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6/1/2010 The Cochlear Nucleus Salamanca June 2010 Maria E. Rubio University of Pittsburgh Cajal The Cochlear Nucleus The cochlear nucleus (CN) contains the circuits through which information about sound is coupled to the brain. In the CN, fibers of the auditory nerve contact neurons that form multiple, parallel representations of the acoustic environment. These circuits vary from simple synapses that preserve the timing of auditory events to complex neuropils that are sensitive to features that identify sounds. The parallel pathways each perform a different analysis of the auditory signal. Thus calculations such as the localization of a sound source in the space or the identification of a sound so nd are separated in the CN and performed in parallel as signals ascend through the brainstem auditory nuclei. (Young and Oertel) Schematic View of the Human Auditory Pathway 1 6/1/2010 The Cochlear Nucleus Gross Anatomy Pathways (afferents and efferents) Cell types Synaptic Circuitries (intrinsic connections) Specialized Synapses Plasticity: deafness and hearing loss Cajal Rat Brain: Gross Anatomy Lateral view: dissection Superior view Ventral view Dorsal view: dissection Auditory Nerve (AN) Ventral cochlear nucleus (VCN) Dorsal cochlear nucleus (DCN) 2 6/1/2010 Sectional Anatomy of the Cochlear Nucleus and Auditory Nerve Fibers Distribution AN: Ascending and descending branches Lateral view DCN AVCN R t l Rostral AN PVCN Caudal A sagittal slice of the cochlear nucleus of a mouse, with the auditory nerve entering from the bottom leftt, the anteroventral cochlear nucleus in the top left, and the dorsal cochlear nucleus in the top right. Auditory nerve fibers were labelled by injecting dextran‐conjugated Alexa488 into the cochlea. They label frequency‐specific bands in the AVCN. The molecular layer of the dorsal cochlear nucleus is labelled with an antibody against the cannabinoid receptor CB1 (courtesy of Dr. Ken Mackie, UWash). Cell nuclei are labelled with a DAPI counterstain. The scale bar is 200 µm. Cat CN (Ryugo and Parks, 2003) Cochlear Nucleus & Auditory Nerve Fibers Distribution Tonotopy!!! Lateral view The innervation of the CN by AN fibers is orderly and reflects the tonotopic organi ation of the cochlea organization R t l Rostral Auditory Nerve (Type I fibers): Low frequencies: ventral & lateral g frequencies: q dorsal & medial High Caudal Cat CN (Ryugo and Parks, 2003) 3 6/1/2010 Ventral Cochlear Nucleus (VCN) 1 The Core The granular cell domain (GCD; cap) 2 3 Dorsal Cochlear Nucleus (DCN; layered) 1 Molecular layer 2 Fusiform cell layer 3 Deep layer Oertel D et al. PNAS 2000 Ventral Cochlear Nucleus (VCN): Subdivisions The Core The granular cell domain (GCD; cap) Photomicrograph (A) and drawing (B) illustrating the GCD of the CN in the rat. Granule cells were retrogradely labeled by placing an extracellular injection of diamidino yellow in the DCN. The labeled cell bodies form a shell along the lateral, dorsal, and dorsomedial surface of the VCN. This distribution is coincident with the distribution of the GCD as previously described (Mugnaini et al 1980).Scale bar=100um. Zhang and Ryugo, 2007 JCN 4 6/1/2010 Targets of the Cochlear Nucleus Cant and Benson 2003 The figure is based on degeneration studies in the cat by Warr and Fernandez and Karapas with additional details gleaned from studies done using a variety of different retrograde and anterograde tracing techniques. AVCNa: anterior part of the anteroventral cochlear nucleus; AVCNp: posterior part of the AVCN; CN: central nucleus of the inferior colicullus; DAS: dorsal acoustic stria; DC: dorsal cortex of the inferior colliculus; DCN: dorsal cochlear nucleus; DMPO: dorsomedial periolivary nucleus; DNLL: dorsal nucleus of the lateral lemniscus; EC: external cortex of the inferior colliculus; IAS: internal acoustic stria; IC: inferior colliculus; INLL: intermediate nucleus of the lateral lemniscus; LSO: lateral superior olivary nucleus; mc: magnocellular division of the medial geniculate body; MGB: medial geniculate body; MNTB: medial nucleus of the trapezoid body; MSO: medial superior olivary nucleus; PGCL: lateral paragigantocellular nucleus; PnC: caudal pontine reticular nucleus; PnO: oral pontine reticular nucleus; PO: periolivary nuclei; pm: posteromedial part of the ventral nucleus of the lateral lemniscus; PVCNa: anterior part of the posteroventral cochlear nucleus; PVCNp: posterior part of the posteroventral cochlear nucleus; sag: sagulum; SC: superior colliculus; SPN: superior paraolivary nucleus; TB: trapezoid body; VCN: ventral cochlear nculeus; VLMN: ventral medullary nucleus; VLTg: ventral tegmental area; vm: ventromedial part of the ventral nucleus of the lateral lemniscus; VNLL: ventral nucleus of the lateral lemniscus. The Cochlear Nucleus Targets within the Cochlear Nucleus - Intrinsic connections (axons from interneurons) - Commissural fibers (from the other cochlear nucleus) Targets to the Cochlear Nucleus Auditory - Cortex - Inferior f colliculi - Medial olivary complex (MOC) Non-auditory - Trigeminal nucleus - Reticular formation - others.. 5 6/1/2010 The Cochlear Nucleus Gross Anatomy Pathways (afferents and efferents) Cell types Synaptic Circuitries (intrinsic connections) Specialized Synapses Plasticity: deafness and hearing loss Cajal Neurons as independent entities Neuron doctrine 6 6/1/2010 The Structure of a Neuron Dendrites - branching fibers that get narrower as they extend from the cell body toward the periphery; information- receiver Dendritic spines - short outgrowths that increase the surface area available for synapses Cell body - contains the nucleus and other structures found in most cells Axon - thin fiber of constant diameter, in most cases longer then the dendrites; informationinformation sender Myelin sheath - insulating material covering the axons; speed up communication in the neuron Presynaptic terminal - the point on the axon that releases chemicals Martinotti Cajal-Retzius Sertoli Deiters Golgi Purkinje Lugaro Meynert Stellate Multipolar Bi l Bipoloar Unipolar Pseudo-unipolar Octopus Mitral Horizontal Pyramidal Globular Fusiform Granule Spherical Projection Motor Sensory Basket Interneuron Local Horizontal Tuberculoventral 7 6/1/2010 Neuronal types Dendritic arborization Body shape Function Dendrites exhibit enormously diverse forms The shape of the dendritic arbor can be related to the of connectivity among neurons Complexity of dendrites reflects the number of connections that a neuron receives Cajal Terms Associated with Neurons Intrinsic/interneuron -the cell’s dendrites and axon’s are entirely contained within a single structure Projection neuron -the cell’s dendrites and axon’s are contained in different structures Efferent axon -carries information away from the structure Afferent axon -brings information into a structure 8 6/1/2010 The Cochlear Nucleus Cytoartichecture (cell types) Cajal Principal neurons (Projection neurons) Other (interneurons) The Cochlear Nucleus Each cochlear nucleus cell type has a unique pattern of response to sound, consistent wit the idea that each type is involved in a different aspect of the analysis of the information of the auditory nerve. Cajal The diversity of the pattern can be accounted for by three features that vary among the principal cells: 1) The pattern of the innervation of the cell by the AN fibers 2) The electrical properties of the cells that shape synaptic inputs 3) The interneuronal circuitry associated with the cell 9 6/1/2010 The Cochlear Nucleus Cytoartichecture Principal neurons (Projection neurons).. Cajal .. are arranged in such a way that each type receives input from AN fibers over the whole tonotopic range. Each principal cell type carries a separate but complete representation of the sound coming to the ear on that side of the head. Project to different targets in the brainstem, they form separate, parallel pathways Other (interneurons) The Cochlear Nucleus Cytoartichecture Old classification Santiago Ramon y Cajal Rafael Lorente de No Cajal Modern Classification Kristen Osen (1969) Kent Morest / Nell Cant and colleagues (1974-1984) 10 6/1/2010 The Cochlear Nucleus Ventral Cochlear Nucleus (VCN) Anterior (AVCN) Posterior (PVCN) Sound localization in the lateral plane!! Timing!!!! The Ventral Cochlear Nucleus (VCN): AVCN Timing!!!! Bushy cells Spherical bushy cells (SBC) (+) Globular bushy cells (GBC) (+) Multipolar cells D-stellate (+) ( ) T-stellate (-) 11 6/1/2010 The Ventral Cochlear Nucleus (VCN): AVCN Timing!!!! Bushy cells - Spherical bushy cells (SBC) (+): located in the most rostral region short dendrites that terminate in a “bush” Multipolar cells located more caudally y multiple, long dendrites T-stellate (-) (planar) dendrites aligned with AN fibers D-stellate (+) (radiate) dendrites not aligned with AN fibers - Globular bushy cells (GBC) (+) located more caudally more ovoid and larger cell bodies Projections differ 1-2 short dendrites AN on cell body and dendrites /different coverage Projections differ / axons have collateralss Posteroventral Cochlear Nucleus (PVCN) “teardrop-shaped area” Octopus cells Dendrites are: - oriented, inspiring their name - perpendicular to the AN fibers/ - receive a wide range of best frequencies (BFs) Cell bodies low BF / dendrites towards high BF Oertel D et al. PNAS 2000 12 6/1/2010 Rostral Caudal/Posterior Hackney et al., 1990 The Cochlear Nucleus Anterior (AVCN) / Posterior (PVCN) Dorsal Cochlear Nucleus (DCN) In nonprimate mammals, the DCN is thought to play a role in the orientation of the head toward sounds of interest by integrating acoustic & somatosensory information Cajal 13 6/1/2010 The Dorsal Cochlear Nucleus: Cytoartichecture Layered structure Molecular Layer (ML) Fusiform Layer (FCL) Deep layer (DL) Cajal The Dorsal Cochlear Nucleus: Cytoartichecture Schematic rendering of part of the circuit of the dorsal cochlear nucleus, looking en face at an isofrequency sheet (top), and looking down from the top of the nucleus at 3 such sheets (bottom). Hackney et al., 1990 Paul Manis (Chapel Hill North Caroline) 14 6/1/2010 DCN Principal Neurons (projection neurons) DCN main interneurons 15 6/1/2010 The Dorsal Cochlear Nucleus: Cytoartichecture Layered structure Molecular Layer (ML) Cartwheel cells (-) Stellate cells (-) Dendrites off …. Axons of….. Fusiform Layer (FCL) Cartwheel cells (-) Fusiform or pyramidal cells (+) Granule cells (+) Dendrites of…. A Axons off … Deep layer (DL) Vertical cells (-) Giant (multipololar) cells (+) Dendrites of …. Axons of …. The Dorsal Cochlear Nucleus: Cytoartichecture To the immediate left is a f schematic rendering of part of the circuit of the dorsal cochlear nucleus, looking en face at an isofrequency sheet (top), and looking down from the top of the nucleus at 3 such sheets (bottom). Pyramidal cells, cartwheel cells, stellate cells, vertical cells, and granule cells. Paul Manis (Chapel Hill North Caroline) 16 6/1/2010 Brainstem targets of seven cell types in the ventral cochlear nucleus (A–G) and two cell types in the dorsal cochlear nucleus (H, I). For each cell type the heavy black line indicates the projections that have been identified directly or for which there is solid indirect evidence (see text). The route out of the cochlear nucleus taken by the axons (trapezoid body, ) intermediate or dorsal acoustic stria) is indicated at the origin of the line. The boxes indicate the multiple brainstem targets of the cochlear nucleus; those that are not known to receive inputs from the cell in question are shown in gray outline, and those that do receive inputs are shown in black outline and labeled. The boxes are in the same positions on all parts of the figure. Abbreviations are same as in slide #9; also: POL, lateral periolivary group; POV, ventral periolivary group. (A) Large spherical bushy cell. Dashed line in box labeled MSO indicates that the projection is to only one‐half of the nucleus. (B) Small spherical bushy cell. The LSO is the only known target of these cells. The dashed line ending in a question mark indicates that very little is known about their projections. (C) Globular bushy cell. The projection to LSO has been described in rat but appears to be minor or absent in cats (see text). (D) Octopus cell. (E) Cochlear root neuron. (F) Type I multipolar cell. The LSO and lateral PO groups receive inputs from multipolar cells in the VCN, but it has not been established that these arise from the type I multipolar cells. (G) Type II multipolar cell. (H) Fusiform cell of the DCN. (I) Giant cell of the DCN. Cant and Benson 2003 Cochlear Nucleus Parallel Pathways to IC Py/Gi PON & nLL O DAS & IAS LSO M LSO MSO MSO SBC IHC GBC SBC LnTB TB Contra CN MnTB ANF (modified from Oertel and Young) 17 6/1/2010 The Cochlear Nucleus Synaptic circuits VCN DCN Cajal Human The auditory pathway The Cochlear Nucleus as Experimental Model (rodents; primates) FUSIFORM CELLS dorsal cochlear nucleus (DCN) CARTWHEEL CELLS PF GRANULE CELLS VERTICAL CELLS EXTRINSIC INHIBITORY INPUT SOMATOSENSORY INPUT AUDITORY NERVE BUSHY CELLS ventral cochlear nucleus (VCN) 18 6/1/2010 Chemical Synapses Gray Type I: excitatory Gray Type II: inhibitory Types of contacts: Axo-dendritic Axo-somatic Dendro-dendritic Axo-axonic Glutamate Acetylcholine GABA Glycine dendrite Spiny Non-spiny Electron microscopy: Ultrastructure 19 6/1/2010 Glutamate Acetylcholine Ultrastructure of Synapses GABA Glycine Multiple Cell Types Pyramidal Cells Purkinje Cells Fusiform Cells Granule Cells Afferents Efferents 20 6/1/2010 VCN: The Core The granular cell domain (GCD; cap) DCN (layered): 1 Molecular layer 2 Fusiform cell layer 3D Deep llayer FUSIFORM CELLS in the dorsal cochelar nucleus (DCN) PF CARTWHEEL CELLS GRANULE CELLS VERTICAL CELLS EXTRINSIC INHIBITORY INPUT SOMATOSENSORY INPUT AUDITORY NERVE BUSHY CELLS in the anteroventral cochlear nucleus (AVCN) 21 6/1/2010 The Cochlear Nucleus Synaptic circuits VCN DCN Synaptic specializations Deafness and Hearing Loss models Cajal Presynaptic membrane Postynaptic membrane 22 6/1/2010 Targets of the Auditory nerve in ventral and dorsal divisions of the cochlear nucleus FUSIFORM CELLS in the dorsal CN Contralateral Inferior Colliculus (IC) Type I BCs and FCs receive glutamatergic innervation from the AN, but they respond differently to sound, they also have different pathways in the brain. Different morphological characteristics and the arrangement of neurotransmitter receptors at those synapses can vary to facilitate the functional role of each synapse. dendrite/ cell body Contralateral Medial Nucleus of the Trapezoid Body (MNTB) Glycine R: 〈1, 〈3?, ® GABA? AUDITORY NERVE AMPA: GluR2-4 NMDA mGluRs BUSHY CELLS in anteroventral CN Electron microscopy: Ultrastructure / Molecular components AN AN 23 6/1/2010 SDS-freeze fracture labeling (SDS-FRL) C-terminus Abs N-terminus Abs Gomez-Nieto and Rubio 2009 JCN Modified from Fujimoto 1995 J Cell Sci IMP (intramembrane particle) cluster of Bushy cells IMPS in basal dendrites of Fusiform cells E-face AN 24 6/1/2010 IMP clusters of AN-BC synapses are compact IMP clusters of AN-FC synapses are less compact DCN: Molecular Layer Membranes of Cartwheel cell - spines PF Golgi-TEM CwC AMPARs: GluR1 GluR2 GluR3 little GluR4 NMDARs: NR1 Metabotropic Delta 1/2 These synapses are plastic: LTP (long term potentation) LTD (long term depresion) Wouterlood and Mugnaini JCN ‘84 25 6/1/2010 PF CwC DCN: Molecular Layer IMP clusters of synapses involved in synaptic plasticity are large and very irregular in shape panAMPA (5nm) + NR1 (10nm) GluR3 (5nm) Average area IMPs = 0.074+0.015um2 Inhibitory Synapses GABA and/or Glycine Receptors Excitatory Synapses Glutamate Receptors Ionotropic AMPA NMDA Kainate Delta Metabotropic 26 6/1/2010 Low levels of GluR2 AMPA receptor subunit in the AVCN GluR2 GluR2/3 The GluR2 subunit is important for Ca++ permeability. Low levels of GluR2 makes the AN-BC Synapse permeable to Ca++. GluR2 GluR2/3 Wang et al.,1998 Relevance of Glutamate receptors in the Excitatory Synaptic Circuit of Fusiform Cells in the Dorsal Cochlear Nucleus slow? PF Parallel Fibers AN fast? GluR1 GluR2 GluR3 GluR4 NR1 NR2A/B mGluR1a Delta 1/2 Auditory Nerve Rubio and Wenthold 1997 Neuron 27 6/1/2010 Postembedding immunocitochemistry for AMPA receptors subunits at excitatory synapses on fusiform cells revealed a differential subunit distribution Parallel Fibers Auditory Nerve Rubio and Wenthold 1997 Neuron Glutamate receptors are selectively targeted to postsynaptic sites in neurons slow? fast? Receptors NUMBER OF GOLD PARTICLES PER ⎧m OF PSD +SEM Auditory Nerve Synapses (basal dendrites) Parallel Fiber Synapses (apical dendrites) 17.7 + 4.0 9 1 + 1.1 9.1 11 19.1 + 2.2 6.4 + 1.4 8.0 + 1.3 8.3 + 1.2 16.5 + 3.2 72 + 1 7.2 1.2 2 0 9.8 + 1.3 0 33.9 + 3.1 GluR2/3 GluR2 GluR4 NR2A/B mGluR1〈 Delta1/2 Rubio and Wenthold 1997 Neuron 28 6/1/2010 The Cochlear Nucleus Synaptic circuits VCN DCN Synaptic specializations Deafness and Hearing Loss models Cajal Deafness and Hearing Loss Plasticity Molecular-Anatomical approach Ryugo lab 29 6/1/2010 Deafness affects the Auditory Nerve Synapse on Bushy Cells Cat CN (Ryugo and Parks, 2003) Deafness affects the Auditory Nerve Synapse on Bushy Cells Reconstruction of serial electron micrographs Cat CN (Ryugo and Parks, 2003) 30 6/1/2010 Time frame after peripheral damage Unilateral cochlear ablation D Degeneration ti off auditory dit nerve fibers fib Day 1 Day 0 4 hours Sprouting 2 days 7 days ABR Rubio 2006 Hearing Research Morphological changes at the postsynaptic sites precede presynaptic changes at the AN ending in response to peripheral damage Control X Thickn ness in nm 60 * 4 hours Control Ipsilateral side Rubio 2006 Hearing Research 31 6/1/2010 Summary/Conclusions: The synapse is plastic The auditory nerve maintains synapse morphology Do changes in synapse morphology reflect function? Neurotransmitter Receptors Inhibitory Synapses GABA and/or Glycine Receptors Excitatory Synapses Glutamate Receptors p Ionotropic AMPA NMDA Kainate Delta Metabotropic 32 6/1/2010 =? DNA RNA PROTEIN Changes in AMPA receptors accumulation Davis 2006 Ann Rev Neurosci Chronic suppression of neuronal activity can also lead to compensatory changes in the surface expression of excitatory and inhibitory neurotransmitter receptors: quantal signaling Turrigiano and Nelson 2004 Nature Rev Neurosci 33 6/1/2010 FUSIFORM CELLS in the dorsal cochelar nucleus (DCN) PF CARTWHEEL CELLS GRANULE CELLS VERTICAL CELLS EXTRINSIC INHIBITORY INPUT SOMATOSENSORY INPUT AUDITORY NERVE BUSHY CELLS in the anteroventral cochlear nucleus (AVCN) Does conductive hearing loss lead to changes in the expression of neurotransmitter receptors in the adult CNS? A unilateral An il t l ear-plugging l i model d l to asses the role of activity in synaptic organization Questions to investigate: 1) Whether hearing loss alters the composition of synaptic AMPAR in cochlear nucleus neurons receiving the AN. Do they respond in the same manner? 3) Whether cochlear neurons respond to hearing loss by downregulating synaptic glycine receptors. 2) Whether these changes occurred in a relatively short time (1 day) after unilateral earplug. Are the changes reversible? 34 6/1/2010 Ear plug provides ~20 dBA attenuation ABR response was determined before ear-plugging and quantified by measuring the latency of P2 as a function of stimulus intensity Whiting, Moiseff, Rubio 2009 Neuroscience AN Plugged Side AN SBC Auditory Nerve/Bushy cell synapse in VCN responds to earplugging GluR2/3 SBC GluR2 AN AN SBC SBC AN SBC AN GluR4 SBC Normal Hearing Density of gold particles/ length of PS SD Normal Hearing 45 40 35 30 25 20 15 10 5 0 *** 45 40 35 30 25 20 15 10 5 0 45 40 35 30 25 20 15 10 5 0 Plugged side (1 day) 35 6/1/2010 Plugged Side AN AN GluR2/3 FC FC AN GluR2 AN FC Auditory Nerve/Fusiform cell synapse in DCN responds to earplugging FC AN GluR4 AN FC Density y of gold particles/ length of PSD D Normal Hearing FC Normal Hearing 45 40 35 30 25 20 15 10 5 0 *** 45 40 35 30 25 20 15 10 5 0 45 40 35 30 25 20 15 10 5 0 *** Plugged side (1 day) 1-day earplugging scales synaptic AMPA receptors at the auditory nerve on bushy and fusiform cells synapses Densitty of gold particles/ length of PSD Normal Hearing Plugged side (1 day) Unplugged side (1 day) 45 40 35 30 25 20 15 10 5 0 *** * FUSIFORM CELLS In DCN *** Hearing loss (20dBA attenuation) 45 40 35 30 25 20 15 10 5 0 BUSHY CELLS in AVCN *** ** AUDITORY NERVE GluR2/3 GluR2 GluR4 2 animals per group 50 synapses per each condition and antibody ANOVA *** P<0.005 * P<0.05 36 6/1/2010 Parallel fibers do not show scaling of AMPA receptors in response to earplugging p gg g 1-day earplugging scales down the synaptic expression of GlyR〈1 on bushy and fusiform cells Plugged Side Density of gold particles/ length of P PSD AN/Fusiform cells in DCN 45 40 35 30 25 20 15 10 5 0 * * Normal Hearing Plugged Side (1 day) Unplugged Side (1 day) AN/Bushy cells in AVCN Density of gold particles/ length of PSD Normal Hearing 45 40 35 30 25 20 15 10 5 0 *** 37 6/1/2010 Synaptic changes in AMPA (GluR3) and GlyR〈1 receptors are reversible after ear plug removal AUDITORY NERVE Excitatory/glutamatergic synapses are found in the E-face membranes G ll Gulley, Wenthold W th ld and d Neises N i 1977 C-terminus Abs N-terminus Abs Modified from Fujimoto 1995 J Cell Sci 38 6/1/2010 SDS-freeze fracture labeling (SDS-FRL) IMP (intramembrane particle) cluster E-face Average area IMPs = 0.033+0.004um2 Bushy cells (BC) David Ryugo The Glur3 AMPAR subunit is a major component of the Auditory Nerve-Bushy Cell synapse panAMPA GluR2 GluR3 GluR4 39 6/1/2010 SDS-FRL detects an upregulation of the GluR3 AMPAR subunit at the Auditory nerve-Bushy cell synapse in response to hearing loss Normal Hearing Earplugged as well as morphological changes in the IMP cluster pan-AMPA GluR3 Student t-test p<0.005 Conclusions: Hearing reduction leads to changes in synaptic expression GluR3 and GlyR〈1 in neurons directly influenced by the AN. These changes g are fast,, depend p on the cell type yp and synapse y p and are reversible. The same neurons in the DCN contralateral to the hearing reduction and with normal AN synaptic input also redistribute synaptic GluR3 but differ in the expression of GlyR〈1. Conductive hearing loss leads to morphological changes of the AN BC synapse, AN-BC synapse and seems to alter intramembrane particles particles. The data suggest that the imbalance caused by attenuation of sound may be compensated by an increase in the excitatory and a decrease in the inhibitory receptors expression. 40 6/1/2010 Levels of Brain Organization Behavioral System Interregional Circuits Local (Regional) Circuits Neurons Dendritic Trees Synaptic Microcircuits Synapses Molecules Ions Genes DCN ML PF PF CwC GC FCL DL spine SS FC AN In nonprimate mammals, the DCN is thought to play a role in the orientation of the head toward sounds of interest by integrating acoustic & somatosensory information (synaptic circuitry; lamination; specific distribution of key proteins; synaptic plasticity) A putative source for tinnitus HOWEVER HOWEVER…..!!!! !!!! Humans & higher primates might not use this system because of reported phylogenetic changes in DCN cytoartichecture & associated granule cell regions Rubio et al. 2008 Neuroscience 41 6/1/2010 Phylogenetic changes in DCN cytoartichecture & associated granule cell regions CAT ml / fgl / cr MARMOSET egl / ml / fl / cr GIBBON pbf / mz / cr floc ml egl pbf ml fgl fl cr AVCN m mz AVCN cr cr PVCN PVCN PVCN AVCN lat Granular layer External granular layer Pbf: pontobulbar fibers post (modified from Moore 1980) egl pbf ml mz ml fl fl fl 42