT-PCR. Candidates include voltage-gated sodium (Nav) channels, which are responsible for AP generation and one major determinant for setting the excitability of neurons as well as Nav channel ?-subunits ?1~3 and Src family kinases, which are known to modulate the property of Nav channels. We will use a gene chip array to compare spiral ganglia constituents in nonbiased manner focusing on those molecules that establish excitability. Outcome of the proposed study will advance our understanding in the field of auditory neurophysiology by providing input-output functions of SGNs. It will also reveal possible molecular players underlying heterogeneity of SGNs, which are important for proper auditory functions and for finding clinical solutions for hearing deficits.

DESCRIPTION (provided by applicant): One astonishing feature of the auditory system is its broad dynamic range - the auditory system detects sounds from a water droplet to jet engine without causing damage. At the first neural processing stage of the auditory system, different groups of spiral ganglion neurons (SGNs) are thought to represent distinct dynamic ranges. Given that the dynamic range of inner hair cells is thought to be largely homogeneous, how afferent fibers acquire such heterogeneous dynamic ranges remains to be resolved. Recent studies provide evidence that the difference in dynamic range among afferent fibers originates, at least partially, at IHC/afferent synapses. Here, the proposed study hypothesizes an additional contributor to dynamic range by action potential (AP) generation mechanisms. In Specific Aim 1, we will determine whether the size of injected current required to fire an AP is variable among afferent fibers, thus testing for differences in postsynaptic threshold as a means of establishing dynamic range. For this, we will perform a current-clamp recording on single afferent fiber's bouton, and measure the minimum current injection required to fire an AP. A broad distribution of current threshold for AP firing would support that synaptic current may be differently propagated and integrated to fire AP among afferent fibers. In Specific Aim 2, we will determine whether AP generation mechanisms indeed contribute in creating heterogeneous dynamic range among afferent fiber. For this, excitatory post- synaptic currents (EPSCs) as well as APs from a single afferent fiber will be recorded while depolarizing the IHC contacted by the recorded fiber to a sequence of voltages. This experiment allows us to determine the afferent fiber's dynamic range at the level of EPSCs (output of pre- and post-synaptic mechanisms) as well as its dynamic range at the level of SGN output, AP firing rate. By comparing the lower and upper bounds of dynamic ranges by EPSC with those by AP firing rate, we will determine the respective contributions of synaptic and AP generation mechanisms in creating heterogeneous dynamic range among afferent fibers. In Specific Aim 3, we will determine whether there are variations in molecular profiles among afferent fibers. We are particularly interested in what specific molecules are involved in AP generation mechanisms that play a role in establishing heterogeneous dynamic range of SGNs. We will examine mRNA expression of candidate molecules at single-cell level by qRT-PCR. Candidates include voltage-gated sodium (Nav) channels, which are responsible for AP generation and one major determinant for setting the excitability of neurons as well as Nav channel ?-subunits ?1~3 and Src family kinases, which are known to modulate the property of Nav channels. We will use a gene chip array to compare spiral ganglia constituents in nonbiased manner focusing on those molecules that establish excitability. Outcome of the proposed study will advance our understanding in the field of auditory neurophysiology by providing input-output functions of SGNs. It will also reveal possible molecular players underlying heterogeneity of SGNs, which are important for proper auditory functions and for finding clinical solutions for hearing deficits.