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Age-related spatial memory deficits are correlated with septohippocampal cholinergic system degeneration. The present study examined the effect of intraseptal infusions of the cholinergic agonist, oxotremorine, on spatial reference memory in middle-aged rats using place discrimination in the water maze, and on cholinergic activity using choline acetyltransferase (ChAT) activity. Oxotremorine mildly improved the rate of place discrimination acquisition of middle-aged rats during initial sessions only, but did not affect asymptotic levels of performance achieved. Of the brain regions assayed, ChAT activity increased with age in the temporal cortex and dorsal CA2/3 region of the hippocampus. Oxotremorine significantly decreased ChAT activity in the dorsal hippocampus. In contrast to our previous results in aged rats indicating a more robust effect of oxotremorine on spatial working memory, the present results suggest a modest effect of intraseptal oxotremorine on the acquisition of a spatial reference memory task.

Cognitive impairments in humans and animals have been linked to dysfunction of neurons in the basal forebrain cholinergic system (BFCS). Degeneration of these cells may be, in part, responsible for some of the cognitive deficits observed in Alzheimer's disease (AD). Although memory deficits are associated with lesions of the BFCS in rats, impairments in memory have been more subtle following similar lesions in monkeys. To evaluate the effects of BFCS lesions on cognitive processes in monkeys, we have systematically investigated the behavioral effects of ibotenic acid injections in the medial septum, nucleus of the diagonal band of Broca, and nucleus basalis of Meynert in cynomolgus monkeys, using a large series of cognitive tasks that examined different mnemonic and attentional abilities. These lesions did not impair accuracy in delayed nonmatching-to-sample, delayed response, simple or concurrent visual discriminations, spatial discriminations, or discrimination reversals. However, these lesions disrupted attentional focusing. Similar impairments in attention have been noted in patients with AD. BFCS lesions increased sensitivity to injections of the cholinergic antagonist scopolamine in a delayed nonmatching-to-sample task, indicating that the central cholinergic system was compromised in these monkeys. In concert, the results of this study suggest that the primate basal forebrain may be more involved in attentional than mnemonic processes, and that degeneration of neurons in the BFCS in cases of AD may contribute to the attention deficits observed in these individuals.

Traumatic brain injury (TBI) in humans typically produces neurological suppression and a longer lasting impairment of memory clinically defined as post-traumatic amnesia. An animal model that reliably reproduces the physiological changes associated with TBI was used to assess the memory deficits following brain injury. Prior to TBI, rats were trained to perform one of four tasks that assessed either motor performance, long-term or recent memory. Rats were randomly assigned to one of three groups (anesthesia only, sham operation or fluid percussion). Following fluid percussion, used to produce TBI, rats were tested for 6 test sessions. The first session occurred 1-2 min after the experimental manipulation. The next 5 sessions followed the training schedule maintained prior to experimental manipulation. Differences in long-term memory occurred only in the first post-operative test session. Differences in recent memory performance were found across all 6 test sessions. The memory deficits were clearly dissociated from motor deficits. The similar memory deficits observed following human head injury and the experimentally produced TBI injury demonstrate that fluid percussion is a useful approach to examine underlying neurobiological mechanisms involved in head injury and possible clinical interventions.