Hearing Research Hearing Research 216–217 (2006) 90–99 Research Paper Somatosensory Inﬂuence on the Cochlear Nucleus and Beyond

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Hearing Research Hearing Research 216–217 (2006) 90–99 www.elsevier.com/locate/heares Research paper Somatosensory inﬂuence on the cochlear nucleus and beyond

Susan E. Shore *, Jianxun Zhou

University of Michigan, Otolaryngology, 1301 E Ann St, Ann Arbor, MI 48109, United States

Received 31 October 2005; received in revised form 5 January 2006; accepted 5 January 2006 Available online 2 March 2006

Abstract

Interactions between somatosensory and auditory systems occur at peripheral levels in the central nervous system. The cochlear nucleus (CN) receives innervation from trigeminal sensory structures: the ophthalmic division of the trigeminal ganglion and the caudal and interpolar regions of the spinal trigeminal nucleus (Sp5I and Sp5C). These projections terminate primarily in the granule cell domain, but also in magnocellular regions of the ventral and dorsal CN. Additionally, new evidence is presented demonstrating that cells in the lateral paragiganticular regions of the reticular formation (RF) also project to the CN. Not unlike the responses obtained from electri- cally stimulating the trigeminal system, stimulating RF regions can also result in excitation/inhibition of dorsal CN neurons. The origins and central connections of these projection neurons are associated with systems controlling vocalization and respiration. Electrical stim- ulation of trigeminal and RF projection neurons can suppress acoustically driven activity of not only CN neurons, but also neurons in the inferior colliculus. Together with the anatomical observations, these physiological observations suggest that one function of somatosensory input to the auditory system is to suppress responses to ‘‘expected’’ body-generated sounds such as vocalization or respiration. This would serve to enhance responses to ‘‘unexpected’’ externally-generated sounds, such as the vocalizations of other animals. 2006 Elsevier B.V. All rights reserved.

Keywords: Auditory; Cochlear nucleus; Pathways; Trigeminal; Reticular formation; Somatosensory; Non-auditory projections

1. Introduction tex (Aitkin et al., 1978, 1981; Eliades and Wang, 2003, 2005). However, more recent neuroanatomical and physi- It is well established that somatosensory and auditory ological data indicate that somatosensory and auditory signals are integrated by auditory neurons in the inferior information converge at more peripheral sites: for exam- colliculus (IC), superior colliculus (SC) and auditory cor- ple, the trigeminal ganglion (TG), dorsal column nuclei and interpolar and caudal spinal trigeminal nuclei send ﬁbers directly to the dorsal cochlear nucleus (DCN) and Abbreviations: AVCN, anteroventral cochlear nucleus; BBN, broad- the granule cell regions of the ventral cochlear nucleus band noise; BDA, biotinylated dextran-amine; BF, best frequency; Ca, cartwheel cells; CN, cochlear nucleus; Cu, cuneate nucleus; DAS, dorsal (VCN) (Weinberg and Rustioni, 1987; Wright and Ryugo, acoustic striae; DCN, dorsal cochlear nucleus; Fu, fusiform cell; GCD, 1996; Zhou and Shore, 2004; Haenggeli et al., 2005; Itoh granule cell domain; Gi, giant cell; gr, granule cell; Gr, gracile nucleus; et al., 1987). The trigeminal sensory complex that receives IAS, intermediate acoustic striae; IC, inferior colliculus; ICX, external sensory information from the head, face and vocal tract/ cortex of inferior colliculus; ICXV, ventrolateral border region of IC; IO, intra oral structures is one major component of this inte- inferior olive; LPGi, lateral paragigantocellular reticular nucleus; PVCN, posteroventral cochlear nucleus; RF, reticular formation; RVL, rostral gration. The excitatory and inhibitory responses evoked in ventrolateral reticular formation; SC, superior colliculus; SG, subnucleus cochlear nucleus (CN) neurons by stimulating the origins gelatinosus; sp5, spinal trigeminal tract; Sp5, spinal trigeminal nucleus; of trigeminal projections (Shore et al., 2003; Zhou and Sp5C, pars caudalis of spinal trigeminal nucleus; Sp5I, pars interpolaris of Shore, 2004; Shore, 2005) suggest that these projections spinal trigeminal nucleus; Sp5O, pars oralis of spinal trigeminal nucleus; may be involved in mechanisms related to suppression TG, trigeminal ganglion; VCN, ventral cochlear nucleus * Corresponding author. Tel.: +1 734 647 2116; fax: +1 734 764 0014. of self-generated sounds such as respiration, chewing or E-mail address: [email protected] (S.E. Shore). self-vocalizations.

2. Anatomy of somatosensory connections with the cochlear afferents from head and face, such as those sensitive to gen- nucleus tle pressure and vibrissa deflection (Hayashi et al., 1984; Jacquin et al., 1989). In addition, Sp5 receives propriocep- 2.1. Trigeminal ganglion to cochlear nucleus pathway tive inputs from vocal tract/intra oral structures including the temporo-mandibular joint and tongue muscles (Romfh Sensory information from the head and face is conveyed et al., 1979; Jacquin et al., 1989; Nazruddin et al., 1989; to the central trigeminal sensory nuclear complex via the Takemura et al., 1991; Suemune et al., 1992). ophthalmic, maxillar, and mandibular branches of the tri- Projections from Sp5 to the CN originate primarily in geminal nerve. The ophthalmic nerve innervates the fore- Sp5I and Sp5C (Wolff and Kunzle, 1997; Zhou and Shore, head, upper eyelid, or extraocular muscles; the maxillary 2004; Haenggeli et al., 2005). CN projection neurons in Sp5 nerve supplies the upper lip, the lower eyelid and the upper vary in size and have either polygonal somata, ranging in jaw and roof of the mouth; and the mandibular nerve diameter from 10 · 12 lmto25· 28 lm, or elongated innervates the lower lip, the mucous membranes of the somata, ranging from 10 · 30 lmto7· 40 lm(Fig. 1). lower jaw, the floor of the mouth, and anterior two thirds Projection cells in Sp5I tend to be aggregated in the dorso- of the tongue (Aigner et al., 1997). medial and marginal areas within the non-laminated part Trigeminal ganglion cells that project to the CN are of Sp5I (Fig. 1C). The Sp5C, in contrast, is a laminated located in the medial portion of the ganglion and at the ori- structure comprised of: (1) the outmost subnucleus margin- gin of the ophthalmic nerve, as well as in the mandibular alis, (2) the intermediate subnucleus gelatinosus, and (3) division of the ganglion. Some projection cells are located the medial subnucleus magnocellularis (Darian-Smith in the maxillary division (Shore et al., 2000). The locations et al., 1963; Usunoff et al., 1997). The majority of CN pro- of these projection neurons overlap with the regions that jection cells in Sp5C are located in either the subnucleus innervate both the cochlea and the middle ear: The oph- marginalis or the subnucleus magnocellularis, whereas very thalmic division innervates the cochlea, and the mandibu- few are found in the subnucleus gelatinosus (Fig. 1D). The lar region innervates the middle ear (Vass et al., 1997, paucity of projection cells in the subnucleus gelatinosus, 1998). The TG projection cells to the VCN are usually which receives nociceptive afferents, indicates that the neu- smaller, with a smaller, less prominent nucleus, than those rons in Sp5 that project to the auditory system convey pri- labeled by skin injections, and had uneven surfaces (Shore marily vocal structure mechanosensory information, and et al., 2000). not pain information. The location and morphological Terminal endings of the TG projection to the CN are appearance of the Sp5 neurons that project to the CN primarily located in the ipsilateral marginal cell areas, resemble those that project to the ventrolateral inferior col- which contain small cells and granule cells, as well as liculus (Zhou and Shore, 2006). magnocellular regions of VCN. The axons of TG–CN Fibers and terminal endings of the Sp5 projection to the projection cells in these areas are thin (1 lm) and typi- CN are diverse: many of the projection fibers are small to cally form en passant boutons. The most dense concentra- medium with en passant or large, irregular terminal swell- tion of puncta is in the marginal cell area of the VCN in ings that are mainly located in the marginal area of VCN the form of beads or varicosities. Terminals in this area and the fusiform cell layer of DCN (Fig. 1H). The postsyn- contain small, spherical vesicles indicative of excitatory aptic targets of these terminals include dendrites of granule neurotransmission, which mostly synapse on dendrities. cells. En passant terminal endings can be found in the In the magnocellular regions of anteroventral and pos- molecular and deep layers of DCN, and magnocellular teroventral cochlear nucleus (AVCN and PVCN), trigem- regions of VCN where they make contacts with the princi- inal terminals cluster around the edges of the CN both pal neurons (Zhou and Shore, 2004; Haenggeli et al., 2005). medially and laterally. In contrast to the terminal distri- Electron microscopic evaluation of these endings reveals butions in the marginal area, terminals of the TG in cen- round synaptic vesicles and asymmetric synaptic specializa- tral VCN are located not only on neurons, but also tions indicative of excitatory synapses (Haenggeli et al., around the lumina of blood vessels (Shore et al., 2000). 2005). The terminal distribution pattern of the Sp5–CN This suggests that, in addition to direct neural modulation pathway resembles that of other somatosensory projec- from the TG-to-CN pathway, there is an involvement of tions, such as those arising in the TG and dorsal column this pathway in the regulation of blood flow or metabo- nuclei. However, unlike the TG-CN projection, terminal lism in the CN. endings around blood vessels are not observed in the Sp5–CN projection. 2.2. Spinal trigeminal nucleus to Cochlear nucleus pathways 2.3. Projections from other non-auditory structures to the The spinal trigeminal nucleus (Sp5) extends from the cochlear nucleus main sensory nucleus to the second cervical segment. This nucleus is comprised of three nuclei: pars oralis (Sp5O), Somatosensory innervation to the CN also originates in pars interpolaris (Sp5I), and pars caudalis (Sp5C). All three the dorsal column nuclei (Itoh et al., 1987; Weinberg and subdivisions receive either nociceptive or non-nociceptive Rustioni, 1987; Wright and Ryugo, 1996; Wolff and Kunzle, 92 S.E. Shore, J. Zhou / Hearing Research 216–217 (2006) 90–99

Fig. 1. Projections from non-auditory brainstem regions to the CN in the guinea pig. (A)–(G): Retrograde labeling in the brainstem after an injection of biotinylated dextran amine (BDA) into the CN. (A) Photomicrograph of the injection site. The injection site is virtually restricted to granule cell domain of the PVCN. (B)–(D): Drawings of 1 mm transverse sections across the medulla. Each dot represents one labeled cell. The labeled neurons are located primarily on the contralateral side of Sp5, in the Sp5I and Sp5C. Very few labeled cells, if any, are located in the SG (D). Labeled neurons can also be found in the medular reticular formation (RVL and LPGi, C), inferior olive (IO, C), and dorsal column nuclei (Gr and Cu, D). Projection neurons in Sp5 have either polygonal or elongated somata. (E) Projection neurons in dorsal column nuclei and reticular formation are multipolar (F) and (G). (H): Terminal labeling in the CN after placement of an anterograde tracer into Sp5I. Most Sp5 ﬁbers enter the CN via DAS/IAS and terminate primarily in the granule cell domain (grey area), but also in deep DCN. Each dot represents one to three labeled terminal endings. Scale bars = 25 lm (E)–(G). (Abbreviations: CN – cochlear nucleus; Cu – cuneate nucleus; DAS – dorsal acoustic striae; DCN – dorsal cochlear nucleus; GCD – granule cell domain; Gr – gracile nucleus;IAS – intermediate acoustic striae; IO – inferior olive; LPGi – lateral paragigantocellular reticular nucleus; PVCN – posteroventral cochlear nucleus; RVL – rostral ventrolateral reticular formation; SG – subnucleus gelatinosus;Sp5 – spinal trigeminal nucleus; Sp5C – pars caudalis of Sp5; Sp5I – pars interpolaris of Sp5; Sp5O – pars oralis of Sp5).

1997; Zhou and Shore, 2004), which receive proprioceptive two separate somatosensory systems together may provide afferents from head, trunk, and limbs. CN projection cells head-to-space and eye-to-head orientation for the purpose are located in both the cuneate and gracile nuclei of pursing a sound source, which is important for prey (Fig. 1D) and project primarily to the granular cell domain tracking or recognizing danger. Projections from the pri- of the CN (Itoh et al., 1987; Weinberg and Rustioni, 1987; mary somatosensory cortex to the CN (Wolff and Kunzle, Wright and Ryugo, 1996; Wolff and Kunzle, 1997). Some 1997), may play a role in modulating orienting responses. of this proprioceptive information, such as pinna and head In addition to somatosensory connections, neurons in position, might provide important spectral cues for sound the pontine nuclei (Ohlrogge et al., 2001), vestibular system localization (Rice et al., 1992; Young et al., 1996). Interest- (Burian et al., 1989; Kevetter and Perachio, 1989; Gstoett- ingly, neurons that innervate the muscle spindles of the extra ner et al., 1991), and ventral medullary and pontine reticu- ocular muscles are located in the ophthalmic division of tri- lar formation (RF) project to the CN (Fig. 1). Fig. 1 shows geminal ganglion (Porter and Spencer, 1982), that also pro- that the projection neurons in the RF are multipolar jects to the CN (Shore et al., 2000). It is therefore plausible (Fig. 1G), and are located in the ipsilateral and contralat- that trigeminal inputs to the CN may provide propriocep- eral lateral paragiganto cellular and rostroventrolateral tive information related to eye-to-head orientation. The RF (Fig. 1C).