Hippocampal galanin and acetylcholine in spatial learning

Sammanfattning: The aim of the present thesis was to study how the neuropeptide galanin affects the neurochemistry and functional activity of the cholinergic septohippocampal projection, which plays a pivotal role in learning and memory. This cholinergic system is strongly impaired in Alzheimer's disease and in age-related dementias. The effects of exogenous porcine galanin peptide, infused via chronic bilateral cannulae (placed in different subareas of the hippocampal formation), were examined in a spatial memory task which is dependent on hippocampal functions (the Morris swim maze). Rats have to learn to find a hidden platform in a water maze using extra-maze spatial "cues". Brain acetylcholine release was monitored by in vivo microdialysis and high-performance liquid chromatography (HPLC). The distribution and kinetics of infused galanin was examined by immunohistochemical techniques with antiserum towards porcine galanin. Similar to many neuropeptides, galanin displayed an inverted-U shaped dose-response learning curve in most studies. Galanin (3 nmol/rat), infused into the ventral hippocampal region (mainly the CA3 area), caused an impairment of spatial learning related to a decrease in basal acetylcholine release. Infusions of galanin (I nmol/rat) into the dorsal hippocampal CAI area facilitated spatial learning. In contrast, combined infusions of galanin (3 nmol/rat) into both the dorsal and ventral CAI region retarded spatial learning, indicating that the action of galanin depends on the pattern of activation of galanin receptors in the hippocampal network. Infusions of galanin (3 nmol/rat) in the dentate gyrus, which contains high levels of GAL-R2 receptor mRNA and a high degree of gala-nin-noradrenaline coexistence, markedly retarded spatial learning, blocked by the nonselective galanin antagonist M35. This suggests that the GAL-R2 receptor subtype has a particularly important role in modulation of afferent input from the cerebral cortex. Infusions of galanin into the medial septal area, containing the cholinergic cell bodies, increased basal acetylcholine release in the ventral hippocampus and tended to facilitate spatial learning. Galanin perfused through the microdialysis probe in the ventral hippocampus, decreased basal acetylcholine release in this area. In contrast, when perfused through the probe, galanin enhanced acetylcholine release in the dorsal hippocampus suggesting a differential modulatory role of galanin on acetylcholine transmission in these two regions. Microinjections of the nonselective muscarinic antagonist scopolamine demonstrated that both the dorsal and ventral hippocampal cholinergic systems play a tonic role in spatial learning and memory. Analysis of memory performance in a probe trial (without the hidden platform) suggests that intrahippocampal galanin primarily acts via disruption of acquisition mechanisms. However, when there exists a concomitant cholinergic dysfunction by scopolamine, galanin can enhance the memory impairment induced by the locally injected muscarinic antagonist in the medial septal area and in the dorsal hippocampus. Intrahippocampally infused galanin was shown to be internalized (possibly via galaninreceptor mediated mechanisms) in the soma and dendrites of a subpopulation of hippocampal GABA/NPY/somatostatin containing interneurons. These findings suggest a possible role for galanin and/or galanin fragments on gene regulation. The combined behavioural and neurochemical results suggest an important role for galanin within septohippocampal networks of importance for learning and memory with potential relevance for Alzheimer's disease.