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PubMed1989

Successful performance by monkeys with lesions of the hippocampal formation on AB and object retrieval, two tasks that mark developmental changes in human infants.

In this study, (a) what determines success or failure on the AB and object retrieval tasks and (b) the relation between brain maturation and cognitive development as indexed by these tasks were examined. Specifically, does improved performance on these tasks with age reflect maturation of memory functions dependent on the medial temporal lobe? In AB, the S watches a reward being hidden in 1 of 2 wells; after a brief delay S reaches for that reward. The AB error consists of the S continuing to reach to the first location (A) when side of hiding is shifted to the second location (B). In object retrieval, a reward is placed in a transparent box open on 1 side. Although the reward is visible through all sides of the box, it can only be retrieved through the 1 open side. Intact cynomolgus monkeys and those with bilateral lesions of the hippocampal formation (H+) were tested. Although H+ monkeys exhibited impaired memory by performing poorly on the delayed nonmatching to sample taks, they performed well on AB at delays of 2-15 s. Performance declined as delays increased to 30 s, but H+ monkeys never showed the AB error pattern. On object retrieval, H+ monkeys succeeded quickly and efficiently, even when required to detour to the box opening. This reseach demonstrates that memory impairment alone cannot account for deficits on AB or on object retrieval and strengthens the conclusion (Diamond, 1988a, 1988b, in press) that improved performance on AB and object retrieval during infancy reflects maturation of dorsolateral prefrontal cortex.

Aging↗
PubMedDate not supplied

Collaborative Behavioral Teratology Study: programmed data entry and automated test systems.

The automated laboratory systems described in this paper were developed for use at the National Center for Toxicological Research (NCTR) and each of five collaborating laboratories. These laboratories participated in a study designed to evaluate the intra- and interlaboratory reliability and sensitivity of several behavioral test methods used in developmental toxicity studies. This paper describes two microcomputer systems. System I was designed to control stimulus delivery to and record behavioral responses from rats during a visual discrimination learning task and to accept data from physical landmark, negative geotaxis, and olfactory discrimination evaluations. The microprocessor system was an S-100 bus, Z-80 processor with 8K PROM, 16K RAM, nine 8-bit parallel I/O ports, and one serial I/O port. For discrimination learning, the animal testing apparatus consisted of six operant chambers, equipped with two stimulus lights, two nose-poke apertures each containing a phototransmitter and receiver, an electromechanical liquid dispenser unit, and a reward bowl also containing a photodiode. Each chamber was interfaced with the microprocessor at a parallel I/O port which permitted the delivery of response- or time-contingent control signals for the lights and liquid dispenser units. System II controlled stimulus delivery and recorded behavioral responses from rats during an auditory startle habituation task, and also recorded rodent activity levels in figure 8 mazes for periods of 1, 4, or 23 hours. The microprocessor system was an S-100 bus, Z-80 processor with 8K PROM, 16K RAM, nine parallel I/O ports, an analog to digital (A/D) I/O board, and one serial I/O port.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed2003

Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics.

Oxidative stress has been implicated in cognitive impairment in both old experimental animals and aged humans. This implication has led to the notion that antioxidant defense mechanisms in the brain are not sufficient to prevent age-related increase in oxidative damage and that dietary intake of a variety of antioxidants might be beneficial for preserving brain function. Here we report a dramatic loss of learning and memory function from 8 to 11 months of age in mice, associated with marked increases in several markers of brain oxidative stress. Chronic systemic administration of two synthetic catalytic scavengers of reactive oxygen species, Eukarion experimental compounds EUK-189 and EUK-207, from 8 to 11 months almost completely reversed cognitive deficits and increase in oxidative stress taking place during this time period in brain. In particular, increase in protein oxidation was completely prevented, whereas increase in lipid peroxidation was decreased by approximately 50%. In addition, we observed a significant negative correlation between contextual fear learning and levels of protein oxidation in brain. These results further support the role of reactive oxygen species in age-related learning impairment and suggest potential clinical applications for synthetic catalytic scavengers of reactive oxygen species.

Aging↗
PubMed1990

Sparing of attentional relative to mnemonic function in a subgroup of patients with dementia of the Alzheimer type.

Patients with dementia of the Alzheimer type (DAT) received two tests of visual selective attention, together with tests of spatial and visual recognition memory and visuospatial conditional learning previously used to show deficits early in the course of DAT. One set of attentional tests compared visual discrimination learning along intra- and extra-dimensional shifts, using a "total change" design. In the 12 DAT patients capable of attempting the extra-dimensional shift (subgroup 1), performance was equivalent to that of controls. This subgroup was also unimpaired at simple and compound discrimination learning and reversal and an intra-dimensional shift. They were as accurate as controls on a visual search task requiring matching of stimuli on two dimensions with variable numbers of alternatives, but were significantly impaired in the tests of recognition memory and learning. By contrast, the other 13 patients showed marked impairments in the attentional tasks. This subgroup was also significantly worse than subgroup 1 in performance on the visual recognition and conditional learning tasks, and showed greater severity on most of the clinical ratings of dementia. The sparing of attentional shifting in patients early in the course of DAT is contrasted with the impairments previously described in patients with Parkinson's disease with only mild or absent memory loss. The implications of this double dissociation of deficits for understanding the neural bases of the cognitive deficits in these two neurodegenerative diseases are discussed and their significance for the staging of DAT is considered.

Aged↗
PubMed2002

Caramiphen and scopolamine prevent soman-induced brain damage and cognitive dysfunction.

Exposure to soman, a toxic organophosphate nerve agent, causes severe adverse effects and long term changes in the peripheral and central nervous systems. The goal of this study was to evaluate the ability of prophylactic treatments to block the deleterious effects associated with soman poisoning. scopolamine, a classical anticholinergic agent, or caramiphen, an anticonvulsant anticholinergic drug with anti-glutamatergic properties, in conjunction with pyridostigmine, a reversible cholinesterase inhibitor, were administered prior to sbman (1 LD50). Both caramiphen and scopolamine dramatically attenuated the process of cell death as assessed by the binding of [3H]RoS-4864 to peripheral benzodiazepine receptors (omega3 sites) on microglia and astrocytes. In addition, caramiphen but not scopolamine, blocked the soman-evoked down-regulation of [3H]AMPA binding to forebrain membrane preparations. Moreover, cognitive tests utilizing the Morris water maze, examining learning and memory processes as well as reversal learning, demonstrated that caramiphen abolished the effects of soman intoxication on learning as early as the first trial day, while scopolamine exerted its effect commencing at the second day of training. Whereas the former drug completely prevented memory deficits, the latter exhibited partial protection. Both agents equally blocked the impairment of reversal learning. In addition, there is a significant correlation between behavioral parameters and [3H]RoS-4864 binding to forebrain membrane preparations of rats, which participated in these tests (r(21) = 0.66, P < 0.001; r(21) = 0.66, P < 0.001, -0.62, P < 0.002). These results demonstrate the beneficial use of drugs exhibiting both anti-cholinergic and anti-glutamatergic properties for the protection against changes in cognitive parameters caused by nerve agent poisoning. Moreover, agents such as caramiphen may eliminate the need for multiple drug therapy in organophosphate intoxications.

Animals↗
PubMed2000

Increased septal 5-HIAA efflux in rats that do not develop learned helplessness after inescapable stress.

Learned helplessness is a behavioral deficit that can be induced by exposure to inescapable stress. Previous studies have implicated the lateral septum in mediating this phenomenon, and in this brain region, serotonin plays an important role in the development, maintenance, prevention, and reversal of learned helplessness behavior. Using the technique of in vivo microdialysis, we measured the efflux of serotonin (5-HT), dopamine (DA), and their respective metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 3, 4-dihydroxyphenylacetic acid (DOPAC), from the lateral septum of rats that either developed or did not develop learned helplessness. During the microdialysis session all rats were subjected to restraint stress. Control groups included naïve, home cage rats as well as tested control rats that were subjected to the identical handling, restraint, and shuttlebox testing as the rats that received inescapable shock. Overall, levels of 5-HIAA were significantly higher in non-helpless rats. There were no significant effects of restraint or differences in levels of 5-HT, DA, or DOPAC. We propose that this increase in 5-HIAA is indicative of an overall increase in serotonin metabolism in the lateral septum of rats that do not become helpless after inescapable stress. This increased serotonin metabolism in the lateral septum may protect the animal from adverse behavioral consequences of inescapable stress. J. Neurosci. Res. 61:101-106, 2000. Published 2000 Wiley-Liss, Inc.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Learning and memory disabilities in young adult rats from mildly zinc deficient dams.

Three experiments were conducted to test the behavior of the offspring of rat dams (ZD) fed a mildly zinc deficient diet (10.0 micrograms Zn/g) during pregnancy and lactation. Since zinc deficiency causes anorexia, a second group of rat dams (PF) was fed the same quantity of the diet during gestation and lactation as was consumed by their ZD mates. A third group of rats (AL) was fed the diet ad lib during gestation and lactation. The PF and AL dams were given zinc supplemented (25.0 micrograms Zn/ml) drinking water whereas the ZD dams were given double distilled, deionized drinking water. After weaning, the offspring of all dams were fed Purina Laboratory Chow ad lib until they were 100 days old. The offspring were then reduced to 85% of their ad lib weight and tested on a 17-arm radial maze for memory and learning. In Experiments 1 and 2, the ZD males suffered a significant learning deficit when compared to the AL males. Whereas the PF males suffered a significant learning impairment in Experiment 1, the learning deficit of the PF group was not as severe as the deficit of the ZD group. There was no impairment in reference (long-term) memory for any of the groups. In Experiment 3, significant differences in working (short-term) memory were found among the three groups of females. The ZD group was significantly inferior in working memory when compared to the PF and AL groups. No significant differences in working memory were found between the PF and AL groups.

Animals↗
PubMed1997

Strain-dependent effects of D2 dopaminergic and muscarinic-cholinergic agonists and antagonists on memory consolidation processes in mice.

The interaction between muscarinic-cholinergic and dopaminergic systems in the modulation of memory storage of Y-maze discrimination (YMD) task was examined in C57BL/6 and DBA/2 strains of mice. In C57BL/6 mice, post-training systemic (i.p.) administration of the D2-agonist quinpirole facilitated retention and the D2-antagonist (-)-sulpiride impaired retention. Opposite effects were observed in DBA/2 strain. The facilitating or impairing effects of quinpirole and (-)-sulpiride were blocked by simultaneous post-training administration of muscarinic-cholinergic agonists and antagonists. The memory enhancing effects of the cholinergic agonist oxotremorine were not blocked by simultaneous administration of sulpiride in C57BL/6 mice or quinpirole in DBA/2 mice. Furthermore, the memory impairing effects of the cholinergic antagonist atropine were not blocked by simultaneous administration of quinpirole in C57BL/6 mice or sulpiride in DBA/2 mice. These findings indicate that the effects of D2-receptor agonists and antagonists on retention of YMD task are strain-dependent and mediated through muscarinic-cholinergic mechanisms.

Animals↗