Alterations of white matter tracts following neurotoxic hippocampal lesions in macaque monkeys: a diffusion tensor imaging study.

Diffusion tensor imaging (DTI) is a valuable tool for assessing presumptive white matter alterations in human disease and animal models. The current study used DTI to examine the effects of selective neurotoxic lesions of the hippocampus on major white matter tracts and anatomically related brain regions in macaque monkeys. Two years postlesion, structural MRI, and DTI sequences were acquired for each subject. Volumetric assessment revealed a substantial reduction in the size of the hippocampus in experimental subjects, averaging 72% relative to controls, without apparent damage to adjacent regions. DTI images were processed to yield measures of fractional anisotropy (FA), apparent diffusion coefficient (ADC), parallel diffusivity (lADC), and perpendicular diffusivity (tADC), as well as directional color maps. To evaluate potential changes in major projection systems, a region of interest (ROI) analysis was conducted including the corpus callosum, fornix, temporal stem, cingulum bundle, ventromedial prefrontal white matter, and optic radiations. Lesion-related abnormalities in the integrity of the fiber tracts examined were limited to known hippocampal circuitry, including the fornix and ventromedial prefrontal white matter. These findings are consistent with the notion that hippocampal damage results in altered interactions with multiple memory-related brain regions, including portions of the prefrontal cortex.

Individual differences in the cognitive and neurobiological consequences of normal aging.

Defining the neural basis of age-related cognitive dysfunction is a major goal of current research on aging. Compelling evidence from laboratory animals and humans indicates that aging does not inevitably lead to cognitive decline. Conducting neurobiological investigations in subjects that have previously undergone behavioral characterization has therefore emerged as a promising strategy for identifying those alterations in brain structure and function that are specifically associated with age-related cognitive impairment.

Toward a nonhuman primate model of age-dependent cognitive dysfunction.

Neuropsychological studies of memory function in young subjects have provided a valuable strategy for developing a nonhuman primate model of age-dependent cognitive dysfunction. This approach suggests specific directions for future research and underscores the importance of appropriate behavioral analyses in efforts to identify the neural basis of age-related cognitive decline.

Recognition memory deficits in a subpopulation of aged monkeys resemble the effects of medial temporal lobe damage.

The present study examined individual differences in recognition memory function in a group of Old World monkeys (Macaca mulatta). Four young (9-11 years) and 10 aged (22-33 years) monkeys were tested in the same delayed-nonmatching-to-sample (DNMS) recognition memory procedure that has been widely used to study the effects of experimental hippocampal lesions in young subjects. Animals were first trained to a 90% correct learning criterion in the DNMS task using a 10-second delay between the sample and recognition phase of each trial. The memory demands of the task were then increased by gradually extending the retention interval from 15 seconds to 10 minutes. Three of the aged monkeys performed as accurately as young subjects at all delays. The remaining aged monkeys performed well at the shortest delays (15 and 30 seconds), but progressively greater impairments emerged across delays of 60 seconds, 2 minutes, and 10 minutes. These results suggest that recognition memory is only compromised in a subpopulation of aged monkeys. Moreover, aged monkeys that are impaired in the DNMS task exhibit the same delay-dependent pattern of deficits that is the hallmark of memory dysfunction resulting from medial temporal lobe damage.

Cerebral glucose metabolism and memory in aged rhesus macaques.

Positron emission tomography and the glucose metabolic tracer [18F]fluorodeoxyglucose were used to evaluate the relationship between regional cerebral metabolic rates for glucose (rCMRglc), age, and performance on a delayed response (DR) test of memory in the aged monkey. Eleven aged animals, 21-26-years old, were included in the analysis. Regional CMRglc, normalized to values for the entire brain, were determined for the dorsal prefrontal cortex, orbitofrontal cortex, hippocampus, and temporal cortex. The aged animals exhibited significant DR deficits relative to a cohort of normal young monkeys. Variability in DR performance among the aged subjects was significantly correlated with relative hippocampal rCMRglc, and chronological age was a reliable predictor of orbitofrontal rCMRglc ratios. This pattern of results suggests that DR impairments in the aged monkey may partly reflect age-related dysfunction distributed among multiple limbic system structures that participate in normal learning and memory. Overall, the findings support the use of positron emission tomography in efforts to define the relationship between cognitive performance, age, and brain physiology in nonhuman primates.

Morphometric studies of the aged hippocampus: I. Volumetric analysis in behaviorally characterized rats.

The present investigation examined the structural integrity of the aged hippocampus by using computer-aided morphometry to quantify the volume of principal hippocampal circuits in young, mature adult, and aged Long-Evans rats. A key feature of the experimental design was that the status of hippocampal-dependent learning and memory was documented prior to histologic evaluation. The following regions, which were visualized by using Timm staining, were included in the analysis: 1) outer portions of the dentate gyrus molecular layer (OML) innervated by the lateral entorhinal cortex, 2) middle portions of the molecular layer (MML) that receive input from the medial entorhinal cortex, 3) the commissural/associational zone (IML) immediately adjacent to the granule cell layer, and 4) the hilus and mossy fiber projection to the CA3 pyramidal cell field (MF). To identify morphometric changes that emerge during the same segment of the life span as age-related learning impairment, analysis of the volumetric results focused on comparisons between the mature adult group and the aged group. Among the individual regions that were analyzed, age-related decreases in total volume were restricted to the MML. This effect, however, occurred against a background of other, subtle changes that, together, reflected substantial reorganization in the normal balance of hippocampal circuitry. Age-related decreases in the proportion of the molecular layer (ML) that comprises the MML were accompanied by a corresponding increase in relative IML volume. The ratio between the volumes of the MML and the MF also displayed significant age-related decline. Overall, aging affected septal levels of the hippocampus disproportionately, and, with the exception of MML/MF volume ratio, the temporal hippocampus was spared. Finally, the status of spatial learning among the aged animals correlated selectively with decreases in the MML/ML and MML/MF ratios. These results demonstrate that the effects of aging are regionally selective and circuit specific, and they suggest that connectional reorganization may contribute to age-related decline in the computational functions of the hippocampus.

Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats.

Hippocampal N-methyl-D-Aspartate (NMDA) receptors mediate mechanisms of cellular plasticity critical for spatial learning in rats. The present study examined the relationship between spatial learning and NMDA receptor expression in discrete neuronal populations, as well as the degree to which putative age-related changes in NMDA receptors are coupled to the effects of normal aging on spatial learning. Young and aged Long-Evans rats were tested in a Morris water maze task that depends on the integrity of the hippocampus. Levels of NR1, the obligatory subunit for a functional NMDA receptor, were subsequently quantified both biochemically by Western blot in whole homogenized hippocampus, and immunocytochemically by using a high-resolution confocal laser scanning microscopy method. The latter approach allowed comprehensive, regional analysis of discrete elements of excitatory hippocampal circuitry. Neither method revealed global changes, nor were there region-specific differences in hippocampal NR1 levels between young and aged animals. However, across all subjects, individual differences in spatial learning ability correlated with NR1 immunofluorescence levels selectively in CA3 neurons of the hippocampus. Parallel confocal microscopic analysis of the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor failed to reveal reliable differences as a function of age or spatial learning ability. This analysis linking age, performance, and NR1 levels demonstrates that although dendritic NR1 is generally preserved in the aged rat hippocampus, levels of this receptor subunit in selective elements of hippocampal circuitry are linked to spatial learning. These findings suggest that NMDA receptor abundance in CA3 bears a critical relationship to learning mediated by the hippocampus throughout the life span.

Visual discrimination and reversal learning in the aged monkey (Macaca mulatta).

Visual discrimination and reversal learning were assessed in young adult (10-12 years old, n = 4) and aged (23-27 years old, n = 5) female rhesus monkeys. Performance was comparable across age groups in many tasks, suggesting that the acquisition of stimulus-reward associations remains largely intact in the aged monkey. Most older subjects, however, required more training than any young animal to learn an initial pattern discrimination. In combination with previous findings from the same groups of monkeys, these data suggest that deficits in attending to the relevant stimulus features in novel testing procedures may contribute to poor performance in aged subjects across a variety of learning and memory tasks. In addition, preliminary findings from a discrimination probe procedure raise the possibility that aged subjects may adopt alternate testing strategies that compensate for some aspects of age-dependent cognitive dysfunction.

An evaluation of spatial information processing in aged rats.

The spatial learning abilities of young, middle-age, and senescent rats were investigated in two experiments using several versions of the Morris water maze task. In Experiment 1, Long-Evans hooded rats were trained to find a submerged escape platform hidden within the water maze. During this phase of testing, aged rats exhibited acquisition deficits compared with either young or middle-age subjects. With continued training, however, all age groups eventually achieved comparable asymptotic levels of performance. Subsequent testing in Experiment 1 revealed that following original training, aged rats were not impaired in learning a novel escape location or in their ability to locate a visible, cued escape platform. In an attempt to identify the basis of the age-related impairments observed in Experiment 1, naive young and aged rats in Experiment 2 were initially tested for their ability to locate a cued escape platform in the water maze. During this phase of testing, the escape latencies of both young and aged rats rapidly decreased to equivalent asymptotic levels. Subsequent analyses revealed that following cue training, young subjects exhibit a significant spatial bias for the region of the testing apparatus where the platform was positioned during training. In contrast, aged rats showed no spatial bias. Training was continued in Experiment 2 using a novel submerged platform location for each subject. During these place training trials, the escape latencies of senescent rats were longer than those of young subjects. These impairments were also accompanied by a lack of spatial bias among aged rats relative to young control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Learning and memory for hierarchical relationships in the monkey: effects of aging.

Young and aged rhesus monkeys were tested on 2 versions of a transitive inference task measuring learning and memory for hierarchical relationships. Animals initially acquired 4 object discrimination problems arranged such that the relationship between the stimuli followed the hierarchy A > B > C > D > E. The second version of the task was similar but involved a series of 7 objects. Learning and memory for the hierarchical relationships were evaluated during probe trials in which novel pairs of nonadjacent items (e.g., B and D) were presented for a response. Standard task accuracy measures failed to distinguish young and aged subjects at any point in training. In contrast, response latency effects that are indicative of relational information processing in young monkeys were entirely absent in aged subjects. The findings highlight the value of a relational memory framework for establishing a detailed neuropsychological account of cognitive aging in the monkey.

Impaired spatial information processing in aged monkeys with preserved recognition memory.

Spatial information processing was examined in a non-human primate model of cognitive aging, using procedures formally similar to tasks designed for rats. The test apparatus was a large open field containing eight reward locations. Monkeys rapidly learned to visit each location once per trial, and probe manipulations confirmed that young animals navigated according to the distribution of cues surrounding the maze. In contrast, aged monkeys solved the task using a response sequencing strategy, independent of extramaze spatial information. Object recognition memory was normal in the aged group. The results reveal substantial correspondence in the cognitive effects of aging across rat and primate models, and they establish appropriate procedures for testing the long-standing proposal that the role of the hippocampus in normal spatial learning is similarly conserved.

Reproductive senescence predicts cognitive decline in aged female monkeys.

The present investigation provide evidences from a non-human primate model that naturally occurring menopause predicts a prominent signature of age-related cognitive decline. Young and aged rhesus monkeys were tested on a delayed response (DR) task known to the sensitive to aging, and reproductive status was evaluated according to menstrual cyclicity and urinary hormone profiles. Peri-/postmenopausal monkeys exhibited significant DR impairments relative to either age-matched premenopausal females, or young control subjects. In addition, markers of endocrine decline in the aged animals were selectively correlated with behavioral performance measures that distinguished premenopausal and peri-/postmenopausal monkeys. These results document that menopause is coupled to cognitive decline in the monkey, and they establish a valuable primate model for defining the effects of endocrine aging on brain and behavioral function.

The time of origin of somatostatin-immunoreactive neurons in the rat hippocampal formation.

Experiments utilizing a combination of [3H]thymidine autoradiography and immunohistochemistry were conducted to determine the time of origin of somatostatin-immunoreactive (SSIR) neurons in the hippocampal formation of the rat. A quantitative and topographic description of neurogenesis in this peptide-containing neuronal system was generated using a computer-aided system to plot the position of labeled cells. Dissected and 'flattened' hippocampal preparations were used to facilitate the analysis of spatial gradients of SSIR cell development. The results indicate that most SSIR hippocampal cells are generated during a short embryonic period which extends from the 12th through the 15th day of gestation (E12-E15). Within this period of development, the distribution of SSIR cells follows a spatial gradient along the transverse or subiculo-dentate axis of the hippocampus. The earliest formed SSIR neurons, generated on E12 and E13, are preferentially distributed to the subiculum, those generated on E14 are most commonly observed throughout the CA1-CA3 fields of the hippocampus and SSIR neurons which become postmitotic on E15 are more heavily represented in the hilar region of the dentate gyrus than cells born at other stages of development. There was no clear-cut neurogenic gradient along the septotemporal axis of the hippocampus. These results indicate that somatostatin cells in the rat hippocampal formation are generated during the same prenatal period when glutamic acid decarboxylase (GAD)-positive neurons become postmitotic. These studies also suggest that quantitative developmental analyses of chemically specific cell types can reveal prominent features of cortical ontogeny that are not readily apparent in standard [3H]thymidine preparations.

Opiate antagonist facilitation of time-dependent memory processes: dependence upon intact norepinephrine function.

Post-training administration of opiate antagonists improves retention of recent learning in laboratory animals tested on a variety of tasks. We examined the possibility that this effect of opiate antagonist treatment might be due to release of brain norepinephrine (NE) function from opioid peptide inhibition. The behavioral testing procedure in the experiments consisted of one-trial passive avoidance conditioning. Rats received post-training treatments immediately after the training trial and retention was tested 24 h later. Lesions of the dorsal noradrenergic bundle (DNB) that were induced by 6-hydroxydopamine (6-OHDA) were found to prevent the memory enhancing effect of post-training naloxone administration. The memory enhancing effect of naloxone was restored when NE neurons were protected from 6-OHDA by pretreatment with a NE uptake inhibitor. Earlier research indicated that the amygdala complex is one brain site that is sensitive to the effects of opiate manipulations on memory processes. In this study, lesions of the DNB were also found to prevent the memory enhancing effect of intracranial opiate antagonist administration into the amygdala complex.

Alterations in [3H]desmethylimipramine binding in the aged rat brain: an in vitro autoradiographic demonstration.

Using in vitro autoradiographic receptor binding, the present report provides a descriptive analysis of [3H]desmethylimipramine ([3H]DMI) binding in the aged rat brain. Small circular patches of intense [3H]DMI binding were present within the caudate nucleus in every aged brain examined. Occasionally, similar patches of label were present in restricted cortical regions of aged brains. Comparable patches of [3H]DMI binding were never observed in young brains used in these investigations. Additional evidence suggests that these age-dependent changes in [3H]DMI binding are anatomically restricted to the loci indicated above.

beta-Adrenergic manipulation in amygdala central n. alters rabbit heart rate conditioning.

The present study was conducted to assess the effects of beta-adrenergic manipulation within the central nucleus of the amygdala on Pavlovian heart rate conditioning in the rabbit. Administration of the beta-adrenergic antagonist dl-propranolol into the central nucleus impaired the acquisition of conditioned heart rate responding compared to a vehicle injected control group. No significant effects of dl-propranolol on either baseline heart rate or on the heart rate orienting response were observed. The effect of dl-propranolol on conditioning exhibited stereospecificity, and animals receiving combined intracerebral injections of dl-propranolol and the beta-adrenergic agonist 1-isoproterenol did not exhibit comparable conditioning impairments. In addition, dl-propranolol administration dorsal to the central nucleus or into amygdala sites anterior or posterior to the central nucleus was less effective. These results support the interpretation that beta-adrenergic activity within the central nucleus region of the amygdala complex contributes to the acquisition of classically conditioned heart rate responding.

Differential effects of aging on dendritic spines in visual cortex and prefrontal cortex of the rhesus monkey.

Aging decreases the density of spines and the proportion of thin spines in the non-human primate (NHP) dorsolateral prefrontal cortex (dlPFC). In this study, we used confocal imaging of dye-loaded neurons to expand upon previous results regarding the effects of aging on spine density and morphology in the NHP dlPFC and compared these results to the effects of aging on pyramidal neurons in the primary visual cortex (V1). We confirmed that spine density, and particularly the density of thin spines, decreased with age in the dlPFC of rhesus monkeys. Furthermore, the average head diameter of non-stubby spines in the dlPFC was a better predictor than chronological age of the number of trials required to reach criterion on both the delayed response test of visuospatial working memory and the delayed nonmatching-to-sample test of recognition memory. By contrast, total spine density was lower on neurons in V1 than in dlPFC, and neither total spine density, thin spine density, nor spine size in V1 was affected by aging. Our results highlight the importance and selective vulnerability of dlPFC thin spines for optimal prefrontal-mediated cognitive function. Understanding the nature of the selective vulnerability of dlPFC thin spines as compared to the resilience of thin spines in V1 may be a promising area of research in the quest to prevent or ameliorate age-related cognitive decline.