KUOPION YLIOPISTO UNIVERSITY OF KUOPIO Neurologian klinikan julkaisusarja, No 51, 2000 Series of Reports, Department of Neurology JUKKA PUOLIVÄLI AN EXPERIMENTAL STUDY ON THE CHOLINERGIC MODULATION OF CORTICAL AROUSAL AND COGNITIVE FUNCTIONS

The brain cholinergic system is involved in a number of behaviors including arousal and cognitive processes. In Alzheimer’s disease (AD) patients, the function of the cholinergic system is severely compromised. AD patients with apolipoprotein E (apoE) ε4 allele(s) suffer more pronounced cholinergic deficits which are associated with severe cognitive impairments, pronounced cortical electroencephalogram (EEG) slowing, impaired synaptic plasticity, and decreased responsiveness to cholinomimetic treatment compared to AD patients without apoE ε4 allele. The purpose of this study was to investigate the function of the brain cholinergic system and its interaction with apoE in the regulation of cortical arousal and cognitive functions. First, a rat EEG model of thalamocortically generated high-voltage spindles (HVS) was used to study the cholinergic modulation of neocortical arousal. The effects of intrathalamic (reticular nucleus of thalamus (NRT) and ventroposteromedial nucleus of thalamus (VPM)) infusions of a muscarinic M1 receptor agonist, McN-A-343, a muscarinic M2 receptor antagonist, methoctramine, and a muscarinic receptor agonist, oxotremorine, on HVSs were studied. Second, the role of apoE in the regulation of biochemical, cognitive and electrophysiological functions was investigated. The effects of quisqualic acid induced nucleus basalis (NB) -lesion and ageing on cholinergic activity, spatial navigation in water maze (WM), cortical EEG activity and EEG response to a muscarinic receptor antagonist, scopolamine, were investigated in apoE-deficient and control mice. The major findings of this study were: 1) intrathalamic NRT and/or VPM infusions of McN-A-343, methoctramine, and oxotremorine, decreased HVSs in rat, indicating increased neocortical arousal. These results suggest that intrathalamic infusions of cholinergic muscarinic drugs modulate neocortical arousal via muscarinic M1 and M2 receptors in thalamus. Furthermore, these results suggest that intracerebroventricularly and systemically administered cholinergic drugs may also modulate neocortical arousal via the thalamus. 2) The apoE-deficient mice did not suffer any apparent impairment in their cortical and hippocampal choline acetyltransferase (ChAT) -activity, number of ChAT-positive neurons in NB, or in WM spatial navigation during ageing. Furthermore, apoE-deficiency did not increase the sensitivity to cholinergic, WM spatial navigation or EEG deficits induced by NB-lesion. However, the apoE-deficient mice had slightly altered cortical EEG activity during ageing and blunted EEG response to scopolamine treatment. These results suggest that apoE does not have to be present to preserve the viability of cholinergic neurons and that spatial navigation and behavioral recovery during ageing or after NB-lesion is not affected by apoEdeficiency. However, apoE-deficiency might alter the regulation of cortical arousal during ageing and after cholinergic drug (scopolamine) manipulation. Taken together, this study provides new information about the function of the brain cholinergic system and its interaction with apoE. This may have relevance in the development of new experimental models and therapeutic treatments for clinical disorders such as AD. National Library of Medicine Classification: WL 150, WL 155 Medical Subject Headings: Alzheimer’s disease; apolipoproteins E; arousal; cholinergic agents; electroencephalography; maze learning; memory; nucleus basalis of Meynert