ReviewUnderstanding tinnitus: The dorsal cochlear nucleus, organization and plasticity
Introduction
Tinnitus, the perception of a phantom sound, is a common correlate of damage to the auditory periphery, either to receptor cells or to neurons of the spiral ganglion. Damage can result from aging (Nicolas-Puel et al., 2002) or exposure to noise, the cancer drugs carboplatin and cisplatin (Ding et al., 1999, Godfrey et al., 2005, Hofstetter et al., 1997, Husain et al., 2001, Klis et al., 2002, Stengs et al., 1998), styrene (Chen et al., 2008) or other agents. Systemic administration of the drug salicylate can induce temporary tinnitus (Stolzberg et al., 2011, Sun et al., 2009, Wei et al., 2010, Yang et al., 2007). Tinnitus is thought to result from plastic reorganization in the central processing of auditory information triggered by these manipulations (reviews in Kaltenbach, 2011, Roberts et al., 2010, Wang et al., 2011). Many studies have sought to discover the loci and mechanisms of this reorganization, and to tease out which changes are simply correlates of peripheral damage and which are the critical determinants of tinnitus.
Discovery of the neural correlates of tinnitus must contend with a major obstacle in that tinnitus as a perception is most readily assessed in humans, but the investigation of neural mechanisms in humans is limited to imaging studies and relatively gross electrophysiological measures (review and references in Adjamian et al., 2009, Schaette and McAlpine, 2011). On the other hand, in animals it is relatively easy to assess the electrophysiological or neuroanatomical changes that follow peripheral auditory damage, but it is much more difficult to see how these changes relate to the perception of tinnitus. Several behavioral animal models of tinnitus have been devised to allow a more direct correlation of tinnitus and neural changes.
Section snippets
What is the neural basis of tinnitus?
Investigations of the neural correlates of tinnitus in animals have looked for electrophysiological, anatomical or neurochemical alterations subsequent to peripheral damage. Multiple sites along the auditory pathways have been implicated in tinnitus including the dorsal (DCN) and ventral (VCN) cochlear nuclei (Brozoski et al., 2002, Dehmel et al., 2012, Kaltenbach and Afman, 2000, Kaltenbach et al., 2000, Kaltenbach et al., 2002, Kraus et al., 2009, Middleton et al., 2011, Rachel et al., 2002,
The DCN: laminar and cellular organization
The classic studies of DCN laminar and cellular organization were done in the cat (Brawer et al., 1974, Lorente de No, 1933, Osen, 1969). In that animal, the DCN is a distinctly laminar structure; the layers are easily recognized in Nissl sections. Laminar structure of the DCN is also seen in other animals used in auditory research. However, there are differences among authors regarding how many layers are recognized (3–5 in different studies, e.g. 4 layers in Hackney et al., 1990, Willard and
Physiological correlate of tinnitus: hyperactivity in the DCN
Physiological changes occur in the DCN with interventions that can result in tinnitus, leading to the hypothesis that the DCN is a key structure in its generation. The DCN fusiform/pyramidal cells become spontaneously hyperactive in animals with behavioral evidence of tinnitus (Brozoski et al., 2002, Brozoski and Bauer, 2005, Kaltenbach, 2006b, Kaltenbach, 2007, Kaltenbach and Godfrey, 2008; reviewed in Tzounopoulos, 2008, Wang et al., 2009, Wang et al., 2011, Zhang et al., 2006). The increase
DCN as the site of somatosensory modulation of tinnitus
The second body of evidence supporting a role of the DCN in tinnitus is based on clinical observations. In some patients, tinnitus can be modulated by somatosensory stimuli or voluntary movement, suggesting an interaction between auditory and somatosensory systems (Levine, 1999, Levine et al., 2003, Pinchoff et al., 1998, Shore et al., 2007, Simmons et al., 2008). The DCN is a uniquely suited candidate site for such multisensory interactions (review in Levine, 1999). There is somatosensory
Novel plasticity in the DCN: DCX-expression in unipolar brush cells in the adult rat
We have recently found evidence for a previously unknown form of plasticity in one DCN cell class, the unipolar brush cell (Manohar et al., 2012). This plasticity has the potential to affect the auditory–somatosensory interactions that are anatomically indicated to occur in the DCN. UBCs are excitatory interneurons; they have been extensively studied by Mugnaini and colleagues (review in Mugnaini et al., 2011). UBCs are found in the DCN and also in the cerebellum, another region recently
Organization of the primate DCN: implications for its role in tinnitus
There are behavioral and electrophysiological data in rodents that strongly support the idea that the DCN is critical in the generation of tinnitus. However, the goal of these studies in animals is to illuminate the mechanisms of tinnitus in humans. A significant challenge to that goal is presented by studies suggesting that the anatomical organization of the DCN may be radically different in primates than in rodents. The major differences that have been reported are an absence of laminar
The DCN in the cat
Many early studies in the auditory system, both anatomical and physiological, used the cat (some examples…Aitkin and Phillips, 1984, Aitkin et al., 1985, Brawer et al., 1974, Godfrey et al., 1975a, Godfrey et al., 1975b, Imig et al., 1972, Imig and Weinberger, 1973, Imig and Adrian, 1977, Osen, 1969) and its DCN organization became the standard to which other species were compared. Fig. 3A shows a cresyl violet (CV)-stained section through the cochlear nuclei of a cat. The laminar organization
The rat
In recent years, the rat has become a more popular experimental subject, especially in the development of an animal model of tinnitus (Jastreboff and Sasaki, 1994, Lobarinas et al., 2004, Turner et al., 2006, Wang et al., 2009). It is generally assumed that DCN organization in the rat is similar to the cat. For example, Webster (1992) write “In most mammals the DCN is a laminated structure,” but they reference Osen's, 1969 paper on the cat. Fig. 3A shows a photomicrograph of a CV-stained
The chinchilla
Are differences in the appearance of layer 2 between mice and rats and the cat found in all rodents? We also looked at the organization of the DCN in the chinchilla, another rodent used in auditory research (a few examples… Hamernik et al., 1987, Henderson et al., 1983, Salvi et al., 1978, Salvi et al., 1982a, Salvi et al., 1982b, Salvi et al., 1990, Saunders et al., 1987, Zhou et al., 2009). Results in this animal also support a role of the DCN in tinnitus, since physiological evidence of
The macaque monkey
Rather surprisingly, from Nissl sections, the monkey DCN appears to be more distinctly laminated than the rat DCN. Fig. 6A shows the DCN of a macaque monkey on a CV-stained section. A more lightly stained outer layer (1) and a more darkly stained band comprised of large somata (layer 2) are readily apparent. Fig. 6B shows a higher magnification image of the large somata; many are elongated (examples at arrows) but they are not oriented parallel to each other as in the cat. There are smaller
The human
The idea that the human DCN is unlaminated and lacks granule cells is actually based on very few studies (Adams, 1986, Heiman-Patterson and Strominger, 1985, Moore and Osen, 1979). There are many technical problems that can affect the quality of staining in human material, including the medical state of the person at death, the PMI (postmortem interval, time from death to immersion of the tissue in fixative) and the total time in fixative. There are also differences in staining quality among
Summary and conclusions
Studies in rodents have implicated the DCN as playing a key role in tinnitus. Especially important is the observation of spontaneous hyperactivity in the DCN which in turn affects activity higher in the auditory system, e.g. in the inferior colliculus (Mulders et al., 2011). This hyperactivity is seen in several species, including rat, chinchilla and hamsters. It begins roughly one week post-trauma, and gradually increases over the next 3–4 weeks (Kaltenbach et al., 1998, Kaltenbach et al., 2000
Human
The human cases are from the Witelson Normal Brain Collection (Witelson and McCulloch, 1991). Table 1 shows the age, gender and postmortem interval (PMI) for the cases illustrated in Fig. 7. The brains had been stored in 10% formalin. The brainstems were dissected away from the cerebrum and cerebellum and then cryoprotected in 15% followed by 30% sucrose in 10% formalin. Forty micrometer thick frozen sections were cut on an AO sliding microtome in a plane transverse to the brainstem. Sections
Acknowledgments
We thank Sandra Witelson for the gift of the human tissue and Debra Kigar for help with the initial dissections. This study was supported in part by the Department of Physiology and Biophysics, University at Buffalo (JSB) and NIH grants to RJS (R01DC0090910 and R01DC009219).
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2020, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Bilateral DCN lesions prior to traumatic sound exposure can prevent acoustic-trauma induced tinnitus, DCN ablation after the induction of tinnitus cannot decrease the established tinnitus in rats, suggesting that the DCN is not a necessary source of tinnitus-producing signal but serves as a trigger zone [5,21]. Hyperactivity in DCN has been demonstrated to be a key neural correlate of tinnitus [22]. The present study showed the decreased number of GAD 67-ir neurons in the DCN of rats with behavioral signs of tinnitus following salicylate treatment, which is consistent with a previous study reported that the expression level of GAD 67 decreases in the rat DCN after noise-induced hearing loss [23].
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2019, Hearing ResearchCitation Excerpt :The basic laminar organization of the DCN found in cats, rats, mice and probably humans (Lorente de Nó, 1933. Oertel and Young, 2004; Wagoner and Kulesza, 2009; Baizer et al., 2012) consists of three layers: 1) an external layer called molecular layer, where the axons carrying the multimodal sensory information, the parallel fibers run parallel to the dorso-ventral axis of the nucleus. 2) a middle principal or fusiform layer, where it is found the fusiform neurons, the principal excitatory neuron of the DCN and its output neuron sending its axons to the central nucleus of the inferior colliculus; and a 3) deep internal layer, were the auditory fibers are organized tonotopically.
Volumes of cochlear nucleus regions in rodents
2016, Hearing ResearchThe anti-inflammatory selective melanocortin receptor subtype 4 agonist, RO27-3225, fails to prevent acoustic trauma-induced tinnitus in rats
2015, European Journal of Pharmacology
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