Characteristics of the anterior lateral line nerve input to the Mauthner cell.

The goldfish Mauthner (M-) cells, a bilateral pair of reticulospinal neurons, initiate the auditory evoked escape behavior of teleosts. In an open field the fish reliably turns away from the sound source. This implies that the M-cells are capable of a decision-making process that requires the two cells to receive differential directional inputs. Recent studies have indicated that the lateral line (LL) system is necessary in the initial directionality of the escape. This information is thought to be transmitted to the M-cell by the anterior branch of the lateral line nerve (aLLn), which has a shorter conduction time then the posterior branch. This study is the first attempt to characterize the inputs from the aLLn to the M-cell. M-cell intracellular responses to aLLn stimulation indicate a fast monosynaptic input (0.80±0.03 ms) that has a small amplitude averaging 5.85±0.42 mV. This input is bilateral and has a significantly longer latency and smaller amplitude in the contralateral M-cell. Superimposed on the evoked excitatory postsynaptic potential (EPSP) is a shunting inhibition with a delay of 1 ms, which is characteristic of other sensory inputs to the M-cell. Pharmacological manipulation and 50 Hz stimulation reveal a component of the evoked EPSP that is electrotonic, a property favoring speed of transmission. In addition, this input is localized to the lateral dendrite proximal to the inputs from the inner ear. The short latency of these inputs and their proximity to the posterior eighth nerve afferents indicate a crucial role for the aLLn in influencing the excitability and directionality of the M-cell.

Role of the lateral line mechanosensory system in directionality of goldfish auditory evoked escape response.

Goldfish (Carassius auratus) escape responses to sudden auditory stimuli are mediated by a pair of reticulospinal neurons, the Mauthner (M-) cells, which integrate mechanosensory inputs from the inner ear and the lateral line (LL) to initiate a fast directional response away from the aversive stimulus. This behavior is context dependent; when near an obstruction the fish may rather turn towards the sound to avoid hitting the object. Mechanisms underlying this directionality remain unknown. Here we investigate the contribution of the LL system to auditory evoked escapes and provide behavioral evidence that it transmits stimulus - and environmental-dependent information that determines the initial response direction of the escape. We quantified escape latency, probability and directionality following abrupt sound stimuli before and after removal of the entire LL with 0.03 mmol l(-1) cobalt chloride (CoCl(2)), 0.002% gentamicin or selective posterior LL nerve (pLLn) transection. CoCl(2) significantly increased escape onset latency without affecting probability and reduced open field directionality from 77% to chance, 52%. This effect on directionality was also observed with gentamicin. Transection of the pLLn had no effect on directionality, indicating the anterior LL nerve (aLLn) afferents are more likely to transmit directional information to the M-cell. When the fish were near a wall, the error rate was quadrupled by both CoCl(2) and pLLn transection. Visual elimination had no influence on directionality unless combined with LL elimination.

Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity.

In previous studies we found that neuronal overexpression of human cyclooxygenase (COX)-2 in transgenic mice potentiated excitotoxicity in vivo and in vitro. To clarify the molecular mechanisms involved in COX-2-mediated potentiation of excitotoxicity, we used cDNA microarray to identify candidate genes the expression of which is altered in the cerebral cortex of homozygous human hCOX-2 transgenic mice. We found that the mRNA expression of the cell cycle kinase (CDK) inhibitor-inhibitor kinase (INK) p18(INK4), a specific inhibitor of CDK 4,6, which controls the activation of the retinoblastoma (Rb) tumor suppressor protein phosphorylation, was decreased in the brain of adult hCOX-2 homozygous transgenics. Conversely, chronic treatment of the hCOX-2 transgenics with the preferential COX-2 inhibitor nimesulide reversed the hCOX-2-mediated decrease of cortical p18(INK4) mRNA expression in the brain. Further in vitro studies revealed that in primary cortico-hippocampal neurons derived from homozygous hCOX-2 transgenic mice, COX-2 overexpression accelerates glutamate-mediated apoptotic damage that is prevented by the CDK inhibitor flavoperidol. Moreover, treatment of wild-type primary cortico-hippocampal neuron cultures with the COX-2 preferential inhibitor nimesulide significantly attenuated glutamate-mediated apoptotic damage, which coincided with inhibition of glutamate-mediated pRb phosphorylation. These data indicate that hCOX-2 overexpression causes neuronal cell cycle deregulation in the brain and provides further rationale for targeting neuronal COX-2 in neuroprotective therapeutic research.