The overall goal of this research is to charaerize gene expression associated with both hippocampally-dependent learning and opioid receptor-dependent long-term potentiation (LTP) expressed the mossy- fiber-CA3 pathway, a candidate mechanism for learning. Identification of identical genes involved in both acquisition and maintenance of both learning and LTP will provide convagent evidence thal LTP is a memory storage mechanism in the hippocampus. This research has relevance to drug abuse because craving by definition is a memory of a drug experience. Opioid-receptor dependent LTP provides an opponunity to study at a cellular and molecular level, how endogenous opioid peptides induce a long lasting change in the function of neural tissue using LTP, a model of how the brain may store memories.
In Specific Aim 1 we propose to determine which opioid receptor subtype mediates acquisition and retrieval of learning, after a criterion level of performance is maintained for three days, in a Morris water maze by impairing these processes using selective opioid receptor antagonists. Another series of experiments will examine the expression and time course of several genes we think important for the acquisition and retrieval of learning in this task including lag (LTP-Associated Gene), hzf3, ngfi-b, proenkephalin, proenkephalin, and prodynorphin and others. Genes important for learning will be selected based on whether their expression is under opioid receptor control, such that their expression is blocked by an opioid antagonist, and whether they are expressed under conditions that do not require learning, such as swimming in the Morris tank.
In Specific Aim 2 we propose to determine which opioid receptor subtype is involved in the maintenance of mossy fiber-CA3 LTP at intervals greater than 24 hours by blocking expression of LTP using selective opioid receptor antagonists. A final series of experiments will examine the time course of expression of genes we think are important for induction and maintenance of LTP and those found to be important in acquisition and retrieval of the Morris water maze response. As in the previous experiment important genes will be selected based on whether they are under control of opioid receptors, because opioid receptor antagonists block both induction and expression of LTP, and deselected if the genes are expressed under control conditions in which non-LTP inducing low frequency stimulation is given to the mossy fiber-CA3 pathway.
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