Xiao-Jie Cao

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. T stellate cells receive 6.5 inputs. Octopus cells receive >60 inputs. The N-methyl-d-aspartate (NMDA) components of eEPSCs were largest in T stellate, smaller in bushy, and smallest in octopus cells, and they were larger in neurons from younger than older mice. The average AMPA conductance of a unitary input is 22 ± 15 nS in both groups of bushy cells, <1.5 nS in octopus cells, and 4.6 ± 3 nS in T stellate cells. Sensitivity to philanthotoxin (PhTX) and rectification in the intracellular presence of spermine indicate that AMPA receptors that mediate eEPSCs in T stellate cells contain more GluR2 subunits than those in bushy and octopus cells. The AMPA components of eEPSCs were briefer in bushy (0.5 ms half-width) than in T stellate and octopus cells (0.8-0.9 ms half-width). Widening of eEPSCs in the presence of cyclothiazide (CTZ) indicates that desensitization shortens eEPSCs. CTZ-insensitive synaptic depression of the AMPA components was greater in bushy and octopus than in T stellate cells.

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. In these neurons, phasic excitation from the auditory nerve is made more tonic by feedforward 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.

In the ventral cochlear nucleus Kv1.1 and subunits of HCN1 are colocalized at surfaces of neurons that have low-voltage-activated and hyperpolarization-activated conductances

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 in mice 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 approximately 60% contain Kv1.1 (potassium channels in the shaker or KCNA family) subunits; gh arises through channels that include hyperpolarization and cyclic nucleotide gated (HCN) 1 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 immunofluorescent labeling for only Kv1.1.

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 in je/je mice. J. Comp. Neurol. 510:297–308, 2008.

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. 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.

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

&NA; Low‐voltage‐activated K+ (gKL) and hyperpolarization‐activated mixed cation conductances (gh) mediate currents, IKL and Ih, 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, gKL and gh contribute to the resting potential and shape responses to even small subthreshold synaptic currents. Resting gKL and gh also affect the coupling of somatic depolarization with the generation of action potentials. To learn how these important conductances are regulated we have investigated how genetic perturbations affect their expression in octopus cells of the ventral cochlear nucleus (VCN). We report five new findings: First, the magnitude of gh and gKL varied over more than two‐fold between wild type strains of mice. Second, average resting potentials are not different in different strains of mice even in the face of large differences in average gKL and gh. Third, IKL has two components, one being &agr;‐dendrotoxin (&agr;‐DTX)‐sensitive and partially inactivating and the other being &agr;‐DTX‐insensitive, tetraethylammonium (TEA)‐sensitive, and non‐inactivating. Fourth, the loss of Kv1.1 results in diminution of the &agr;‐DTX‐sensitive IKL, and compensatory increased expression of an &agr;‐DTX‐insensitive, tetraethylammonium (TEA)‐sensitive IKL. Fifth, Ih and IKL are balanced at the resting potential in all wild type and mutant octopus cells even when resting potentials vary in individual cells over nearly 10 mV, indicating that the resting potential influences the expression of gh and gKL. The independence of resting potentials on gKL and gh shows that gKL and gh do not, over days or weeks, determine the resting potential but rather that the resting potential plays a role in regulating the magnitude of either or both gKL and gh. HighlightsThe large size of gh and gKL in octopus cells allowed us to resolve and measure Ih and IKL at the resting potential.Perturbing the magnitude and subunit composition of these conductances genetically did not affect average resting potentials.IKL balanced Ih at rest in all octopus cells, regardless of mouse strain and individual resting potential.Instead of gh and gKL regulating the resting potential, it seems that the resting potential regulates gh and gKL.

Temporal Processing in the Auditory Pathway

The ability to localize sounds and to perceive pitch depends on the ability of neurons to carry acoustic information concerning the fine structure of sounds in the timing of firing, but our understanding of speech depends on our ability to detect envelopes in the acoustic energy. Some neurons at early stages in the auditory pathway are neuronal differentiators that encode transient depolarizations that signal acoustic transients and periodicity with great temporal precision but are unable to respond to slow depolarizations. Other types of neurons encode timing with less precision but can respond to slow depolarizations; these can signal the envelope of the acoustic energy to which they are tuned.