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The hippocampus, a major site of neurogenesis in the adult brain, plays an important role in memory. Based on earlier observations where exposure to high-intensity noise not only caused hearing loss but also impaired memory function, it is conceivably that noise exposure may suppress hippocampal neurogenesis. To evaluate this possibility, nine rats were unilaterally exposed for 2 h to a high-intensity, narrow band of noise centered at 12 kHz at 126 dB SPL. The rats were also screened for noise-induced tinnitus, a potential stressor which may suppress neurogenesis. Five rats developed persistent tinnitus-like behavior while the other four rats showed no signs of tinnitus. Age-matched sham controls showed no signs of hearing loss or tinnitus. The inner ear and hippocampus were evaluated for sensory hair cell loss and neurogenesis 10 weeks post-exposure. All noise exposed rats showed severe loss of sensory hair cells in the noise-exposed ear, but essentially no damage in the unexposed ear. Frontal sections from the hippocampus were immunolabeled for doublecortin to identify neuronal precursor cells, or Ki67 to label proliferating cells. Noise-exposed rats showed a significant reduction of neuronal precursors and fewer dividing cells as compared to sham controls. However, we could not detect any difference between rats with behavioral evidence of tinnitus versus rats without tinnitus. These results show for the first time that high intensity noise exposure not only damages the cochlea but also causes a significant and persistent decrease in hippocampal neurogenesis that may contribute to functional deficits in memory.

A unilateral cochlear lesion induces expression of the growth and plasticity-associated protein 43 (GAP-43) in fibers and their varicosities on specific types of postsynaptic profiles in the ventral cochlear nucleus (VCN), suggesting the induction of synaptic remodeling. One candidate population from which GAP-43 might emerge was neurons of the lateral olivocochlear (LOC) system residing in the lateral superior olive (LSO). Upon cochleotomy, these neurons express GAP-43 mRNA and GAP-43 protein. However, retrograde axonal tracing with Fast Blue or biotinylated dextran amine from VCN revealed that the number of 6.8 +/- 1.3 neurons in the whole ipsilateral LSO labeled in normal adult rats was distinctly small and did not rise after cochleotomy. Concluding that LOC neurons cannot be the source of GAP-43 in the VCN, we reinvestigated the pattern of GAP-43 in situ hybridization and found that, after cochleotomy, shell neurons in the regions surrounding the LSO and medial olivocochlear (MOC) neurons in the ventral nucleus of the trapezoid body up-regulated GAP-43 mRNA. We then lesioned these regions by means of stereotaxic injections of kainic acid. Destruction of shell neurons preceding an ipsilateral cochleotomy did not change the emergence of GAP-43 immunoreactivity in the VCN. However, if the contralateral MOC system was lesioned, the rise of GAP-43 immunoreactivity in VCN on the side of the cochleotomy was significantly reduced. We conclude that, after cochlear dysfunction, MOC neurons are the major (if not exclusive) source of synaptic reorganization in the VCN that could possibly entail compensatory activation of the affected ascending auditory pathway.

Aberrant, lesion-induced neuroplastic changes in the auditory pathway are believed to give rise to the phantom sound of tinnitus. Noise-induced cochlear damage can induce extensive fiber growth and synaptogenesis in the cochlear nucleus, but it is currently unclear if these changes are linked to tinnitus. To address this issue, we unilaterally exposed nine rats to narrowband noise centered at 12 kHz at 126 dB SPL for two hours and sacrificed them 10 weeks later for evaluation of synaptic plasticity (GAP-43 expression) in the cochlear nucleus. Noise-exposed rats along with three age-matched controls were screened for tinnitus-like behavior with gap prepulse inhibition of the acoustic startle (GPIAS) before, 1–10 days after and 8–10 weeks after the noise exposure. All nine noise-exposed rats showed similar patterns of severe hair cell loss at high- and mid-frequency regions in the exposed ear. Eight of the 9 showed strong up-regulation of GAP-43 in auditory nerve fibers and pronounced shrinkage of the ventral cochlear nucleus (VCN) on the noise-exposed side, and strong up-regulation of GAP-43 in the medial ventral VCN, but not in the lateral VCN or the dorsal cochlear nucleus. GAP-43 up-regulation in VCN was significantly greater in Noise-No-Tinnitus rats than in Noise-Tinnitus rats. One Noise-No-Tinnitus rat showed no up-regulation of GAP-43 in auditory nerve fibers and only little VCN shrinkage, suggesting that auditory nerve degeneration plays a role in tinnitus generation. Our results suggest that noise-induced tinnitus is suppressed by strong up-regulation of GAP-43 in the medial VCN. GAP-43 up-regulation most likely originates from medial olivocochlear neurons. Their increased excitatory input on inhibitory neurons in VCN may possibly reduce central hyperactivity and tinnitus.

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Inner ear damage may lead to structural changes in the central auditory system. In rat and chinchilla, cochlear ablation and noise trauma result in fiber growth and synaptogenesis in the ventral cochlear nucleus (VCN). In this study, we documented the relationship between carboplatin induced hair cell degeneration and VCN plasticity in the chinchilla. Unilateral application of carboplatin (5 mg/ml) on the round window membrane resulted in massive hair cell loss. Outer hair cell degeneration showed a pronounced basal-to-apical gradient while inner hair cell loss was more equally distributed throughout the cochlea. Expression of the growth associated protein GAP-43, a well-established marker for synaptic plasticity, was up-regulated in the ipsilateral VCN at 15 and 31 days postcarboplatin, but not at 3 and 7 days. In contrast, the dorsal cochlear nucleus showed only little change. In VCN, the high-frequency area dorsally showed slightly yet significantly stronger GAP-43 upregulation than the low-frequency area ventrally, possibly reflecting the high-to-low frequency gradient of hair cell degeneration. Synaptic modification or formation of new synapses may be a homeostatic process to re-adjust mismatched inputs from two ears. Alternatively, massive fiber growth may represent a deleterious process causing central hyperactivity that leads to loudness recruitment or tinnitus.

The hippocampus plays an important role in memory, mood and spatial navigation. In the dentate gyrus of the adult hippocampus, in the subgranular zone (SGZ), new cells are generated that differentiate and mature into new neurons. Cisplatin, a highly effective antineoplastic drug with nephrotoxic and ototoxic side effects, induces apoptosis and suppresses neurogenesis in the hippocampus leading to memory impairment. Previous studies have shown that the antioxidant D-methionine protects against cisplatin-induced ototoxicity and nephrotoxicity suggesting that it might also prevent neurogenesis from being suppressed by cisplatin treatment. To test this hypothesis, rats were treated with cisplatin, D-methionine, cisplatin plus D-methionine, or saline (controls). Seven days after treatment, the rats were sacrificed and hippocampal sections immunolabeled for doublecortin (DCX) to identify neuronal precursor cells and maturing neurons in the SGZ. Cisplatin significantly reduced the number of DCX labeled cells (~80%) relative to controls. In contrast, DCX cell counts in rats treated with D-methionine prior to cisplatin were similar to controls. D-methionine treatment alone did not affect the number of DCX cells. These results indicate that D-methionine prevents the dramatic cisplatin-induced decrease of neurogenesis.