Imaging Voltage Globally and in Isofrequency Lamina in Slices of Mouse Ventral Cochlear Nucleus.

The cochlear nuclei (CNs) receive sensory information from the ear and perform fundamental computations before relaying this information to higher processing centers. These computations are performed by distinct types of neurons interconnected in circuits dedicated to the specialized roles of the auditory system. In the present study, we explored the use of voltage imaging to investigate CN circuitry.

Local targets of T-stellate cells in the ventral cochlear nucleus.

T-stellate cells in the ventral cochlear nucleus (VCN) are known to have local axon collaterals that terminate in the vicinity of their dendrites and cell bodies within the same isofrequency lamina in parallel with the auditory nerve fibers that innervate them. Excitatory synaptic connections between stellate cells within an isofrequency lamina are hypothesized to be involved in the nitric oxide-mediated upregulation of T-stellate responses to their auditory input. This could serve as a mechanism of variable gain control in the enhancement of responses to vowel spectral peaks.

Nitric Oxide-Mediated Plasticity of Interconnections Between T-Stellate cells of the Ventral Cochlear Nucleus Generate Positive Feedback and Constitute a Central Gain Control in the Auditory System.

T-stellate cells in the ventral cochlear nucleus (VCN) form an ascending pathway that conveys spectral information from the cochlea to brainstem nuclei, the inferior colliculi, and the thalamus. The tonotopic array of T-stellate cells enhances the encoding of spectral peaks relative to their auditory nerve fiber inputs. The alignment of local collaterals and T-stellate cell dendrites within the isofrequency lamina suggests that the cells make connections within the isofrequency lamina in which they reside.

Cellular Computations Underlying Detection of Gaps in Sounds and Lateralizing Sound Sources.

In mammals, acoustic information arises in the cochlea and is transmitted to the ventral cochlear nuclei (VCN). Three groups of VCN neurons extract different features from the firing of auditory nerve fibers and convey that information along separate pathways through the brainstem. Two of these pathways process temporal information: octopus cells detect coincident firing among auditory nerve fibers and transmit signals along monaural pathways, and bushy cells sharpen the encoding of fine structure and feed binaural pathways.

Genetic perturbations suggest a role of the resting potential in regulating the expression of the ion channels of the KCNA and HCN families in octopus cells of the ventral cochlear nucleus.

Low-voltage-activated K (g) and hyperpolarization-activated mixed cation conductances (g) mediate currents, I and I, through channels of the Kv1 (KCNA) and HCN families respectively and give auditory neurons the temporal precision required for signaling information about the onset, fine structure, and time of arrival of sounds. Being partially activated at rest, g and g contribute to the resting potential and shape responses to even small subthreshold synaptic currents. Resting g and g also affect the coupling of somatic depolarization with the generation of action potentials.

Deleting the HCN1 Subunit of Hyperpolarization-Activated Ion Channels in Mice Impairs Acoustic Startle Reflexes, Gap Detection, and Spatial Localization.

It has been proposed that the high temporal and spatial acuities of human listeners and animals tested in the hearing laboratory depend in part on the short time constants of auditory neurons that are able to preserve or sharpen the information conveyed in the timing of firing of auditory nerve fibers. We tested this hypothesis in a series of in vivo experiments, based on previous in vitro experiments showing that neuronal time constants are raised in brainstem slices when HCN1 channels are blocked or in slices obtained from Hcn1 null mutant mice. We compared Hcn1 and Hcn1 mice on auditory brainstem responses (ABRs) and behavioral measures.

Mutation of Npr2 leads to blurred tonotopic organization of central auditory circuits in mice.

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.

Synaptic transmission between end bulbs of Held and bushy cells in the cochlear nucleus of mice with a mutation in Otoferlin.

Mice that carry a mutation in a calcium binding domain of Otoferlin, the putative calcium sensor at hair cell synapses, have normal distortion product otoacoustic emissions (DPOAEs), but auditory brain stem responses (ABRs) are absent. In mutant mice mechanotransduction is normal but transmission of acoustic information to the auditory pathway is blocked even before the onset of hearing. The cross-sectional area of the auditory nerve of mutant mice is reduced by 54%, and the volume of ventral cochlear nuclei is reduced by 46% relative to hearing control mice.

Synaptic integration in dendrites: exceptional need for speed.

Some neurons in the mammalian auditory system are able to detect and report the coincident firing of inputs with remarkable temporal precision. A strong, low-voltage-activated potassium conductance (g(KL)) at the cell body and dendrites gives these neurons sensitivity to the rate of depolarization by EPSPs, allowing neurons to assess the coincidence of the rising slopes of unitary EPSPs. Two groups of neurons in the brain stem, octopus cells in the posteroventral cochlear nucleus and principal cells of the medial superior olive (MSO), extract acoustic information by assessing coincident firing of their inputs over a submillisecond timescale and convey that information at rates of up to 1000 spikes s(-1).

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 magnitudes of hyperpolarization-activated and low-voltage-activated potassium currents co-vary in neurons of the ventral cochlear nucleus.

In the ventral cochlear nucleus (VCN), neurons have hyperpolarization-activated conductances, which in some cells are enormous, that contribute to the ability of neurons to convey acoustic information in the timing of their firing by decreasing the input resistance and speeding-up voltage changes. Comparisons of the electrophysiological properties of neurons in the VCN of mutant mice that lack the hyperpolarization-activated cyclic nucleotide-gated channel α subunit 1 (HCN1(-/-)) (Nolan et al. 2003) with wild-type controls (HCN1(+/+)) and with outbred ICR mice reveal that octopus, T stellate, and bushy cells maintain their electrophysiological distinctions in all strains.

The multiple functions of T stellate/multipolar/chopper cells in the ventral cochlear nucleus.

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 brainstem. T Stellate cells are sharply tuned; as a population they encode the spectrum of sounds.

Auditory nerve fibers excite targets through synapses that vary in convergence, strength, and short-term plasticity.

Auditory nerve fibers are the major source of excitation to the three groups of principal cells of the ventral cochlear nucleus (VCN), bushy, T stellate, and octopus cells. Shock-evoked excitatory postsynaptic currents (eEPSCs) in slices from mice showed systematic differences between groups of principal cells, indicating that target cells contribute to determining pre- and postsynaptic properties of synapses from spiral ganglion cells. Bushy cells likely to be small spherical bushy cells receive no more than three, most often two, excitatory inputs; those likely to be globular bushy cells receive at least four, most likely five, inputs.

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.

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 (g(KL)) and a large mixed-cation, hyperpolarization-activated conductance (g(h)) 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 Ca(2+) conductance was also detected.

Voltage-sensitive conductances of bushy cells of the Mammalian ventral cochlear nucleus.

Bushy cells in the ventral cochlear nucleus convey firing of auditory nerve fibers to neurons in the superior olivary complex that compare the timing and intensity of sounds at the two ears and enable animals to localize sound sources in the horizontal plane. Three voltage-sensitive conductances allow bushy cells to convey acoustic information with submillisecond temporal precision. All bushy cells have a low-voltage-activated, alpha-dendrotoxin (alpha-DTX)-sensitive K(+) conductance (g(KL)) that was activated by depolarization past -70 mV, was half-activated at -39.

Rate thresholds determine the precision of temporal integration in principal cells of the ventral cochlear nucleus.

The three types of principal cells of the ventral cochlear nucleus (VCN), bushy, octopus, and T stellate, differ in the detection of coincidence among synaptic inputs. To explore the role of the action-potential-generation mechanism in the detection of coincident inputs, we examined responses to depolarizing currents that increased at varying rates. To fire an action potential, bushy cells, likely of the globular subtype, had to be depolarized faster than 4.

Hyperpolarization-activated currents regulate excitability in stellate cells of the mammalian ventral cochlear nucleus.

The differing biophysical properties of neurons the axons of which form the different pathways from the ventral cochlear nucleus (VCN) determine what acoustic information they can convey. T stellate cells, excitatory neurons the axons of which project locally and to the inferior colliculus, and D stellate cells, inhibitory neurons the axons of which project to the ipsi- and contralateral cochlear nuclei, fire tonically when they are depolarized, and, unlike other cell types in the VCN, their firing rates are sensitive to small changes in resting currents. In both types of neurons, the hyperpolarization-activated current (I(h)) reversed at -40 mV, was activated at voltages negative to -60 mV, and half-activated at approximately -88 mV; maximum hyperpolarization-activated conductances (g(h max)) were 19.

Temperature affects voltage-sensitive conductances differentially in octopus cells of the mammalian cochlear nucleus.

Temperature is an important physiological variable the influence of which on macroscopic electrophysiological measurements in slices is not well documented. We show that each of three voltage-sensitive conductances of octopus cells of the mammalian ventral cochlear nucleus (VCN) is affected differently by changes in temperature. As expected, the kinetics of the currents were faster at higher than at lower temperature.

Cell-specific, spike timing-dependent plasticities in the dorsal cochlear nucleus.

In the dorsal cochlear nucleus, long-term synaptic plasticity can be induced at the parallel fiber inputs that synapse onto both fusiform principal neurons and cartwheel feedforward inhibitory interneurons. Here we report that in mouse fusiform cells, spikes evoked 5 ms after parallel-fiber excitatory postsynaptic potentials (EPSPs) led to long-term potentiation (LTP), whereas spikes evoked 5 ms before EPSPs led to long-term depression (LTD) of the synapse. The EPSP-spike protocol led to LTD in cartwheel cells, but no synaptic changes resulted from the reverse sequence (spike-EPSP).

What's a cerebellar circuit doing in the auditory system?

The shapes of the head and ears of mammals are asymmetrical top-to-bottom and front-to-back. Reflections of sounds from these structures differ with the angle of incidence, producing cues for monaural sound localization in the spectra of the stimuli at the eardrum. Neurons in the dorsal cochlear nucleus (DCN) respond specifically to spectral cues and integrate them with somatosensory, vestibular and higher-level auditory information through parallel fiber inputs in a cerebellum-like circuit.

Bidirectional synaptic plasticity in the cerebellum-like mammalian dorsal cochlear nucleus.

The dorsal cochlear nucleus integrates acoustic with multimodal sensory inputs from widespread areas of the brain. Multimodal inputs are brought to spiny dendrites of fusiform and cartwheel cells in the molecular layer by parallel fibers through synapses that are subject to long-term potentiation and long-term depression. Acoustic cues are brought to smooth dendrites of fusiform cells in the deep layer by auditory nerve fibers through synapses that do not show plasticity.