Mark G. Baxter

The amygdala and reward

The amygdala — an almond-shaped group of nuclei at the heart of the telencephalon — has been associated with a range of cognitive functions, including emotion, learning, memory, attention and perception. Most current views of amygdala function emphasize its role in negative emotions, such as fear, and in linking negative emotions with other aspects of cognition, such as learning and memory. However, recent evidence supports a role for the amygdala in processing positive emotions as well as negative ones, including learning about the beneficial biological value of stimuli. Indeed, the amygdalas role in stimulus–reward learning might be just as important as its role in processing negative affect and fear conditioning.

Selective immunotoxic lesions of basal forebrain cholinergic cells: Effects on learning and memory in rats.

Male Long-Evans rats were given injections of either 192 IgG-saporin, an apparently selective toxin for basal forebrain cholinergic neurons (LES), or vehicle (CON) into either the medial septum and vertical limb of the diagonal band (MS/VDB) or bilaterally into the nucleus basalis magnocellularis and substantia innominata (nBM/SI). Place discrimination in the Morris water maze assessed spatial learning, and a trial-unique matching-to-place task in the water maze assessed memory for place information over varying delays. MS/VDB-LES and nBM/SI-LES rats were not impaired relative to CON rats in acquisition of the place discrimination, but were mildly impaired relative to CON rats in performance of the memory task even at the shortest delay, suggesting a nonmnemonic deficit. These results contrast with effects of less selective lesions, which have been taken to support a role for basal forebrain cholinergic neurons in learning and memory.

Cognitive functions of the basal forebrain.

Studies of the function of the basal forebrain have focused on cholinergic neurons that project to cortical and limbic structures critical for various cognitive abilities. Recent experiments suggest that these neurons serve a modulatory function in cognition, by optimizing cortical information processing and influencing attention.

Age-related spatial reference and working memory deficits assessed in the water maze

Aged rats have spatial memory deficits relative to young rats. The extent of these deficits in intermediate-aged rats is not well established. The present study examined the pattern of age-related changes in spatial reference and working memory in four ages of Fischer-344 rats. Place discrimination (PD) in the Morris water maze measured spatial reference memory. Repeated acquisition (RA), a discrimination in which the escape platform location varied from session to session, measured spatial working memory. Fischer-344 rats, 4 months, 11 months, 17 months, and 24 months of age, were tested. Compared to 4-month-olds, 24-month-olds were significantly impaired on all six PD measures of performance, 17 months were significantly impaired on five PD measures, and 11 months were significantly impaired on only one PD measure. Only 24-month-olds had a significant working memory impairment in RA relative to 4 months. Reference and working memory measures were distinct as assessed by a principal components analysis. The results indicate a nonlinear age-related spatial memory decline in Fischer-344 rats from 4 to 24 months of age.

Opposite relationship of hippocampal and rhinal cortex damage to delayed nonmatching-to-sample deficits in monkeys.

Three recent studies in macaque monkeys that examined the effects on memory of restricted hippocampal lesions (Murray and Mishkin, J Neurosci 1998;18:6568–6582; Beason‐Held et al., Hippocampus 1999;9:562–574; Zola et al., J Neurosci 2000;20:451–463) differed in their conclusions about the involvement of the hippocampus in recognition memory. Because these experiments used a common behavioral procedure, trial‐unique visual delayed nonmatching‐to‐sample (DNMS), a quantitative synthesis (“meta‐analysis”) was performed to determine whether hippocampal lesions produced a reliable net impairment in DNMS performance, and whether this impairment was related to the magnitude of hippocampal damage. A similar analysis was performed on data from monkeys with perirhinal or rhinal cortex damage (Meunier et al., J Neurosci 1993;13:5418–5432; Buffalo et al., Learn Mem 1999;6:572–599). DNMS performance scores were transformed to d′ values to permit comparisons across studies, and a loss in d′ score, a measure of the magnitude of the recognition deficit relative to the control group, was calculated for each operated monkey. Two main findings emerged. First, the loss in d′ following hippocampal damage was reliably larger than zero, but was smaller than that found after lesions limited to the perirhinal cortex. Second, the correlation of loss in d′ with extent of hippocampal damage was large and negative, indicating that greater impairments were associated with smaller hippocampal lesions. This relationship was opposite to that between loss in d′ and rhinal cortex damage, for which larger lesions were associated with greater impairment. These findings indicate that damage to the hippocampus and to the rhinal cortex affects recognition memory in different ways. Furthermore, they provide a framework for understanding the seemingly disparate effects of hippocampal damage on recognition memory in monkeys, and by extension, for interpreting the conflicting reports on the effects of such damage on recognition memory abilities in amnesic humans. Hippocampus 2001;11:61–71.

Multiple brain-memory systems: the whole does not equal the sum of its parts

Most contemporary theories of memory are based on the assumption that memory can be divided into multiple psychological systems that are subserved by different neural substrates and that contribute to performance in a relatively independent manner. Although the study of individual memory systems has proved to be enormously useful, recent data increasingly point towards complex interactions between memory systems during performance of any given memory task. Three basic classes of interactions between different memory systems (competition, synergism and independence) are presented that appear to be congruent with the findings of many behavioral studies. Consideration of interactions among multiple memory systems will enhance our current understanding of memory by encouraging the view that memory systems are dynamic interactive units, rather than independent modules that act in isolation.

D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats

D-cycloserine, a partial agonist of the NMDA receptor-associated glycine site, can enhance cognition. The present experiment examines the behavioral effects of D-cycloserine on cognitive deficits in male Fischer-344 rats, 24 months old. Rats 24 months old (n = 42) received either vehicle or one of 3 doses of D-cycloserine prior to testing. Young rats, 4 months old (n = 13), received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. D-cycloserine improved performance in place discrimination and repeated acquisition. No doses affected sensorimotor function. These results support the hypothesis that D-cycloserine has cognition enhancing properties and that it may be useful in treating disorders involving cognitive impairment.

Intact spatial learning in both young and aged rats following selective removal of hippocampal cholinergic input

Studies using the selective cholinergic immunotoxin 192 IgG-saporin have demonstrated that lesions of the cholinergic input to the hippocampus from the medial septum/vertical limb of the diagonal band (MS/VDB) do not disrupt spatial learning in the water maze in young rats. However, age-related deficits in spatial learning correlate with the integrity of cholinergic neurons in the MS/VDB, suggesting that these neurons may be more crucial for spatial learning in aged rats. To investigate this hypothesis directly, we selectively lesioned these neurons in aged rats that demonstrated relatively intact spatial learning in an initial screening as well as in a comparison set of young rats. Intact and lesioned rats of both ages rapidly acquired a new place discrimination in a different spatial environment. These results indicate that the cholinergic input to the hippocampus is not differentially involved in spatial learning in aged rats.

Intact spatial learning following lesions of basal forebrain cholinergic neurons

The role of the basal forebrain cholinergic system in learning and memory has held considerable interest since the discovery of cholinergic neurodegeneration in the basal forebrain in Alzheimers disease. Contrary to expectation, selective removal of basal forebrain cholinergic neurons projecting to either hippocampus or neocortex fails to impair learning in a spatial task widely used to study hippocampal/cortical function. If cholinergic neurons contribute to learning and memory by integrated regulation of hippocampal and cortical processing, combined removal of hippocampal and cortical cholinergic projections might be necessary to produce impairment. However, this combined lesion failed to impair spatial learning. These data argue against the view that basal forebrain cholinergic deficiency plays a prominent role in disorders of learning and memory.

Selective immunolesions of hippocampal cholinergic input fail to impair spatial working memory.

The septo‐hippocampal cholinergic pathway has traditionally been thought of as essential for spatial memory. Recent studies have demonstrated intact spatial learning following removal of this pathway with an immunotoxin selective for cholinergic neurons. In the present experiment, rats with selective removal of hippocampal cholinergic input were tested in a delayed nonmatching‐to‐position task in a water version of the radial arm maze. This allowed us to increase and parametrically vary the memory load compared with the standard Morris water maze (by varying the delay between the initial four choices and the final four choices) to determine if this would reveal a deficit in rats with lesions of septo‐hippocampal cholinergic projections. Male Long‐Evans rats were given injections of 192 lgG‐saporin, a selective immunotoxin for cholinergic neurons, into the medial septum/vertical limb of the diagonal band (MS/VDB) to remove cholinergic projections to the hippocampus, or a control surgery. The rats were trained on the radial maze task following surgery. An escape platform was located at the end of each arm of the maze and was removed after an arm was utilized for escape. After initial training, a delay was interposed between the first four trials and the second four trials. Errors during the second four‐trial component were scored in two categories: retroactive (reentering an arm chosen before the delay) and proactive (reentering an arm chosen after the delay). Retroactive errors increased as delay increased (from 60 s to 6 h) but were equivalent in control and MS/VDB‐lesion groups. Proactive errors did not vary with delay and were also unaffected by the lesion. Radioenzymatic assays for choline acetyltransferase activity in the hippocampus of lesioned rats confirmed a significant loss of cholinergic input from the MS/VDB. These results indicate that normal spatial working memory is possible after substantial loss of septo‐hippocampal cholinergic projections. Hippocampus 7:130–136, 1997.