| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1998: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1997: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
It has been reported that information flow in the hippocampus was modulated by afferent inputs from the supramammillary nucleus (SuM) of the hypothalamus. However, it is still unknown how this hypothalamo-hippocampal afferent regulates the signal flow in the hippocampus and whether generation of seizure activities in the temporal lobe epilepsy and the subsequent neuron damage in the hippocampus can be controlled by modulation of this afferent inputs. In the present study, 1) we demonstrated duringthe first term of project that there exists a gating mechanism at the dentate gyrus controlled by the hypothalamic afferent inputs which acts as a gate for the signal flow into the hippocampus in the manner of on/off switch, and in the second term of project 2) we tested using rat model of temporal lobe epilepsy induced by intraamygdala injection of kainic acid (KA) whether the sustained enhancement or sustained interruption of the hypothalamic afferent inputs modulates (ameliorates or deterio
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rates) the hippocampal neuron damage following the repetitive limbic seizures induced by intra-amygdala KA injection due to regulation of the gating mechanism. To enhance the hypothalamic afferent inputs during the long period (1-2 weeks), we used the cationic HVJ-liposome mediated gene transfer method for focal introduction of antisense oligodeoxynucleotides (ODNs) to synapsin I, regulatory protein for transmitter release, into the SuM of the hypothalamus which resulted in chronically enhanced efficacy of transmitter release in synaptic terminals of antisense-transfered hypothalamic neurons. Three-4 days after the antisense ODNs injection to the SuM, the rat received 0.4 mug/200 nl kainic acid into the ipsilateral amygdala which induced the class 5 limbic seizures, and subsequantly lead hippocampal neuron damage. As a results, the sustained enhancement of the hypothalamic afferent produced by the antisense ODNs injection to the SuM altered the hippocampal neuron damage from moderate damage of CAl neurons to severe damage of CA3 neurons. From the finding that the antisense ODNs treatment resulted in deterioration of hippocampal neuron damage following KA-induced limbic seizures, we concluded that the sustained enhancement of the hypothalamic afferent inputs intensified the limbic seizure activities in the hippocampus probably due to activation of the gate mechanism at the dentate gyrus and subsequently enhanced the process of glutamate excitotoxicity in the CA3 pyramidal neurons. Less
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