The projection of regenerated neurons to the cochlear nucleus is an inevitable term of conditions (Fig. 29.1). However, there have been limited publications showing the central projection of transplant-derived neurons located in the cochlea [1, 2]. The potential of stem cell-derived neurons for projection to the cochlear nucleus has been demonstrated using brain stem slice cultures [3]. One of the major obstacles is limited knowledge of molecular mechanisms for central projections of spiral ganglion neurons. In the development of spiral ganglion neurons, after delamination of immature neurons from the otocyst, immature neurons form the central projection to the cochlear nucleus [4]. The potential of netrin-1 for axon guidance in spiral ganglion neurons has been reported [5, 6]. The netrin-1 receptor, deleted in colorectal carcinoma (DCC), is expressed in spiral ganglion neurons [5, 6]. Investigations using ES cell-derived neurons showed the projection of ES cell-derived neurons that had settled in the cochlear modiolus to the cochlear nucleus [1, 2]. Netrin-1 also mediated axon guidance in ES cell-derived neurons [7]. Therefore, netrin-DCC signaling might contribute to the central projection of transplanted ES cell-derived neurons in the cochlea. On the other hand, loss of inputs from spiral ganglion neurons induced an increase of insulin-like growth factor-1 (IGF-1) in the cochlear nucleus leading to the reorganization of synaptic contacts [8, 9]. In addition, upregulation of netrin-1 by exogenous IGF-1 application has been reported damaged cochleae [10]. Hence, these molecules could contribute to form synaptic contacts between the cochlear nucleus neurons and regenerated spiral ganglion neurons. Further investigations, especially for axon guidance in developing spiral ganglion neurons, are crucial to realize highly functional regeneration of spiral ganglion neurons.

Comparing with the central projection of spiral ganglion neurons, mechanisms for peripheral projection are well understood [11]. Neurotrophins play key roles for the guidance of afferent dendrites of spiral ganglion neurons. Among neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are crucial for the guidance of afferent dendrites [12–16]. These neurotrophins are secreted by inner ear hair cells. Previous reports have demonstrated neurite projections from ES cell-derived neurons to cochlear or vestibular hair cells [17–19]. In addition, the formation of ribbon synapses between inner hair cells and ES-derived neurons has been demonstrated [17]. Gene transfer of BDNF into the cells located in the scala tympani resulted in neurite elongation of spiral ganglion neurons into the scala tympani [20]. This technique may be utilized for the induction of neurites from spiral ganglion neurons or transplanted neurons to the electrodes of the cochlear implant. Recently, the efficacy of several small molecules to stimulate BDNF receptors has been reported in models for Huntington’s disease [21, 22]. These small molecules might be utilized for the induction of neurite outgrowth from transplanted neurons.