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Home , Cochlear nucleus

5/23/19

Auditory & Cochlear Auditory nerve Ventral Cochlear Dorsal Nucleus Nucleus

Amanda M. Lauer, Ph.D. Associate Professor Center for and Balance Dept. of Otolaryngology-HNS Johns Hopkins University SOM www.lauerlab.com Overview

Physiology: in situ vs. slices Anatomical techniques: and in vivo single cell recordings staining and microscopy

DCN AVCN

PVCN VIII 200 µm Mouse Chanda, Oh, & X-F (2011)

Auditory nerve in the cochlea ( Neurons)

Spiral ganglion neurons (SGNs)

Lauer lab: CBA/CaJ mouse

Ribbon synapse

Basic structure of the auditory nerve

Nouvian et al. 2005

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126 M. A. MERCHAN AND OTHERS

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Central projections of the4 auditory nerve Type I and type II SGNs I+ labeled with tracers, antibodies, genetic tags

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Spoendlin 1979 VCN- Two types of auditory nerve fibers: ( . _ • I-myelinated; ~90%; form synapses

with IHCs; extensive projections to Fig. 4(a-c). HRP tracing. Transverse sections of the DCN and the VCN (posterior division). Merchan(a) General, Merhcanpattern, Saldanaof distribution 1994of HRP,primary ratcochlear afferents. LauerVCN (*) Lab,shows VGLUT1HRP labelling Lauer Lab, VGLUT1 CN the concentration of label appears in the DCN, in a semilunar area (S) although higher antibody, mouseplaced reporter mouse at the boundary with the VCN The remaining areas of the DCN (arrowheads) are practically Muniak et al. 2016 devoid of label. x 200. (b) Detail of the HRP-positive areas in Fig. 4(a). Axons in the VCN • II-unmyelinated; ~5-10%; form turn parallel when they arrive at the interface with the DCN (DN). The DCN shows higher positivity and an irregular distribution pattern. x 4160. (c) Labelled axons in the DCN. Primary synapses with OHCs; limited cochlear afferents are distributed over the deep layer (1), but some of them reach the central layer (fusiform cell layer; 2) of the nucleus. No primary cochlear afferents appear at the molec- projections ular layer (3). Arrows point to mossy enlargements of the fibres. x 1500.

Auditory nerve projections to CN are tonotopically organized

Auditory nerve fibers bifurcate and Muniak et al. 2016 send tonotopic projections to dorsal (DCN) and ventral (VCN) cochlear nucleus. The nerve projects anteriorly and posteriorly in VCN.

These projections form synapses with several CN principal neuron types, which we will cover later. Normal auditory How do you think these data were obtained (experiments)? nerve physiological

3-D Frequency Map of Mouse CN responses

Thresholds and frequency tuning Thresholds and spontaneous (spectral coding) activity

Adapted from Palmer and Evans 1975

Base Bharadwaj et al. 2014

Auditory nerve fibers with high spontaneous activity have low thresholds.

Low spontaneous activity fibers have high thresholds. Do you recall why there is a big onset response followed by a smaller sustained response? From Pickles (2008)

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Spontaneous activity and rate-level Temporal coding: phase locking and the functions (dynamic range/intensity coding) volley theory

Auditory nerve fibers increase Volleying Phase locking firing rate with increasing sound levels up to a saturation point.

Low spontaneous activity fibers have higher saturation points than high spontaneous fibers..

Bharadwaj et al. 2014

A short lesson about speech

Time waveform

Spectrogram How does the auditory nerve encode stimuli with complex stimuli that change in frequency and intensity over time?

A short lesson about speech Speech coding

Five women played basketball

The auditory nerve must convey the Speech temporal fluctuations in amplitude and frequency from the cochlea to the brain. ANF How does it represent this complex information? Speech (higher Rate coding plus place coding: auditory time res) nerve fibers with best frequencies closest to the speech formant will response at the highest rates. ANF (higher time res)

Representation of vowel formants Young 2008 (Fourier transform) 18

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Enter code: #C230 Cochlear nucleus: Submit answers to First stage in the question. central auditory Type in questions processing you have about the auditory nerve.

Ascending central Descending central auditory system

System tasks: Cortex System tasks: • What to pay attention to • Receives frequency, timing, intensity • Modulation of afferent information cues from cochlea depending on behavioral state • Requires coordinated effort of many • Hearing in noise, separating out structures & neuron types to transform these cues into perceptions competing sounds – Detect a sound – Where is the sound coming from? – What is the source of the sound? – What does the sound mean? – Separate simultaneous sound streams in an acoustic scene (cocktail party)

Kubke and Wild 2018 Kubke and Wild 2018 Fuchs and Lauer 2018

Early studies of auditory brainstem Early studies of auditory brainstem structure were performed in Spain! structure were performed in Spain!

Santiago Ramon y Cajal

Which theory of nervous system organization is illustrated in this drawing? What was the other prevailing theory?

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Auditory nerve input to cochlear nucleus

First place in brain that processes acoustic information (not just a relay)

Multiple jobs: How does • Encoding cues used for sound cochlear localization (timing and intensity in AVCN with inhibition from DCN, nucleus do all monaural/spectral in DCN with input from VCN) of these jobs?

• Differentiating self-generated vs. external sounds and coordinating with other senses (DCN)

Muniak et al. 2016 • Encoding spectrotemporal cues in complex sounds such as vocalizations

Different cell types: Major input from auditory

Adapted from Osen, 1969 nerve.

Diverse types of neurons in different regions are optimized to encode different acoustic cues: Break? Spherical bushy cell • Bushy cells: timing, intensity

Octopus cell • Multipolar/stellate: spectral shape

• Octopus cells: broadband Globular bushy cell onsets Multipolar cell

Auditory nerve endbulb/bushy cell interface

Bushy cell receives ~1-20 endbulbs.

Endbulbs: specialized axosomatic auditory nerve synapses with many release sites for high-fidelity transmission of information.

Lauer & Xu-Friedman labs Dendrites of other bushy cells form synapses with endbulbs, forming nests VCN response of cells—for what? types Lauer et al. 2013, PLOS ONE

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Bushy cells are very good at encoding Bushy cell responses temporal cues

Responses to tones are similar to Excitatory auditory nerve responses and are Inhibitory narrowly tuned.

Primary-like=spherical bushy cells (low frequency). Primary-like with notch=globular bushy cells (high

frequency). Slightly different inputs. Young and Oertel

Lauer et al., 2013 Responses shaped by glycinergic Bushy cells are very good at processing (and GABAergic) input from ~5 temporal information. sources (most from DCN, VCN), Some units actually show better phase Pri-N cholinergic inputs from multiple Lauer Lab Pri sources. locking than auditory nerve fibers.

The endbulbs are very plastic in response to acoustic experience! Blackburn and Sachs 1990

Endbulbs & bushy cells can fire at high rates Auditory brainstem responses (ABRs) as an assay and show activity-dependent plasticity of auditory nerve/bushy cell-driven pathways

Larger synapses and more release sites ABRs are a rapid, high through-put Early age exposure to 1 week ~85 dB SPL assessment of synchronous activity in background noise facilitates endbulb synapses and auditory nerve/bushy cell-driven pathways. improves the fidelity of bushy cell action potential firing by increasing the number of release sites in Auditory Brainstem Response (ABR) Also a standard estimate of hearing status in juvenile and young adult. P4 94 dB click P3 small animals and babies. P2 P5 These changes are recoverable. P1 A useful tool to compare hearing across N5 N2 many species and after experimental N3 N4 N1 manipulations. 2 ms 5 ms Visit my lab for a demo at JHU!

Facilitation of EPSCs More reliable spiking with high frequency Ngodup et al. 2015, PNAS (Xu-Friedman and Lauer labs) stimulation

T stellate cells (type I multipolar, planar, T stellates-responses and non- chopper) AN sources of inputs

Oertel et al. 2011

Chanda and Xu-Friedman 2010 T stellates are excitatory and show tonic T stellates are most populous in the area (chopping) responses to tones. Narrow around the the auditory nerve root and frequency tuning. Oertel et al. 2011 near the granule cell domain. “T” because axons pass through the . They receive inputs from many sources.. Most inputs are to the (multiple) dendrites..

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T stellates specialize in coding the spectral D Stellate cells: Inhibitory interneurons shapes of sounds such as speech

T stellates encode spectral D (dorsally projecting) stellates are features of sound very well). inhibitory (glycinergic) interneurons that showtransient responses to onset of Why do the peaks look sharper tones. than in the auditory nerve? Broad tuning. Many axosomatic and Lauer lab axodendritic inputs.

Source of broadband inhibition within VCN and DCN..Inhibit bushy and T stellate cells in VCN.

Eric Young, Smith and Rhode 1989

Stellate cell projections within CN Octopus cells

Integration between VCN and DCN. Octopus cells (excitatory) receive auditory nerve inputs via small T (planar) stellates project to DCN in a bouton terminals covering their frequency-specific manner. soma and dendrites.

D stellates (radiate) have more diffuse Lauer lab They fire at the onset of terminal fields. broadband sounds, requiring many simultaneously active auditory nerve inputs.

Occasional inputs from other Blackburn and Sachs 1990 octopus cells or inhibitory sources (rare) are observed..

Malmierca 2013, based on work by Ryugo

Octopus cells compensate for cochlear delay VCN seems to take care of most of the encoding of important acoustic cues. So what does DCN do?

McGinley et al. 2012

Octopus cells receive high frequencies on their dendrites and low frequencies on their soma, which compensates for the auditory nerve delay.

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Laminar organization of DCN DCN cell layers and types compared to VCN Layer 1-Molecular (Superficial) • Granule cell axons and small stellate interneurons • Cartwheel cell and pyramidal/fusiform cell dendrites

Layer 2-Pyramidal (Fusiform) • Pyramidal cell bodies-most numerous principal cells • Cartwheel cells • Granule cells

Layer 3&4-Deep From Osen 1990 • Auditory nerve fiber axons Osen (tonotopic) • Giant cells (2nd principal cell type) • Vertical/tuberculoventral cells 5/23/19 43

Cerebellum-like circuit in DCN

DCN, Oertel & Young DCN response What does this suggest about DCN’s role in hearing? types

Responses depend on stimulus level Response types and role of inhibition

There are many response types in DCN-complex circuitry.

Note: DCN neurons do not all respond to sound, do not normally show much spontaneous activity.

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DCN may tell your brain what sounds Processing monaural spectral cues to pay attention to

DCN neurons are good at processing monaural spectral Hernandez-Peon et al (1956) cues from the pinnae.

These cues are mainly used to localize sound in the median vertical plane, where binaural cues are absent.

DCN neurons also cancel responses to self-generated sounds.

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Answer the questions! End of ANF/CN lecture! Questions?

Coronal sections of ventral (VCN) and dorsal (DCN) cochlear nucleus

In case of questions

Muniak et al 2013

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Major outputs of VCN neurons Main--DCN projections

Young and Oertel

A closer look at the granule cell domain Responses are shaped by synaptic integration/inhibition

Weedman and Ryugo 1995 Granule Fusiform and giant cell cell responses to sound are shaped by multiple excitatory and inhibitory inputs.

Combined, these two types of responses allows detection of Golgi cell sounds with spectral peaks and notches.

Fluorescence: Yaeger & Trussell 2015; Borges-Merjane & Trussell 2015

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