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Karina S Cramer

Publications and source records attributed to Karina S Cramer.

10 recordsLinked to original sources
PubMed2006

Deafferentation induces novel axonal projections in the auditory brainstem after hearing onset.

Deafferentation of neural tissue can result in cell death, morphological changes, and/or alterations in sources of innervation. These changes often occur during a limited period of development. In the auditory brainstem, the ventral cochlear nucleus (VCN) projects to the contralateral but not ipsilateral medial nucleus of the trapezoid body (MNTB). This pathway is part of a circuit that computes interaural intensity differences used in sound localization. Previous studies have shown that, after the cochlea is removed early in postnatal development, cells in the VCN on the deafferented side die, and the intact VCN innervates MNTB on both sides of the brain. These changes after cochlea removal are limited to an early postnatal period that preceeds hearing onset. In this study, we lesioned the VCN directly to evaluate plasticity in axonal pathways after hearing onset. We found that novel projections from the intact VCN to ipsilateral MNTB emerge after lesions performed as late as postnatal day 25. The morphological sequence of events is similar to that seen during the initial development of this pathway. These data suggest that plasticity in the auditory brainstem is possible when pathways are challenged with denervation of target nuclei. The results show that the opportunity for plasticity in auditory brainstem circuitry is more prolonged than previously thought and that novel pathways can form after the normal pathways are fully mature and functional. Moreover, sensitive periods for changes in individual pathways are independently regulated.

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PubMed2006

EphB2 regulates axonal growth at the midline in the developing auditory brainstem.

Eph receptors play important roles in axon guidance at the midline. In the auditory system, growth of axons across the midline is an important determinant of auditory function. The avian cochlear nucleus, n. magnocellularis (NM), makes bilateral projections to its target, n. laminaris (NL). We examined the time course of NM axon growth toward the midline, the expression of Eph proteins at the midline during this growth, and the effects of Eph receptor misexpression on axonal growth across the midline. We found that NM axons reach the midline at E4. At this age, EphB receptors are expressed at the ventral floor plate. Expression extends dorsally to the ventricular zone beginning at E5. NM axons thus grow across the midline at a time when EphB receptor expression levels are low. Overexpression of EphB2 at E2 resulted in misrouted axons that deflected away from transfected midline cells. This effect was observed when midline cells were transfected but not when NM cells alone were transfected, suggesting that EphB2 acts non-cell autonomously and through reverse signaling. These data suggest an inhibitory role for midline Eph receptors, in which low levels permit axon growth and subsequently high levels prohibit growth after axons have crossed the midline.

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PubMed2005

Differential expression of Eph receptors and ephrins in the cochlear ganglion and eighth cranial nerve of the chick embryo.

The cochleovestibular ganglion of the chick differentiates at early embryonic stages as VIIIth nerve axons enter the brainstem. The tonotopic organization of the auditory portion of the VIIIth nerve can be discerned at the time axons initially reach their brainstem targets. The mechanisms underlying this early organization are not known. Eph receptor tyrosine kinases and their ligands, the ephrins, have a demonstrated role in guiding axons to topographically appropriate locations in other areas of the nervous system. In order to begin to test whether Eph proteins have a similar role in the auditory system, we investigated the tonotopic expression of several Eph receptors and ephrins in the VIIIth nerve during embryonic ages corresponding to the initial innervation of the auditory brainstem. Expression patterns of EphA4, EphB2, EphB5, ephrin-A2, and ephrin-B1 were evaluated immunohistochemically at embryonic days 4 through 10. Protein expression was observed in the cochlear ganglion and VIIIth nerve axons at these ages. EphB5, ephrin-A2, and ephrin-B1 were expressed throughout the nerve. EphA4 and EphB2 had complementary expression patterns within the nerve, with EphA4 expression higher in the dorsolateral part of the nerve and EphB2 expression higher in the ventromedial part of the nerve. These regions may correspond to auditory and vestibular components, respectively. Moreover, EphA4 expression was higher toward the low-frequency region of both the centrally and peripherally projecting branches of cochlear ganglion cells. Regional variation of Eph protein expression may influence the target selection and topography of developing VIIIth nerve projections.

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PubMed2005

Avian superior olivary nucleus provides divergent inhibitory input to parallel auditory pathways.

The avian auditory brainstem displays parallel processing, a fundamental feature of vertebrate sensory systems. Nuclei specialized for temporal processing are largely separate from those processing other aspects of sound. One possible exception to this parallel organization is the inhibitory input provided by the superior olivary nucleus (SON) to nucleus angularis (NA), nucleus magnocellularis (NM), and nucleus laminaris (NL) and contralateral SON (SONc). We sought to determine whether single SON neurons project to multiple targets or separate neuronal populations project independently to individual target nuclei. We introduced two different fluorescent tracer molecules into pairs of target nuclei and quantified the extent to which retrogradely labeled SON neurons were double labeled. A large proportion of double-labeled SON somata were observed in all cases in which injections were made into any pair of ipsilateral targets (NA and NM, NA and NL, or NM and NL), suggesting that many individual SON neurons project to multiple targets. In contrast, when injections involved the SONc and any or all of the ipsilateral targets, double labeling was rare, suggesting that contralateral and ipsilateral targets are innervated by distinct populations of SON neurons arising largely from regionally segregated areas of SON. Therefore, at the earliest stages of auditory processing, there is interaction between pathways specialized to process temporal cues and those that process other acoustic features. We present a conceptual model that incorporates these results and suggest that SON circuitry, in part, functions to offset interaural intensity differences in interaural time difference processing.

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PubMed2005

Eph proteins and the assembly of auditory circuits.

Many kinds of information are carried in the acoustic signal that reaches auditory receptor cells in the cochlea. The analysis of this information is possible in large part because of the neuronal architecture of the auditory system. The mechanisms that establish the precise circuitry that underlies auditory processing have not yet been identified. The Eph receptor tyrosine kinases and their ligands are proteins that regulate axon guidance and have been shown to contribute to the establishment of topographic projections in several areas of the nervous system. Several studies have begun to investigate whether these proteins are involved in the formation of auditory system connections. Studies of gene expression show that Eph proteins are extensively expressed in structures of the inner ear as well as in neurons in the peripheral and central components of the auditory system. Functional studies have demonstrated that Eph signaling influences the assembly of auditory pathways. These studies suggest that Eph protein signaling has a significant role in the formation of auditory circuitry.

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PubMed2004

EphA4 signaling promotes axon segregation in the developing auditory system.

Precision of synaptic connections within neural circuits is essential for the accurate processing of sensory information. Specificity is exemplified at cellular and subcellular levels in the chick auditory brainstem, where nucleus magnocellularis (NM) neurons project bilaterally to nucleus laminaris (NL). Dorsal dendrites of NL neurons receive input from ipsilateral, but not contralateral, branches of NM axons whereas ventral dendrites are innervated by contralateral NM axons. This organization is analogous to that of the mammalian medial superior olive (MSO) and represents an important component of the circuitry underlying sound localization. However, the molecular mechanisms that establish segregated inputs to individual regions of NL neurons have not been identified. During synapse formation in NL, the EphA4 receptor is expressed in dorsal, but not ventral NL, neuropil, suggesting a potential role in targeting synapses to appropriate termination zones. Here, we directly tested this role by ectopically expressing EphA4 and disrupting EphA4 signaling using in ovo electroporation. We found that both misexpression of EphA4 and disruption of EphA4 signaling resulted in an increase in the number of NM axons that grow aberrantly across NL cell bodies into inappropriate regions of NL neuropil. EphA4 signaling is thus essential for targeting axons to distinct subsets of dendrites. Moreover, loss of EphA4 function resulted in morphological abnormalities of NL suggestive of errors in cell migration. These results suggest that EphA4 has multiple roles in the formation of auditory brainstem nuclei and their projections.

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PubMed2004

Ephrin-A5 exerts positive or inhibitory effects on distinct subsets of EphA4-positive motor neurons.

Eph receptor tyrosine kinases and ephrins are required for axon patterning and plasticity in the developing nervous system. Typically, Eph-ephrin interactions promote inhibitory events; for example, prohibiting the entry of neural cells into certain embryonic territories. Here, we show that distinct subsets of motor neurons that express EphA4 respond differently to ephrin-A5. EphA4-positive LMC(l) axons avoid entering ephrin-A5-positive hindlimb mesoderm. In contrast, EphA4-positive MMC(m) axons extend through ephrin-A5-positive rostral half-sclerotome. Blocking EphA4 activation in MMC(m) neurons or expanding the domain of ephrin-A5 expression in the somite results in the aberrant growth of MMC(m) axons into the caudal half-sclerotome. Moreover, premature expression of EphA4 in MMC(m) neurons leads to a portion of their axons growing into novel ephrin-A5-positive territories. Together, these results indicate that EphA4-ephrin-A5 signaling acts in a positive manner to constrain MMC(m) axons to the rostral half-sclerotome. Furthermore, we show that Eph activation localizes to distinct subcellular compartments of LMC(l) and MMC(m) neurons, consistent with distinct EphA4 signaling cascades in these neuronal subpopulations.

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PubMed2004

Tonotopic gradients of Eph family proteins in the chick nucleus laminaris during synaptogenesis.

Topographically precise projections are established early in neural development. One such topographically organized network is the auditory brainstem. In the chick, the auditory nerve transmits auditory information from the cochlea to nucleus magnocellularis (NM). NM in turn innervates nucleus laminaris (NL) bilaterally. These projections preserve the tonotopy established at the level of the cochlea. We have begun to examine the expression of Eph family proteins during the formation of these connections. Optical density measurements were used to describe gradients of Eph proteins along the tonotopic axis of NL in the neuropil, the somata, and the NM axons innervating NL at embryonic day 10, when synaptic connections from NM to NL are established. At E10-11, NL dorsal neuropil expresses EphA4 at a higher concentration in regions encoding high frequency sounds, decreasing in concentration monotonically toward the low frequency (caudolateral) end. In the somata, both EphA4 and ephrin-B2 are concentrated at the high frequency end of the nucleus. These tonotopic gradients disappear between E13 and E15, and expression of these molecules is completely downregulated by hatching. The E10-11 patterns run counter to an apparent gradient in dendrite density, as indicated by microtubule associated protein 2 (MAP2) immunolabeling. Finally, ephrin-B2 is also expressed in a gradient in tissue ventral to the NL neuropil. Our findings thus suggest a possible conserved mechanism for establishing topographic projections in diverse sensory systems. These results of this study provide a basis for the functional examination of the role of Eph proteins in the formation of tonotopic maps in the brainstem.

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PubMed2002

Expression of EphB receptors and EphrinB ligands in the developing chick auditory brainstem.

Nucleus magnocellularis (NM) in the avian auditory brainstem receives auditory input from nerve the VIIIth and projects bilaterally to nucleus laminaris (NL). This projection preserves binaural segregation in that ipsilateral NM projects to dorsal dendrites of NL and contralateral NM projects to ventral dendrites of NL. We have begun to examine the molecular signals that influence segregation of inputs onto discrete regions of NL cells. We previously showed that the Eph receptor, EphA4, is expressed selectively in the dorsal NL neuropil from embryonic day (E) 9 to E11, when NM axons grow into the NL neuropil. This asymmetric distribution suggests that EphA4 acts as a guidance molecule during binaural segregation. We report here on the developmental changes in the expression of two other Eph receptors, EphB2 and EphB5, and two ligands, ephrin-B1 and ephrin-B2, in the chick auditory brainstem. These proteins are expressed in the auditory nuclei during the maturation of the NM-NL projection. EphB2, EphB5, and ephrin-B1 are expressed in dorsal and ventral NL neuropil and at the midline of the brainstem at E10-E12. At this age, ephrin-B2, a ligand for EphB receptors and for EphA4, is expressed in NL cell bodies and NM-NL axons. The expression of these proteins diminishs in the posthatch ages examined. These results suggest that several members of the Eph family are involved in maturation of the nuclei and their projections. Moreover, ephrin-B2 in growing axons may interact with the asymmetrically expressed EphA4 during the establishment of binaural segregation.

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