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Talking back: Development of the olivocochlear efferent system

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Developing sensory systems must coordinate the growth of neural circuitry spanning from receptors in the peripheral nervous system (PNS) to multilayered networks within the central nervous system (CNS). This breadth presents particular challenges, as nascent processes must navigate across the CNS–PNS boundary and coalesce into a tightly intermingled wiring pattern, thereby enabling reliable integration from the PNS to the CNS and back. In the auditory system, feedforward spiral ganglion neurons (SGNs) from the periphery collect sound information via tonotopically organized connections in the cochlea and transmit this information to the brainstem for processing via the VIII cranial nerve. In turn, feedback olivocochlear neurons (OCNs) housed in the auditory brainstem send projections into the periphery, also through the VIII nerve. OCNs are motor neuron‐like efferent cells that influence auditory processing within the cochlea and protect against noise damage in adult animals. These aligned feedforward and feedback systems develop in parallel, with SGN central axons reaching the developing auditory brainstem around the same time that the OCN axons extend out toward the developing inner ear. Recent findings have begun to unravel the genetic and molecular mechanisms that guide OCN development, from their origins in a generic pool of motor neuron precursors to their specialized roles as modulators of cochlear activity. One recurrent theme is the importance of efferent–afferent interactions, as afferent SGNs guide OCNs to their final locations within the sensory epithelium, and efferent OCNs shape the activity of the developing auditory system.

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  • Nervous System Development > Vertebrates: Regional Development
Organization of the mammalian olivocochlear efferent system. Auditory information transduced by inner (IHCs) and outer hair cells (OHCs) is conveyed to the auditory brainstem via Type I and Type II spiral ganglion neurons (SGNs), respectively. SGNs project into the brain via the VIII nerve and synapse onto neurons in the cochlear nuclear complex (CNC). The superior olivary complex (SOC, dashed circle) contains multiple nuclei involved in sound localization, including the medial superior olive (MSO), lateral superior olive (LSO), ventral nucleus of the trapezoid body (VNTB), lateral nucleus of the trapezoid body (LNTB), medial nucleus of the trapezoid body (MNTB), and the superior periolivary nucleus (SPN). Medial (MOCs) and lateral (LOCs) olivocochlear neurons reside primarily in VNTB and LSO, respectively, and project back to the sensory epithelium via the VIII nerve. Other types of neurons are also housed in VNTB and LSO, including the neurons that mediate afferent responses, but only MOCs and LOCs are indicated for simplicity. Within the cochlea, LOCs form synapses with Type I SGNs, whereas MOCs terminate on OHCs
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Development and refinement of cochlear wiring in the mouse. (a) By P0, MOCs have arrived in the vicinity of IHCs. Both Type I and Type II SGNs have projected to IHCs and OHCs, respectively. Between P0 and P4, both MOC neurons and Type I SGNs form synapses with IHCs, while Type II SGNs form connections with OHCs. The MOC axons then grow on toward the OHC region. At least some of these fibers appear to be branches from MOC axons in the IHC region. Over the next two weeks, both SGNs and MOCs prune excess synapses. By adulthood, MOCs project exclusively to OHCs. (b) Development of IHC synapses. At P0, both Type I SGN and MOC projections are present at the IHC surface. Although synaptic machinery is present in IHCs, many components are not yet localized to the cell membrane. Synaptogenesis proceeds over the next several days, and by P4 all IHCs respond to MOC stimulation. The arrival of MOC terminals coincides with the expression of SK2 calcium‐gated potassium channels and α9/α10 nicotinic acetylcholine receptors (nAChR) in IHCs. Ribbon synapses (purple) presynaptic to Type I SGNs also mature over this time period. By adulthood, both MOC terminals and their postsynaptic receptors in IHCs have been eliminated. LOCs also innervate the cochlea during this period (not shown)
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Organization and growth of OCN and SGN projections in the cochlea. (a) Organization of the mature cochlea. MOC axons project along the intraganglionic spiral bundle (IGSB) before turning to branch among the OHC layers. LOCs also travel within the IGSB before turning to the IHC layer. LOCs either turn unilaterally or branch to spiral on either side of IHCs in the inner spiral bundle (ISB) and tunnel spiral bundle (TSB). MOC and LOC neuron traces inspired by Brown, . (b) E17.5 mouse cochlea showing OCNs (red) and SGNs (white). OCNs appear to grow along SGN axons, as indicated by the close association between OCNs and SGNs and the way incoming OCN projections lag behind extending SGN peripheral axons. Image provided by N. Druckenbrod
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Transcription factors driving the production of FBMNs and IEEs. FBMNs and IEEs arise in the fourth rhombomere (r4), which is specified by an autoregulatory Hoxb1/b2 network. Within the pMNv domain of r4, SHH induces expression of a suite of transcription factors (gray box), including Nkx2‐2, Nkx2‐9, Nkx6‐1, and Nkx6‐2 that direct a branchiovisceral motor neuron (MN) fate. The presence of Hoxb1 and Nkx factors collectively induce Phox2b, which is subsequently maintained in branchiovisceral precursors, including those that become IEEs or FBMNs. Within r4, Nkx6 factors are required for the maintenance (but not the onset) of Hoxb1 expression (gray arrow). In branchiovisceral precursors, Phox2b drives expression of early markers of visceral and branchial MN identity, including Phox2a, Isl1, and Chat. In addition, Nkx6‐1 and Ascl1 expression persists after the MNv progenitors exit the cell cycle and become branchiovisceral precursors. Within this pool of precursors, those that will become IEEs likely deviate from an FBMN fate due to the expression of Gata2/3. Together, Phox2b and Hoxb1 drive expression of Gata2, which in turn drives expression of Gata3. Ascl1 remains active in postimitotic IEEs (but not FBMNs) until about E12.5 and influences the level of Gata3 expression. Many of these transcription factors impinge on each other and on common cassettes of gene expression, with some acting at multiple stages and in multiple ways. For simplicity, only the key transcriptional interactions that drive the specification and differentiation of IEEs are shown. See Table for additional details regarding the specific contributions of each factor
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Cell body movements of inner ear efferents (IEEs) and facial branchial motor neurons (FBMNs) during mouse embryogenesis. (a) As shown in a sagittal view, FBMNs and IEEs both derive from a common pool of visceral motor neuron (MNv) progenitors in rhombomere 4 (r4). During embryogenesis, FBMNs move caudally. IEEs gradually separate into distinct subtypes and migrate to their final positions in r4 and r5. Rostral is left and dorsal is up. LOC = lateral olivocochlear neuron; MOC = medial olivocochlear neuron; VEN = vestibular efferent neuron. (b) Starting around E9, IEEs and FBMNs begin to differentiate from a shared pool of cells in the progenitor domain of visceral motor neurons (pMNv), directly adjacent to the floor plate (FP), illustrated in a transverse view of r4. As they develop, immature neurons exit the cell cycle and migrate from the ventricular zone (VZ) to the mantle zone (MZ). By E10.5, IEEs and FBMNs have begun to separate: FBMN cell bodies migrate caudally (see (a)), while IEEs begin to send projections (or translocate) across the floor plate. Both FBMNs and IEEs also begin extending projections to the periphery via the VII and VIII nerves. By E13.5, FBMNs and IEEs have fully separated, and olivocochlear neurons (OCNs) have separated from VENs. OCNs migrate toward the pial surface whereas VENs migrate dorsally. Some other hindbrain neurons derive from progenitors in the rhombic lip (RL)
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