Presynaptic markers of cholinergic function in the rat brain: relationship with age and cognitive status.

The nature of age-related changes in cholinergic function and their relationship to age-related behavioral decline were examined in the present study. Male Fischer-344 rats of four ages (four, 11, 17 and 23 months) were tested in a battery of cognitive tasks. Discrete microdissections of brain areas involved in cognitive function were performed, and activity of choline acetyltransferase and levels of hemicholinium-3 binding were determined to assess the integrity of cholinergic innervation. Age-related changes in cholinergic markers occurred predominantly in the medial septal area and its target areas (hippocampus and cingulate cortex), and were also present in the posterior caudate. However, most of the age-related changes in cholinergic markers were already present at ages at which behavioral impairment was not yet maximal. There were some consistent correlations between behavioral and neurochemical measures, independent of age, but these accounted for relatively small proportions of variance in behavioral performance. For most of these correlations, lower levels of presynaptic cholinergic markers were related to better behavioral performance. In brain areas in which correlations changed with age, lower levels of presynaptic cholinergic markers were associated with better performance in young rats, whereas higher levels were associated with better performance in aged rats. Recent lesion studies using a toxin selective for basal forebrain cholinergic neurons have suggested that these neurons do not play as central a role in learning and memory in young and aged animals as was previously thought. When considered in this context, the present results suggest that preserved cholinergic function in old age might act indirectly to sustain cognitive ability. Changes in cholinergic function may represent one of a number of age-related neurobiological events that underlie behavioral impairments, or may be a permissive factor for other age-related processes that are more directly responsible for cognitive impairments.

Evidence that nerve growth factor influences recent memory through structural changes in septohippocampal cholinergic neurons.

We compared, in 4- and 23-month-old Fischer-344 rats, the effects of nerve growth factor (NGF) on basal forebrain cholinergic neurons with behavioral performance in acetylcholine-dependent memory tasks (recent and reference memory). Noncholinergic monoamine markers in target fields of cholinergic neurons were also investigated. We found that NGF has contrasting effects on recent memory in the two age groups in causing improvement in aged rats and deterioration in young rats. In addition, NGF caused significant increase in the size of cholinergic perikarya in all sectors of the basal nucleus complex (BNC). Higher doses of NGF were required to produce hypertrophy in aged animals, a pattern consistent with a lower sensitivity to NGF of aged cholinergic neurons. Analysis of covariance showed that the behavioral effects of NGF were eliminated after covarying out the hypertrophy of cholinergic perikarya. Therefore, NGF causes hypertrophy of cholinergic perikarya regardless of age, and this neurobiological measure correlates with the effects of NGF on recent memory. Reference memory improved moderately only in old rats. This mild effect covaried with an increase in choline acetyltransferase activity in neocortex. Cortical terminal fields of noradrenergic and serotoninergic pathways were not affected by NGF. Taken together, our results indicate that NGF influences recent memory in an age- and transmitter-specific fashion. We postulate that the direct cause of the effects of NGF on memory is not perikaryal hypertrophy per se but rather an increased density of terminals, which always accompanies perikaryal hypertrophy. Although these results continue to support the use of NGF for the treatment of Alzheimer's disease, they raise questions regarding the therapeutic role of NGF for degeneration of BNC neurons occurring in young age.

Behavioral biomarkers of aging: illustration of a multivariate approach for detecting age-related behavioral changes.

The goal of the current project is to develop a multivariate statistical strategy for the formation of behavioral indices of performance and, further, to apply this strategy to establish the relationship between age and important characteristics of performance. The strategy was to begin with a large set of measures that span a broad range of behaviors. The behavioral effects of the following variables were examined: Age (4, 12, 24, and 30 months), genotype [Fischer 344 and a hybrid (F1) of Fischer 344 and Brown Norway (F344xBN)], gender (Fischer 344 males and Fischer 344 females), long-term diet (ad lib diet or dietary restriction beginning at 4 months of age), and short-term diet (ad lib diet or dietary restriction during testing). The behavioral measures were grouped into conceptually related indicators. The indicators within a set were submitted to a principal component analysis to help identify the summary indices of performance, which were formed with the assumption that these component scores would offer more reliable and valid measures of relevant aspects of behavioral performance than would individual measures taken alone. In summary, this approach has made a number of important contributions. It has provided sensitive and selective measures of performance that indicated contributions of all variables: psychological process, age, genotype, gender, long-term and short-term diet and has increased the sensitivity of behavioral measures to age-related behavioral impairment. It has also improved task-manageability by decreasing the number of meaningful variables without losing important information, consequently providing a simplification of the pattern of changes.

Neuronal number and size are preserved in the nucleus basalis of aged rhesus monkeys.

Neurons in the nucleus basalis of Meynert (NBM) were analyzed morphometrically in 21 rhesus monkeys ranging in age from 9 to 33 years. Numbers of cholinergic neurons were similar across all ages at several NBM levels in either Nissl-stained paraffin sections or sections processed immunocytochemically for nerve growth factor receptor (p75LNGFr). Size of NBM neurons was larger in aged monkeys than young monkeys at all NBM levels, particularly in the most posterior subdivision. A subset of monkeys were behaviorally characterized shortly before death, and partial correlation analyses indicated that increased age was associated with declines in recognition memory, visuospatial orientation, and reaction time. Controlling for age, spatial memory and concurrent discrimination abilities were associated with lower cell number in intermediate NBM. Numbers of neurons in anterior NBM did not correlate with any behavioral measure. These observations indicate that numbers of NBM cholinergic neurons are stable with age, that NBM neurons become hypertrophic in older animals, and that morphometric indices of cholinergic neurons are associated with cognitive function.

Human nerve growth factor improves spatial memory in aged but not in young rats.

The behavioral effects of human nerve growth factor (NGF) were assessed in Fischer-344 rats of two ages: 4 months old (4MO) and 23 months old (23MO). Recent memory was tested in delayed alteration (T maze), reference memory in a place discrimination (water maze), and sensorimotor skills in a battery of sensorimotor tasks. Each rat was preoperatively trained in each task, given either a control procedure (CON), or continuous infusion of human NGF via an osmotic minipump, and retested again 3 weeks later. Two doses of NGF were delivered: 40 micrograms and 160 micrograms (total amount infused over a period of 4 weeks). In 23MO-NGF rats, both doses improved performance in the recent memory task, and in some measures of the place learning task, but had no effect on sensorimotor skills. In 4MO-NGF rats, the low dose impaired performance in the recent memory task, but not in the place discrimination or in the sensorimotor tasks. These data indicate that human NGF can reverse age-related cognitive impairments in old rats. However, the present study also raises the issue of potential detrimental effects that NGF may exert in young normal subjects.

The representation of self in multidimensional cognitive space.

A number of studies point to the efficiency with which people process self-relevant trait information. The derivative models of self-cognition account for many judgement latency and memory effects. These models tend to limit themselves, however, by neglecting the cognitive representation of the traits themselves. In contrast, research on implicit personality theory has focused on the cognitive representation of trait information, but has not always addressed the relationship between self and the judged traits. These two research domains were linked in an effort to specify the cognitive representation of self. A method for locating individuals and traits within the same spatial representation was developed and validated in two studies. In Study 1, subjects exhibited superior recall for traits located closest to self. In Study 2, subjects rapidly selected which of two traits better or least described self. 'Better' judgements were faster with increasing closeness to self of selected traits whereas 'least' judgements were faster with increasing closeness to self of non-selected traits, supporting the view of self as fixed anchor in self-relevant decision making. Taken as a whole, these two studies provided further evidence for the self as an evaluative organization of knowledge.

Individual differences in aging: behavioral and neural analyses.

Aged populations have remarkable variability in recent memory and cognitive mapping. Although some individuals may have substantial age-related impairments, others perform almost as well as young individuals. This paper reviews the relevant data on aged rats and indicates two challenges for biomarkers of aging. The first is to provide an appropriate quantitative description of these individual differences. The second is to use them effectively as markers for age-related changes in psychological functions and their neural substrates.

Applications of covariance structure modeling in psychology: cause for concern?

Methods of covariance structure modeling are frequently applied in psychological research. These methods merge the logic of confirmatory factor analysis, multiple regression, and path analysis within a single data analytic framework. Among the many applications are estimation of disattenuated correlation and regression coefficients, evaluation of multitrait-multimethod matrices, and assessment of hypothesized causal structures. Shortcomings of these methods are commonly acknowledged in the mathematical literature and in textbooks. Nevertheless, serious flaws remain in many published applications. For example, it is rarely noted that the fit of a favored model is identical for a potentially large number of equivalent models. A review of the personality and social psychology literature illustrates the nature of this and other problems in reported applications of covariance structure models.

Scales for the measurement of attitudes toward blood donation.

Attitudes toward blood donation are frequently assumed to vary along a single dimension from unfavorable to favorable. In contrast, theories of attitude structure specify three distinct attitude components: affect, cognition, and behavior. This article describes the development of three new scales for the measurement of affective, cognitive, and behavioral components of attitudes toward blood donation. The scales were developed using the method of equal-appearing intervals and were administered to both donors of blood and nondonors. Correlations among the scales were relatively small and supported the three-component distinction. Affect was more strongly correlated with the number of prior donations than was cognition, which suggested an important role for emotional factors in blood donation. Scores on all three scales showed the attitudes of blood donors to be more favorable than those of nondonors.

Empirical validation of affect, behavior, and cognition as distinct components of attitude.

A prevalent model of attitude structure specifies three components: affect, behavior, and cognition. The validity of this tripartite model was evaluated. Five conditions needed for properly testing the three-component distinction were identified. Two new studies were then designed to validate the tripartite model. A consideration of the tripartite model's theoretical basis indicated that the most important validating conditions are (a) the use of nonverbal, in addition to verbal, measures of affect and behavior, and (b) the physical presence of the attitude object. Study 1, in which subjects' attitudes toward snakes were examined, indicated very strong support for this tripartite model: The model was statistically acceptable, its relative fit was very good, and the intercomponent correlations were moderate (.38 less than r less than .71). Study 2 was a verbal report analogue of Study 1. Results from Study 2 indicated that higher intercomponent correlations occurred when attitude measures derived solely from verbal reports and when the attitude object was not physically present.