| Neurons of the mammalian cochlear nucleus (CN) are dependent on afferent input from the auditory nerve for survival during a critical period of postnatal development. Cochlear removal in mice before the onset of hearing results in rapid neuronal loss, while the same manipulation just days later does not. The molecules underlying this age-dependent susceptibility to afferent deprivation are mostly unknown. In these studies microarray technology was used to identify candidate genes that could define this rapid switch from afferent-dependent to independent survival in the mouse CN. There are two main hypotheses addressed here. First, baseline differences in constitutive gene expression predispose neurons to death during, or survival after, the critical period. Second, differences in the transcriptional response to afferent deprivation are responsible for leading neurons to either a death or survival fate. The results presented here suggest a developmental mechanism whereby pro-death gene expression decreases and pro-survival gene expression increases with age in parallel with the critical period closure. Gene expression profiling also showed an active transcriptional response to cochlear removal both during and after this critical period. Surprisingly, few changes in mRNA expression of pro-apoptotic genes were observed after cochlear removal during the critical period. However, after the critical period, there was both a pro-death response and further increases in expression of pro-survival molecules. Therefore the relatively higher expression of apoptotic genes at baseline levels during the critical period suggests these immature neurons are primed for a death response after cochlear removal, whereas after the critical period the CN responds to afferent deprivation by regulating the expression of death and survival genes that ultimately lead to neuron survival. Finally, I also analyzed the contribution of 8th nerve electrical activity to changes in CN gene expression identified after cochlear removal. Pharmacological blockade of auditory nerve activity using tetrotodoxin (TTX) resulted in similar changes in expression of a subset of genes regulated by cochlear removal. However, not all genes regulated by cochlear removal were also responsive to TTX. Therefore, cochlear removal must also eliminate a non-activity dependent signal, or induce an injury specific signal. |
