Cognitive impainnent is a serious health Concern in the United States; it accompanies not only nonmal aging and dementing disorders such as Alzheimer's, but also several mental illnesses, such as schizophrenia. Basic and clinical studies have long recognized the importance of cholinergic mechanisms for the maintenance of cognitive functioning and treatments which increase synaptic acetylcholine (ACh) levels, using acetylcholinesterase inhibitors (AChEls), are currently the most extensively used for the therapy of Alzheimer's disease. In contrast, treatments which oppose cholinergic tone, such as systemic infusions of the muscarinic cholinergic receptor antagonists, atropine and scopolamine (Atr/Scop), produce an amnesic syndrome both in humans and in rats and emphasize the importance of muscarinic mechanisms. Basic studies suggest that muscarinic mechanisms in the medial septum/diagonal band (MSDB), via the septohippocampal pathway, contribute to the cognitive deficits produced by systemic Atr/Scop. Thus, infusions of muscarinic agonists into the MSDB alleviate the amnesic syndrome, whereas local infusions of Atr/Scop mimic the syndrome. In our preliminary shidies, conducted using electrophysiological recording techniques in rat brain slices, we have found that Atr/Scop, when applied to septal slices, stop spontaneous firing activity in a vast majority of MSDB neurons, including, non-cholinergic (presumably, GABAergic) neurons that project to the hippocampus. In contrast, a wide array of AChEIs, including the clinically used tacrine, produce a profound increase in the firing activity of MSDB neurons, which is blocked by Atr/Scop. Therefore, in the present study, we hypothesize 1) that there is a tonic release of ACh in the MSDB (which carl be unmasked by Atr/Scop and AChEIs) and the released ACh, via muscarinic receptors, provides a major excitatory drive to the septohippocampal GABAergic neurons; 2) the released ACh, via muscarinic receptors, provides a major excitatory drive to the septohippocampal GABA neurons; 3) the tonic release of ACh occurs due to the spontaneous firing activity of septohippocampal cholinergic neurons (which also innervate MSDB GABAergic neurons via axon collaterals); 4) a loss of MSDB cholinergic neurons (as can occur in normal aging and in Alzbeimer's) decreases the activity of septohippocampal GABA neurons. It is speculated that the resultant changes in cholinergic and GABergic transmission to the hippocarnpus will contribute to deficits in learning and memory. The above hypothesis will be tested using state-of-the-art electrophysiological recording methods in antidromically-activated and/or retrogradely labeled septohippocampal neurons visualized using the technique of infrared videomicroscopy. Cholinergic neurons will be selectively lesioned US aboutDig the irnrnunotoxin, 1921gG-saporin. In addition, double and triple-labeling techniques will be employed to identify septohippocampal cholinergic and GABAergic neurons. It is hoped that the proposed research will provide fresh insights into the role of the septohippocampal GABAergic pathway in cognitive functioning.
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