Relationships between neuronal birthdates and tonotopic positions in the mouse cochlear nucleus

Abstract

Tonotopy is a key anatomical feature of the vertebrate auditory system, but little is known about the mechanisms underlying its development. Since date of birth of a neuron correlates with tonotopic position in the cochlea, we investigated if it also correlates with tonotopic position in the cochlear nucleus (CN). In the cochlea, spiral ganglion neurons are organized in a basal to apical progression along the length of the cochlea based on birthdates, with neurons in the base (responding to high-frequency sounds) born early around mouse embryonic day (E) 9.5-10.5, and those in the apex (responding to low-frequency sounds) born late around E12.5-13.5. Using a low-dose thymidine analog incorporation assay, we examine whether CN neurons are arranged in a spatial gradient according to their birthdates. Most CN neurons are born between E10.5 and E13.5, with a peak at E12.5. A second wave of neuron birth was observed in the dorsal cochlear nucleus (DCN) beginning on E14.5 and lasts until E18.5. Large excitatory neurons were born in the first wave, and small local circuit neurons were born in the second. No spatial gradient of cell birth was observed in the DCN. In contrast, neurons in the anteroventral cochlear nucleus (AVCN) were found to be arranged in a dorsal to ventral progression according to their birthdates, which are aligned with the tonotopic axis. Most of these AVCN neurons are endbulb-innervated bushy cells. The correlation between birthdate and tonotopic position suggests testable mechanisms for specification of tonotopic position. K E Y

Semaphorin-5B Controls Spiral Ganglion Neuron Branch Refinement during Development

“…The cochlear sensory domain is comprised of a single row of IHCs and three rows of OHCs, which are innervated by type I and II SGNs respectively. Morphologically, the SGNs are bipolar: they extend peripheral axons (sometimes termed "dendrites") that innervate hair cells, and central axons that project out of the inner ear and innervate neurons within the cochlear nucleus (Nayagam et al, 2011;Shepard et al, 2019). Figure 1A-C shows wholemount or cross-sectional views of these structures with the SGNs labeled with anti-NF200 antibodies and the hair cells labeled with anti-MyoVI antibodies.…”

Primary sensory map formations reflect unique needs and molecular cues specific to each sensory system

“…A, anterior; D, dorsal; L, lateral; M, medial; N, nasal; P, posterior; T, temporal; V, ventral. Modified after 12, 41, 53– 58.…”

“…Migration within the alar plate, as in the spinal cord 179 , suggests that more sophisticated pulse-chase experiments with modern EdU/BrdU double labeling are needed to resolve temporal maps. Indeed, a very recent article showed that the anterior parts of the cochlear nucleus complex show a coordinated cell cycle exit matching that of spiral ganglion neurons 58 . The temporal progression of spiral ganglion cell cycle exit 57, 120 and progressive development of spiral ganglion neurons and their central projections 121 imply a birth-dating bias toward map formation ( Figure 1C and Figure 2B).…”

“…In amphibians and fish, afferents of different senses developing at different times project in a ventral-to-dorsal progression ( Figure 2B) to the hindbrain 65, 183 and form distinct aspects of some lateral line sensory maps 124 . Beyond the birth-date related primary afferent fiber organization, the formation of alar plate nuclei and side branches of primary afferents makes it difficult to extract primary map formation and to derive general organizational principles 5 in mammals without more refined analysis as recently conducted in the visual system 75 and auditory system 58 . In addition to cell cycle exit of alar plate and sensory neurons, there is a rostro-caudal progression in maturation leading to a rhombomere-specific second-order neuron cell cycle exit, matching the arrival and formation of secondary branches of primary sensory afferents 17, 103 .…”

Ephrin-A3 Is Required for Tonotopic Map Precision and Auditory Function in the Mouse Auditory Brainstem

“…In the developing cochlea, the central processes of ANFs innervate the CN in a developmental gradient according to tonotopy 5 . In mice, SGNs are born in a basal to apical progression along the length of the cochlea, with neurons in the base (future high-frequency preference) born early around mouse embryonic day (E) 9.5-10.5 and those in the apex (future low-frequency preference) born later, around E12.5 to 13.5 [6][7][8][9] . This sequential neurogenesis of SGNs results in ANFs from the early-born basal SGNs initiating outgrowth about 2-3 days earlier than ANFs from the late-born apical SGNs.…”