Neurochemical regulators of the septohippocampal pathway : : Role in spatial and aversive learning

Sammanfattning: The aim of this thesis was to investigate the significance of major neurotransmitters in the septohippocampal pathway for hippocampal-dependent learning and memory. The cholinergic and GABAergic neurons in the medial septal/vertical limb of the diagonal band of Broca area (MS/vDB) projecting to the hippocampus, constitute the septohippocampal pathway, which has been implicated in a number of important functions such as attention, anxietylike behavior and hippocampal-dependent learning and memory. Both extrinsic and intrinsic neuroregulators can influence the activity of septohippocampal neurons, including acetylcholine (ACh), serotonin (5-HT), glutamate and the neuropeptide galanin. It has previously been reported that cholinergic muscarinic transmission within the MS/vDB has an excitatory role and that blockade of septal muscarinic transmission impairs hippocampal-dependent learning. To test this hypothesis, the muscarinic receptor antagonist scopolamine was infused into the MS/vDB. Intraseptal scopolamine produced only a minor impairment in spatial acquisition in the Morris water maze, a hippocampal-dependent task, and also caused an increase in basal hippocampal ACh release. Contrary to earlier findings, the present results indicate that the MS/vDB cholinergic neurons are under an inhibitory muscarinic tone and that the impairing effects of systemic scopolamine cannot be related to an inhibitory action on MS/vDB cholinergic neurons. The neuropeptide galanin, which is co-localized with cholinergic septohippocampal neurons, has been proposed to have an inhibitory role in hippocampal-dependent cognition. In contrast, intraseptal galanin enhanced hippocampal ACh release combined with a facilitation in spatial learning, i.e. galanin appears to excite, not inhibit, septohippocampal cholinergic neurons. The combination of galanin and scopolamine produced a marked impairment in spatial learning concomitant with a profound increase in hippocampal ACh release. This finding suggests that the level of muscarinic activity within the MS/vDB is important for the role of galanin in septohippocampal functions. The 5-HT1A receptors are located presynaptically in the raphe nuclei, regulating the firing rate of serotonergic neurons, and postsynaptically on a number of target neurons involved in cognitive functions. Stimulation of 5-HT1A receptors by systemic administration of the agonist 8-OH-DPAT impaired spatial learning in the rat and produced a biphasic effect in an aversive learning task, i.e. passive avoidance (PA). Hence, lower doses facilitated whereas higher doses impaired PA memory in both rats and mice. The learning impairments were abolished by the 5-HT1A receptor antagonist NAD-299, which in itself facilitated PA memory but failed to affect spatial learning. Furthermore, 5-HT1A receptor blockade could eliminate the impairment in PA induced by a reduction in muscarinic or glutamatergic transmission, caused by scopolamine or the NMDA receptor antagonist MK-801. These findings support the view that pre- and postsynaptic brain 5-HT1A receptors play different roles in learning and memory, and that blockade of brain 5-HT1A receptors can enhance cholinergic and/or glutamatergic transmission of importance for cognition. The high density of glutamatergic fibers and the evidence for an intrinsic glutamatergic system within the MS/vDB suggest that medial septal glutamatergic transmission is important for septohippocampal cognitive functions. Blockade of glutamatergic transmission in the MS/vDB by local infusion of the NMDA receptor antagonist D-AP5 impaired spatial learning at a dose of 5 ìg. This impairment appears not to be caused by sensorimotor disturbances or changes in anxiety-like behavior. In contrast to spatial learning, lower doses of D-AP5 (0.3, 1 and 5 ìg) impaired PA retention, suggesting that NMDA receptors in the MS/vDB play different roles in spatial vs. aversive (emotional) learning. The 5-HT1A receptor is located on both cholinergic and GABAergic neurons in the MS/vDB. Intraseptal infusion of 8-OH-DPAT impaired PA memory but did not affect spatial learning, suggesting that the 5-HT1A receptors in the MS/vDB play a more important role in aversive than in spatial learning. Since stimulation of 5-HT1A receptors has been shown to inhibit NMDA receptor signaling in the hippocampus, 8-OH-DPAT was microinjected together with a subthreshold dose of D-AP5 (1 ìg). This combination caused a marginal but significant deficit in spatial learning, but a profound impairment in spatial memory in the retention test. This finding suggests that there exists an interaction between NMDA and 5-HT1A receptors in the MS/vDB of importance for the establishment of a stable, long-term memory. Acquisition of the water maze task involves multiple types of memories, subserved by different neuronal substrates. Learning of the behavioral procedure by non-spatial pretraining (NSP) was shown to improve water maze acquisition in control rats, but only initially. NSP also attenuated, but could not completely abolish, the spatial impairments caused by systemic scopolamine. These results indicate that acquisition of non-spatial information is important for subsequent spatial learning. Importantly, in contrast to earlier suggestions, brain muscarinic receptors appear to be important for spatial learning and memory, while they seem to play a minor role in acquisition of the behavioral procedure. In summary, these results give evidence for a role for ACh, 5-HT and glutamate in the MS/vDB for hippocampaldependent learning and memory. ACh and galanin interactions as well as 5-HT1A and NMDA receptor interactions appear to have major roles in septohippocampal functions. These findings may have important implications for the development of treatments for cognitive impairments.