PHYSIOLOGY AND PHARMACOLOGY OF CHOLINERGIC AND GABAERGIC BASAL FOREBRANE NEURONS

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The long range goal of this research is to understand the role of cholinergic basal forebrain nuclei in normal behavior and in certain diseases such as senile dementia and Alzheimer's disease. In particular, the roles of cholinergic and GABAergic neurons which compose the medial septal/diagonal band (MS/DB) nuclei are of interest because of their involvement in such phenomena as the control of hippocampal rhythmic slow activity (theta rhythms) and spatial learning. Very little is known about the basic physiology and pharmacology of basal forebrain neurons. Recent findings on the electrophysiological properties of MS/DB neurons which express choline acetyltransferase has opened the way for more detailed pharmacological studies on cholinergic neurons. The characterization of GABAergic MS/DB neurons is still to be done. The focus of this proposal is to use the in vitro forebrain slice preparation in combination with intracellular recording techniques and double labeling of recorded neurons to define the basic membrane physiology of GABAergic MS/DB neurons and to begin to explore the pharmacology of cholinergic and presumed GABAergic MS/DB neurons. More specifically, the following questions will be addressed: 1. What are the active and passive membrane properties of GABAergic MS/DB neurons? These neurons will be labeled by intracellular injection of biocytin followed by in situ hybridization of riboprobes or cDNA probes to GAD mRNA. 2. What are the ionic mechanisms which underlie the depolarizing effects of neurotensin and norepinephrine on cholinergic MS/DB neurons, as demonstrated in preliminary data? What subtypes of neurotensin and norepinephrine receptors are involved? 3. Does nerve growth factor acutely depolarize mature cholinergic MS/DB neurons as has been reported for embryonic cholinergic neurons? If so, what receptor subtypes are involved? These questions will be pursued with an attention to a common theme, that of neuronal rhythms, membrane oscillations and their mechanisms. Since the MS/DB region is one of the pacemaker centers for cortical rhythmic activities involved in learning, memory and cognition, we will focus on membrane properties which underlie rhythmic pacemaker and burst firing behavior in GABAergic and cholinergic neurons.