In previous studies, we demonstrated that the nucleus pontis oralis (RPO) and the median raphe nucleus (MR) are directly involved in the synchronization (theta) and desynchronization of the hippocampal EEG, respectively, and further that the supramammilliary nucleus (SUM) is a critical relay between the brainstem and septum hippocampus in the control of the theta rhythm. The proposed studies are divided into two parts; those done with and without collaborators. Non-collaborative studies and the primary aims of the non-collaborative studies are: (1) to examine whether the SUM exerts an indirect (through the septum) and/or direct influence on the hippocampus in the generation of theta by analyzing the effects on the hippocampal EEG of injections of ibotenic acid or the cholinergic neurotoxin, 192 IgG saporin into the medial septum diagonal band; and (2) to characterize the role of several brainstem/diencephalic nuclei putatively involved in the control of hippocampal synchronization (pedunculopontine tegmental nucleus, nucleus reuniens, mammillary body, posterior nucleus of hypothalamus and SUM) and desynchronization (lateral habenula and MR) by examining the connections of these nuclei, their response to pharmacological agents and their neuronal discharge properties in anesthetized and freely moving rats. Collaborative Studies: These studies will be done in collaboration with Dr. Angel Alonso (electrophysiology in slices), Dr. Csaba Leranth (electron microscopy) and Dr. Matthew L. Shapiro (behavior). The primary aims of the collaborative studies are: 1) to examine the electrophysiological properties and response to various transmitter agents of SUM, MB and MS/DBv neurons in in vitro slices; 2) to examine the synaptic organization of brainstem afferents to the SUM and brainstem diencephalic afferents to the MS/DBv at the ultrastructural level; and 3) to examine the effects of ibotenic acid and 192 IgG saporin induced lesions of the MS/DBv on memory, correlating changes in theta to changes in learning and memory. At present, the candidate is very heavily obligated to non-research related activities (i.e., teaching and service). He is seeking a KO2 award to devote more time to research and to develop several new lines of research. Several reports have shown that long-term potentiation (a candidate mechanism for memory) is optimally induced in the hippocampus by stimulation at the theta frequency, and it has been proposed that theta plays a pivotal role in mnemonic processes in the hippocampus. If theta proves to be critical for memory, it is important to fully understand the neural mechanisms responsible for its generation. This work may have important implications for conditions such as Alzheimer's that involve a loss of cholinergic neurons of the MS/DBv.
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