Serotonergic modulation of cholinergic function in the central nervous system: Cognitive implications

Accumulating evidence suggests that serotonin may modulate cholinergic function in several regions of the mammalian brain and that these serotonergic/cholinergic interactions influence cognition. The first part of this review is an overview of histological, electrophysiological and pharmacological (in vitro, in vivo) data indicating that, in several brain regions (e.g., hippocampus, cortex and striatum), there are neuroanatomical substrates for a serotonergic/cholinergic interaction, and that alterations in serotonergic activity may induce functional changes in cholinergic neurons. In the second part, the review focuses on experimental approaches showing or suggesting that central cholinergic and serotonergic mechanisms are cooperating in the regulation of cognitive functions. These arguments are based on lesion, intracerebral grafting and pharmacological techniques. It is concluded that not all mnesic perturbations induced by concurrent manipulations of the serotonergic and cholinergic systems can be attributed to a serotonergic modification of the cholinergic system. The cognitive faculties of an organism arise from interactions among several neurotransmitter systems within brain structures such as, for instance, the hippocampus or the cortex, but also from influences on memory of other general functions that may involve cerebral substrates different from those classically related to mnesic functions (e.g., attention, arousal, sensory accuracy, etc.)

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Modulation of cholinergic functions by serotonin and possible implications in memory: General data and focus on 5-HT1A receptors of the medial septum

Cholinergic systems were linked to cognitive processes like attention and memory. Other neurotransmitter systems having minor influence on cognitive functions - as shown by the weakness of the effects of their selective lesions - modulate cholinergic functions. The serotonergic system is such a system. Conjoined functional changes in cholinergic and serotonergic systems may have marked cognitive consequences [Cassel JC, Jeltsch H. Serotoninergic modulation of cholinergic function in the central nervous system: cognitive implications. Neuroscience 1995;69(1):1-41; Steckler T, Sahgal A. The role of serotoninergic-cholinergic interactions in the mediation of cognitive behaviour. Behav Brain Res 1995;67:165-99]. A crucial issue in that concern is the identification of the neuroanatomical and neuropharmacological substrates where functional effects of serotonergic/cholinergic interactions originate. Approaches relying on lesions and intracerebral cell grafting, on systemic drug-cocktail injections, or even on intracerebral drug infusions represent the main avenues on which our knowledge about the role of serotonergic/cholinergic interactions has progressed. The present review will visit some of these avenues and discuss their contribution to what is currently known on the potential or established implication(s) into memory functions of serotonergic/cholinergic interactions. It will then focus on a brain region and a neuropharmacological substrate that have been poorly studied as regards serotonergic modulation of memory functions, namely the medial septum and its 5-HT(1A) receptors. Based on recent findings of our laboratory, we suggest that these receptors, located on both cholinergic and GABAergic septal neurons, take part in a mechanism that controls encoding, to some extent consolidation, but not retrieval, of hippocampal-dependent memories. This control, however, does not occur by the way of an exclusive action of serotonin on cholinergic neurons

Cognitive performances and locomotor activity following dentate granule cell damage in rats: Role of lesion extent and type of memory tested

Intradentate injection of colchicine is one of the techniques used to destroy granule cells. This study compared the behavioral effects of various amounts of colchicine (1.0, 3.0, and 6.0 microg; Col 1, Col 3, and Col 6, respectively) injected into the dentate gyrus of adult Long-Evans male rats. Starting 10 days after lesion surgery, behavioral testing assessed home-cage and open-field locomotion, alternation in a T-maze, water-maze, and radial-maze learning according to protocols placing emphasis on reference, and working memory. All of these tasks are sensitive to hippocampal disruption. Histological verifications showed that the extent of the lesions depends on the dose of colchicine (index of dentate gyrus shrinkage: -33% in Col 1, -54% in Col 3, and -67% in Col 6 rats). Colchicine dose-dependently increased nocturnal home cage activity (an effect found 10 days but not 5 months after surgery), but had no significant effect on open-field locomotion or T-maze alternation. A dose-dependent reference memory impairment was found during the acquisition of spatial navigation in the water maze; Col 3 and Col 6 rats were more impaired than Col 1 rats. During the probe trial (platform removed), control rats spent a longer distance swimming over the platform area than all rats with colchicine lesions. In the working memory version of the test, all rats with colchicine lesions showed significant deficits. The deficits were larger in Col 3 and Col 6 rats compared to Col 1 rats. The lesions had no effect on swimming speed. In the radial-maze test, there was also a dose-dependent working memory impairment. However, reference memory was disrupted in a manner that did not differ among the three groups of lesioned rats. Our data are in line with the view that the dentate gyrus plays an important role in the acquisition of new information and is an integral neural substrate for spatial reference and spatial working memory. They also suggest that damage to granule cells might have more pronounced effects on reference than on working memory in the radial maze. Finally, they demonstrate that part of the variability in the conclusions from previous experiments concerning the role of granule cells in cognitive processes, particularly in spatial learning and memory, may be due to the type of tests used and/or the extent of the damage produced

The fimbria-fornix/cingular bundle pathways: A review of neurochemical and behavioural approaches using lesions and transplantation techniques

Extensive lesions of the fimbria-fornix pathways and the cingular bundle deprive the hippocampus of a substantial part of its cholinergic, noradrenergic and serotonergic afferents and, among several other behavioural alterations, induce lasting impairment of spatial learning and memory capabilities. After a brief presentation of the neuroanatomical organization of the hippocampus and the connections relevant to the topic of this article, studies which have contributed to characterize the neurochemical and behavioural aspects of the fimbria-fornix lesion "syndrome" with lesion techniques differing by the extent, the location or the specificity of the damage produced, are reviewed. Furthermore, several compensatory changes that may occur as a reaction to hippocampal denervation (sprouting changes in receptor sensitivity and modifications of neurotransmitter turnover in spared fibres) are described and discussed in relation with their capacity (or incapacity) to foster recovery from the lesion-induced deficits. According to this background, experiments using intrahippocampal or "parahippocampal" grafts to substitute for missing cholinergic, noradrenergic or serotonergic afferents are considered according to whether the reported findings concern neurochemical and/or behavioural effects. Taken together, these experiments suggest that appropriately chosen fetal neurons (or other cells such as for instance, genetically-modified fibroblasts) implanted into or close to the denervated hippocampus may substitute, at least partially, for missing hippocampal afferents with a neurochemical specificity that closely depends on the neurochemical identity of the grafted neurons. Thereby, such grafts are able not only to restore some functions as they can be detected locally, namely within the hippocampus, but also to attenuate some of the behavioural (and other types of) disturbances resulting from the lesions. In some respects, also these graft-induced behavioural effects might be considered as occurring with a neurochemically-defined specificity. Nevertheless, if a graft-induced recovery of neurochemical markers in the hippocampus seems to be a prerequisite for also behavioural recovery to be observed, this neurochemical recovery is neither the one and only condition for behavioural effects to be expressed, nor is it the one and only mechanism to account for the latter effects

Effects of 192 IgG-saporin on acetylcholinesterase histochemistry in male and female rats

Sex hormones may exert neuroprotective effects in various models of brain lesions. Male and female Long-Evans rats were subjected to intracerebroventricular injections of 2 microg 192 IgG-saporin or vehicle. Starting 2 days before surgery, half the male rats were treated with estradiol for 7 days. Three weeks after surgery, they were sacrificed for histochemical staining of acetylcholinesterase (AChE) and densitometric evaluations. The lesion induced a substantial to dramatic decrease of the AChE-positive fiber density in the cingulate, somatosensory, piriform, retrosplenial and perirhinal cortices, and in the hippocampus. Weak effects were found in the striatum. There was no significant decrease in the dorsal thalamus. Sex had no significant effect on AChE-positive staining in any brain area. In males, estradiol treatment did not alter the effects of 192 IgG-saporin. These results show that sex or estradiol treatment in male rats does not interfere with the immunotoxic effects of intracerebroventricular injections of 192 IgG-saporin on cholinergic projections from the basal forebrain