Search tips
Search criteria

Results 1-6 (6)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
1.  Mutation of Npr2 Leads to Blurred Tonotopic Organization of Central Auditory Circuits in Mice 
PLoS Genetics  2014;10(12):e1004823.
Tonotopy is a fundamental organizational feature of the auditory system. Sounds are encoded by the spatial and temporal patterns of electrical activity in spiral ganglion neurons (SGNs) and are transmitted via tonotopically ordered processes from the cochlea through the eighth nerve to the cochlear nuclei. Upon reaching the brainstem, SGN axons bifurcate in a stereotyped pattern, innervating target neurons in the anteroventral cochlear nucleus (aVCN) with one branch and in the posteroventral and dorsal cochlear nuclei (pVCN and DCN) with the other. Each branch is tonotopically organized, thereby distributing acoustic information systematically along multiple parallel pathways for processing in the brainstem. In mice with a mutation in the receptor guanylyl cyclase Npr2, this spatial organization is disrupted. Peripheral SGN processes appear normal, but central SGN processes fail to bifurcate and are disorganized as they exit the auditory nerve. Within the cochlear nuclei, the tonotopic organization of the SGN terminal arbors is blurred and the aVCN is underinnervated with a reduced convergence of SGN inputs onto target neurons. The tonotopy of circuitry within the cochlear nuclei is also degraded, as revealed by changes in the topographic mapping of tuberculoventral cell projections from DCN to VCN. Nonetheless, Npr2 mutant SGN axons are able to transmit acoustic information with normal sensitivity and timing, as revealed by auditory brainstem responses and electrophysiological recordings from VCN neurons. Although most features of signal transmission are normal, intermittent failures were observed in responses to trains of shocks, likely due to a failure in action potential conduction at branch points in Npr2 mutant afferent fibers. Our results show that Npr2 is necessary for the precise spatial organization typical of central auditory circuits, but that signals are still transmitted with normal timing, and that mutant mice can hear even with these deficits.
Author Summary
Millions of people suffer from debilitating hearing defects, ranging from a complete inability to detect sound to more subtle changes in how sounds are encoded by the nervous system. Many forms of deafness are due to mutations in genes that impair the development or function of hair cells, which are responsible for changing sound into electrical signals that can be processed by the brain. Both mice and humans carrying these mutations fail standard hearing tests. In contrast, very little is known about the genetic basis of central auditory processing disorders, which are poorly defined and difficult to diagnose, since these patients can still detect sounds. By finding genes that are required for the normal wiring of central auditory circuits in mice, we can investigate how changes at the circuit level affect circuit function and therefore improve our understanding of central auditory processing disorders. Here, we show that the natriuretic peptide receptor Npr2 is required to establish frequency maps in the mouse central auditory system. Surprisingly, despite a dramatic change in circuit organization, Npr2 mutant mice are still able to respond to sounds with normal sensitivity and timing, underscoring the need for better hearing diagnostic methods in mice as in humans.
PMCID: PMC4256264  PMID: 25473838
2.  Generating synchrony from the asynchronous: compensation for cochlear traveling wave delays by the dendrites of individual brainstem neurons 
Broadband transient sounds, such as clicks and consonants, activate a traveling wave in the cochlea. This wave evokes firing in auditory nerve fibers that are tuned to high frequencies several milliseconds earlier than in fibers tuned to low frequencies. Despite this substantial traveling wave delay, octopus cells in the brainstem receive broadband input and respond to clicks with submillisecond temporal precision. The dendrites of octopus cells lie perpendicular to the tonotopically organized array of auditory nerve fibers, placing the earliest arriving inputs most distally and the latest arriving closest to the soma. Here, we test the hypothesis that the topographic arrangement of synaptic inputs on dendrites of octopus cells allows octopus cells to compensate the traveling wave delay. We show that in mice the full cochlear traveling wave delay is 1.6 ms. Because the dendrites of each octopus cell spread across about one third of the tonotopic axis, a click evokes a soma directed sweep of synaptic input lasting 0.5 ms in individual octopus cells. Morphologically and biophysically realistic, computational models of octopus cells show that soma-directed sweeps with durations matching in vivo measurements result in the largest and sharpest somatic excitatory postsynaptic potentials (EPSPs). A low input resistance and activation of a low-voltage-activated potassium conductance that are characteristic of octopus cells are important determinants of sweep sensitivity. We conclude that octopus cells have dendritic morphologies and biophysics tailored to accomplish the precise encoding of broadband transient sounds.
PMCID: PMC3417346  PMID: 22764237
ventral cochlear nucleus; octopus cell; cochlea; broadband transient sounds; cable analysis; compartmental modeling; traveling wave delay
3.  The Multiple Functions of T Stellate/Multipolar/Chopper Cells in the Ventral Cochlear Nucleus 
Hearing research  2010;276(1-2):61-69.
Acoustic information is brought to the brain by auditory nerve fibers, all of which terminate in the cochlear nuclei, and is passed up the auditory pathway through the principal cells of the cochlear nuclei. A population of neurons variously known as T stellate, type I multipolar, planar multipolar, or chopper cells forms one of the major ascending auditory pathways through the brain stem. T Stellate cells are sharply tuned; as a population they encode the spectrum of sounds. In these neurons, phasic excitation from the auditory nerve is made more tonic by feed forward excitation, coactivation of inhibitory with excitatory inputs, relatively large excitatory currents through NMDA receptors, and relatively little synaptic depression. The mechanisms that make firing tonic also obscure the fine structure of sounds that is represented in the excitatory inputs from the auditory nerve and account for the characteristic chopping response patterns with which T stellate cells respond to tones. In contrast with other principal cells of the ventral cochlear nucleus (VCN), T stellate cells lack a low-voltage-activated potassium conductance and are therefore sensitive to small, steady, neuromodulating currents. The presence of cholinergic, serotonergic and noradrenergic receptors allows the excitability of these cells to be modulated by medial olivocochlear efferent neurons and by neuronal circuits associated with arousal. T Stellate cells deliver acoustic information to the ipsilateral dorsal cochlear nucleus (DCN), ventral nucleus of the trapezoid body (VNTB), periolivary regions around the lateral superior olivary nucleus (LSO), and to the contralateral ventral lemniscal nuclei (VNLL) and inferior colliculus (IC). It is likely that T stellate cells participate in feedback loops through both medial and lateral olivocochlear efferent neurons and they may be a source of ipsilateral excitation of the LSO.
PMCID: PMC3078527  PMID: 21056098
ventral cochlear nucleus; brainstem auditory pathways; ion channels; patch-clamp recording
4.  Connections and synaptic function in the posteroventral cochlear nucleus of deaf jerker mice 
Mutations in the gene that encodes espins can cause deafness and vestibular disorders; mice that are homozygous for the autosomal recessive, jerker mutation in the espin gene never hear. Extracellular injections of biocytin into the anteroventral cochlear nucleus (AVCN) revealed that although the cochlear nuclei are smaller in je/je mice, the topography in its innervation resembles that in wild type mice. Auditory nerve fibers innervate narrow, topographically organized, “isofrequency” bands in deaf animals over the ages examined, P18–P70. The projection of tuberculoventral cells was topographic in je/je as in wild type mice. Terminals of auditory nerve fibers in the multipolar cell area included both large and small endings whereas in the octopus cell area they were exclusively small boutons in je/je as in wild type mice but end bulbs near the nerve root of je/je animals were smaller than in hearing animals. In whole-cell recordings from targets of auditory nerve fibers, octopus and T stellate cells, miniature excitatory postsynaptic currents (mEPSCs) had similar shapes as in +/+, indicating that the properties of AMPA receptors were not affected by the mutation. In je/je animals the frequency of spontaneous mEPSCs was elevated and synaptic depression in responses to trains of shocks delivered at between 100 and 333 Hz was greater than in wild type mice indicating that the probability of neurotransmitter release was increased. The frequency of spontaneous mEPSCs and extent of synaptic depression were greater in octopus than in T stellate cells, in both wild type and je/je mice.
PMCID: PMC2553045  PMID: 18634002
brain stem; auditory pathway; auditory nerve; hearing impairment; espin
5.  In the ventral cochlear nucleus Kv1.1 and HCN1 are colocalized at surfaces of neurons that have low-voltage-activated and hyperpolarization-activated conductances 
Neuroscience  2008;154(1):77-86.
Principal cells of the ventral cochlear nucleus (VCN) differ in the magnitudes of low-voltage-activated potassium (gKL) and hyperpolarization-activated (gh) conductances that determine the time course of signaling. Octopus cells have large gKL (500 nS) and gh (150 nS), bushy cells have smaller gKL (80 nS) and gh (30 nS), and T stellate cells have little gKL and a small gh (20 nS). gKL arises through potassium channels of which ~ 60% contain Kv1.1 subunits; gh arises through channels that include HCN1 subunits. The surfaces of cell bodies and dendrites of octopus cells in the dorsocaudal pole, and of similar cells along the ventrolateral edge of the PVCN, were brightly labeled by an antibody against HCN1 that was colocalized with labeling for Kv1.1. More anteriorly neurons with little surface labeling were intermingled among cell bodies and dendrites with surface labeling for both proteins, likely corresponding to T stellate and bushy cells. The membrane-associated labeling patterns for Kv1.1 and HCN1 were consistent with what is known about the distribution and the electrophysiological properties of the principal cells of the VCN. The cytoplasm of large cells and axonal paranodes contained immunoflurorescent labeling for only Kv1.1.
PMCID: PMC2493296  PMID: 18424000
low-voltage-activated potassium conductance; hyperpolarization-activated conductance; hearing; auditory system; brainstem auditory nuclei
6.  Voltage-activated Calcium Currents in Octopus Cells of the Mouse Cochlear Nucleus 
Octopus cells, neurons in the most posterior and dorsal part of the mammalian ventral cochlear nucleus, convey the timing of synchronous firing of auditory nerve fibers to targets in the contralateral superior paraolivary nucleus and ventral nucleus of the lateral lemniscus. The low input resistances and short time constants at rest that arise from the partial activation of a large, low-voltage-activated K+ conductance (gKL) and a large mixed-cation, hyperpolarization-activated conductance (gh) enable octopus cells to detect coincident firing of auditory nerve fibers with exceptional temporal precision. Octopus cells fire conventional, Na+ action potentials but a voltage-sensitive Ca2+ conductance was also detected. In this study, we explore the nature of that calcium conductance under voltage-clamp. Currents, carried by Ca2+ or Ba2+ and blocked by 0.4 mM Cd2+, were activated by depolarizations positive to −50 mV and peaked at −23 mV. At −23 mV they reached 1.1 ± 0.1 nA in the presence of 5 mM Ca2+ and 1.6 ± 0.1 nA in 5 mM Ba2+. Ten micromolar BAY K 8644, an agonist of high-voltage-activated L-type channels, enhanced IBa by 63 ± 11% (n = 8) and 150 μM nifedipine, an antagonist of L-type channels, reduced the IBa by 65 ± 5% (n = 5). Meanwhile, 0.5 μM ω-Agatoxin IVA, an antagonist of P/Q-type channels, or 1 μM ω-conotoxin GVIA, an antagonist of N-type channels, suppressed IBa by 15 ± 4% (n = 5) and 9 ± 4% (n = 5), respectively. On average 16% of the current remained in the presence of the cocktail of blockers, indicative of the presence of R-type channels. Together these experiments show that octopus cells have a depolarization-sensitive gCa that is largely formed from L-type Ca2+ channels and that P/Q-, N-, and R-type channels are expressed at lower levels in octopus cells.
PMCID: PMC2538346  PMID: 17710492
voltage-sensitive calcium channels;  cochlear nucleus; hearing; patch clamp; brain slices

Results 1-6 (6)