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PubMedDate not supplied

Effect of age and cognitive status on basal level AP-1 activity in rat hippocampus.

Activator protein-1 (AP-1) was examined at multiple levels (mRNA, DNA binding, composition) in hippocampus of young and aged rats that were behaviorally characterized for spatial memory. GFAP mRNA was measured as a gene product known to increase with aging and to be regulated by AP-1. The activity of Jun-amino terminal-kinase (JNK) was also assessed. Levels of c-jun and c-fos mRNAs were unchanged with aging or spatial learning ability. Abundance of GFAP mRNA was significantly increased in aged hippocampus but did not correlate with spatial learning. Total AP-1 binding activity was unaltered with age or cognitive ability. In hippocampus of young, aged unimpaired and aged impaired rats, AP-1 consists mainly of c-Jun, phosphorylated c-Jun (p-c-Jun), JunD, and smaller amounts of c-Fos. JNK is constitutively active in young and aged hippocampus. We conclude that the basal expression of c-fos and c-jun mRNA, overall AP-1 binding activity and AP-1 composition are not influenced by aging or cognitive ability.

Aging↗
PubMed1999

Nerve growth factor promoter driven neurotrophin-3 overexpression in the mouse and the protective effect of transgene on age-related behavioral deficits.

To clarify the biological function of neurotrophin-3 (NT-3) at the postnatal stage, we created a line of transgenic mice overexpressing NT-3 under the control of the mouse nerve growth factor gene promoter. Transgenic mice showed high-level NT-3 expression in the hippocampus and several tissues. We performed behavioral tests in young-adult (7-months-old) and aged (25-months-old) mice. Although aged non-transgenic mice exhibited spatial learning impairments in the Morris water maze, overexpression of NT-3 protected against these age-dependent spatial learning impairments in mice.

Aging↗
PubMed2002

Study on cognition disorder and morphologic change of neurons in hippocampus area following traumatic brain injury in rats.

OBJECTIVE: To explore the correlation between cognition disorder and morphologic change of hippocampal neurons after traumatic brain injury (TBI). METHODS: Wistar rat models with severe TBI were made by Marmarou's method. The histopathological change of the neurons in the hippocampus area were studied with hematoxylin-eosin (HE) staining and terminal deoxynucleotidyl transferase-mediated X-dUPT nick end labeling (TUNEL), respectively. The cognitive function was evaluated with the Morris water maze test. RESULTS: The comprehensive neuronal degeneration and necrosis could be observed in CA2-3 regions of hippocampus at 3 days after injury. Apoptotic positive neurons in CA2-4 regions of hippocampus and dentate gyrus increased in the injured group at 24 hours following TBI. They peaked at 7 days and then declined. Significant impairment of spatial learning and memory was observed after injury in the rats. CONCLUSIONS: The rats have obvious disorders in spatial learning and memory after severe TBI. Meanwhile, delayed neuronal necrosis and apoptosis can be observed in the neurons in the hippocampus area. It suggests that delay ed hippocampal cell death may contribute to the functional deficit.

Animals↗
PubMed2003

Abeta levels in serum, CSF and brain, and cognitive deficits in APP + PS1 transgenic mice.

We compared beta-amyloid peptide (Abeta) levels in the serum, CSF and brain (hippocampus) and correlated these with spatial learning in APP+PS1 transgenic mice. Compared with non-transgenic littermates, male 14-month-old APP + PS1 mice were impaired in spatial learning in the water maze. Among the APP + PS1 mice, only the hippocampal insoluble Abeta42 level correlated with spatial memory (r = -0.44). The levels of insoluble Abeta40 and Abeta42 were highly correlated (r = 0.92), and also correlated with soluble hippocampal Abeta42 (r = 0.64/0.69), which further correlated with the CSF Abeta42 (r = 0.52). None of these parameters correlated with serum Abeta40 levels. These findings support the role of insoluble Abeta42 in memory dysfunction and suggest a model with several pools (insoluble, extracellular soluble, CSF) of Abeta being in partial equilibrium with each other.

Alzheimer Disease↗
PubMed1997

LTP, NMDA, genes and learning.

In the past year, several tests of the hypothesis that NMDA-dependent hippocampal long-term potentiation (LTP) underlies learning have been reported. Data from mutant mice point to a potential role for NMDA-dependent LTP in hippocampal place cell function and spatial learning, but evidence for a causal relation is not yet available. Other studies have shown that robust spatial learning is possible without NMDA-dependent hippocampal LTP. Although the current evidence for the role of LTP in learning is mixed, LTP remains the most promising neural mechanism for associative learning. Several new experimental approaches are now available for future research.

Animals↗
PubMed2003

Temporal aspects of spatial task performance during intermittent hypoxia in the rat: evidence for neurogenesis.

Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea, leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in the adult rat. We report that in Sprague-Dawley rats the initial IH-induced impairments in spatial learning are followed by a partial functional recovery over time, despite continuing IH exposure. These functional changes coincide with initial decreases in basal neurogenesis as shown by the number of positively colabelled cells for BrdU and neurofilament in the dentate gyrus of the hippocampus, and are followed by increased expression of neuronal progenitors and mature neurons (nestin and BrdU-neurofilament positively labelled cells, respectively). In contrast, no changes occurred during the course of IH exposures in the expression of the synaptic proteins synaptophysin, SNAP25, and drebrin. Collectively, these findings indicate that the occurrence of IH during the lights on period results in a biphasic pattern of neurogenesis in the hippocampus of adult rats, and may account for the observed partial recovery of spatial function.

Animals↗
PubMed1995

A behavioral assessment of Ts65Dn mice: a putative Down syndrome model.

Mice which are trisomic for only the human chromosome (Chr) 21-homologous segment of mouse Chr 16 (segmental trisomy), including a portion of the Down syndrome region of human Chr 21, have recently been developed. Since these segmentally trisomic mice, designated Ts(17(16))65Dn, survive to adulthood, they may represent a mouse model for the study of Down syndrome. A partial characterization of their behavioral phenotype was undertaken by evaluating the sensorimotor reflexes, exploration, locomotor activity, emotionality and spatial learning in 16 male Ts65Dn mice (TS) and 16 control (CO) littermates. No sensorimotor deficits appeared in TS compared to CO mice. By contrast, head-dipping behaviour in the hold board was increased in TS mice with respect to the CO group, showing a higher repetition rate of previously explored holes. Crossings in the open field and total arm entries in the plus maze were higher in TS than in the CO group during the dark phase of the light-dark (LD) cycle under red light, but not during the light phase of the LD cycle under white light. Entries into the open arms of the plus maze were increased overall in TS mice when compared to CO mice, but no differences were found in time spent in the open arms. TS mice showed impaired place learning in the Morris water maze, whereas they were able to reach the same performance as CO animals in cued learning. Thus, absence of sensorimotor deficits, increased exploration, hyperactivity under certain experimental conditions and a moderate impairment of spatial learning were the principal characteristics observed in TS mice compared to their CO littermates.

Animals↗
PubMed2003

Learning and memory deficits in Notch mutant mice.

Notch is a critical component of evolutionarily conserved signaling mechanisms that regulate development and may contribute to plasticity-related processes, including changes in neurite structure and maintenance of neural stem cells. Deficits in the Notch pathway are responsible for Alagille and Cadasil syndromes, which are associated with mental retardation and dementia. Additionally, in postmitotic neurons, Notch proteins interact with presenilins and with beta-amyloid precursor protein and could therefore have a role in the memory deficits associated with familial and sporadic Alzheimer's disease. To test if alterations in Notch signaling can lead to learning and memory deficits, we studied mice with mutations in this pathway. Here, we show that null heterozygous mutations in Notch1 result in deficits in spatial learning and memory without affecting other forms of learning, motor control, or exploratory activity. We also show that null heterozygous mutations in the downstream cofactor RBP-J result in similarly specific spatial learning and memory deficits. These data indicate that a constitutive decrease in Notch signaling can result in specific learning and memory deficits and suggest that abnormalities in Notch-dependent transcription may contribute to the cognitive deficits associated with Alzheimer's disease and Alagille and Cadasil syndromes.

Analysis of Variance↗
PubMed1996

The chronic administration of docosahexaenoic acid reduces the spatial cognitive deficit following transient forebrain ischemia in rats.

The purpose of this study was to investigate whether chronic administration of docosahexaenoic acid is able to reduce spatial cognitive deficit following transient ischemia in rats. In addition, we investigated whether the chronic treatment of docosahexaenoic acid is able to protect the hippocampal neuronal damage induced by either hypoxia in vitro or cerebral ischemia in vivo. A chronic administration of 200 mg/kg/day docosahexaenoic acid over 21 days did not affect the content of docosahexaenoic acid in the hippocampus, but did tend to increase it in the frontal cortex. On the other hand, this chronic administration decreased the content of arachidonic acid significantly both in the hippocampus and the frontal cortex. Under hypoxic conditions, the onset of the increase in the NADH fluorescence in the hippocampal slice was made significantly slower relative to the control by the chronic administration of docosahexaenoic acid. Rats were subjected to 10 min of transient forebrain ischemia by the method of four-vessel occlusion and were tested in a radial eight-arm maze task after cerebral reperfusion. Docosahexaenoic acid was administered either once 1 h before occlusion or daily for 21 days before occlusion. The single treatment of docosahexaenoic acid (1, 10, 100 or 200 mg/kg) did not significantly affect any aspect of the spatial learning deficit following occlusion. On the other hand, chronic treatment with docosahexaenoic acid (10, 100 or 200 mg/kg/day) significantly improved the spatial learning deficit following occlusion. A comparison of the neuronal densities in the hippocampal CA1 region of the chronically docosahexaenoic acid-treated (200 mg/kg/day) rats with those of the ischemic control revealed a significant neuronal preservation. From these results, it appears that chronic administration of docosahexaenoic acid may be valuable in ameliorating the spatial cognitive deficit induced by transient forebrain ischemia. In addition, docosahexaenoic acid might contribute to the protection of hippocampal neuronal damage caused by either hypoxia or ischemia.

Animals↗
PubMed2000

Tissue-specific expression of a type I adenylyl cyclase rescues the rutabaga mutant memory defect: in search of the engram.

Most attempts to localize physical correlates of memory in the central nervous system (CNS) rely on ablation techniques. This approach has the limitation of defining just one of an unknown number of structures necessary for memory formation. We have used the Drosophila rutabaga type I Ca(2+)/CaM-dependent adenylyl cyclase (AC) gene to determine in which CNS region AC expression is sufficient for memory formation. Using pan-neural and restricted CNS expression with the GAL4 binary transcription activation system, we have rescued the memory defect of the rutabaga mutant in a fast robust spatial learning paradigm. The ventral ganglion, antennal lobes, and median bundle are likely the CNS structures sufficient for rutabaga AC- dependent spatial learning.

Adenylyl Cyclases↗
PubMed2005

Influence of prenatal noise and music on the spatial memory and neurogenesis in the hippocampus of developing rats.

During the prenatal period, the development of individual is influenced by the environmental factors. In the present study, the influence of prenatal noise and music on the spatial memory and neurogenesis in the hippocampus of developing rats was investigated. The exposure to the noise during pregnancy caused growth retardation, decreased neurogenesis in the hippocampus, and impaired spatial learning ability in pups. The exposure to music during pregnancy, on the other hand, caused increased neurogenesis in the hippocampus and enhanced spatial learning ability in pups. The present study has shown the importance of the prenatal environmental conditions for the cognition and brain development.

Animals↗
PubMed2002

Evidence for involvement of glucocorticoid response in the hippocampal changes in aged molarless SAMP8 mice.

The involvement of glucocorticoid response in the hippocampal changes in aged SAMP8 mice after removal of their upper molar teeth (molarless condition) was examined using biochemical, morphological and behavioral techniques. Molarless mice showed plasma corticosterone levels to be significantly greater than those in molar-intact control mice. Pretreatment with metyrapone, which suppresses the stress-induced rise in plasma corticosterone levels, prevented the molarless condition-induced increase in plasma corticosterone levels, reduction in CA1 pyramidal neuron numbers, and impairment of spatial learning. The results suggest a link between the molarless condition and the glucocorticoid response, which may be involved in spatial learning deficits and hippocampal neuronal death in aged SAMP8 mice.

Aging↗
PubMed1975

Developmental effects of neonatal sex hormones on spatial and activity skills in the white rat.

The purpose of this experiment is to extend these experiments by using varying neonatal hormonal differentiation processes and to examine the effects of these different methods of neonatal feminization on changes in spatial and activity skills. The experiment involved three neonatally feminized groups of male rats: 'castration alone', 'estrogen alone', and 'estrogen injected castrates' together with one female sample, 'testosterone injected castrates', while treated and untreated male and female controls were also used. The data provide partial support for the major hypotheses that neonatal gonadectomy and opposite sex hormones administered to male and female castrated rats (together and independently for males) would reverse the normal sex-associated abilities of the white rate (higher male spatial learning and higher female activity). However, the feminization effect for the male 'estrogen alone' and 'castration alone' experimental groups was much greater than for the male estrogen injected castrates. The masculinized females, testosterone injected castrates, also had higher spatial learning and lower activity levels, while the feminized male's spatial and activity skills were also reversed. This confirmed in part the extent to which neonatal gonadal sex hormones are effective at critical periods of development in programming the brain in terms of sex-associated spatial and activity skills. Adult hormonal replacement therapy was also administered at 12 months and supported the hypothesis that sex hormones in adults would be mainly activational and have less marked effects than the significant directional changes obtained by these neonatal sex hormones and castration techniques.

Age Factors↗
PubMed1995

Enhancement of hippocampally-mediated learning and protein kinase C activity by oxiracetam in learning-impaired DBA/2 mice.

The effects of oxiracetam on hippocampally-mediated learning performance and hippocampal protein kinase C (PKC) were examined in C57BL/6Ibg (C57) and DBA/2Ibg (DBA) mice. C57 and DBA mice were subjected to daily injections of oxiracetam (50 mg/kg i.p.) or vehicle (0.9% saline) for a total of 9 days. C57 and DBA mice were examined on a modified version of the Morris water maze task and the contextual fear conditioning task on the last 5 or 2 days, respectively, of the 9-day treatment schedule. When compared with controls, C57 and DBA oxiracetam-treated mice showed no difference in motor skill capability to perform these complex learning tasks (swim speed or ability to freeze). Hippocampal PKC activity was measured in cytosolic, loosely-bound, and membrane-bound homogenate fractions. Oxiracetam-treated DBA mice demonstrated a significant increase in spatial learning performance as determined by the Morris task. DBA performance was also improved in contextual learning as determined by the fear conditioning task. The increase in spatial learning performance was correlated to an increase in membrane-bound PKC. No substantial improvements in C57 mice were observed on either learning task nor did hippocampal PKC activity change in response to oxiracetam treatment. These data demonstrate that the learning impairment of DBA mice can be reversed by treatment with a nootropic agent and support previous studies suggesting that PKC may be one mechanism of action for oxiracetam.

Animals↗
PubMed2005

Administration of vaccinia virus complement control protein shows significant cognitive improvement in a mild injury model.

Previous studies have shown that traumatic mild brain injury in a rat model is accompanied by breakdown of the blood brain barrier and the accumulation of inflammatory cells. A therapeutic agent, vaccinia virus complement control protein (VCP), inhibits both the classic and the alternative pathways of the complement system and, in so doing, prevents cell death and inflammation. With the use of a rat mild injury model, the effects of VCP on spatial learning and memory were tested. Training in a Morris water maze consisted of a total of 16 trials over a 2-day period before rats were anesthetized and subjected to mild (1.0-1.1 atm) lateral fluid percussion injury (FPI) 3.0 mm lateral to the sagittal suture and 4.5 mm posterior to bregma. Ten microl of VCP (1.7 mg/ml) was injected into the injury site immediately after FPI. Two weeks post-FPI the rats were assessed in the Morris water maze for spatial learning and memory. Neurologic motor function tests were carried out after FPI for 14 consecutive days and again after 28 days. The Morris water maze data show that FPI plus saline-injected rats spent a significantly (P <0.05) larger amount of time in one of the incorrect quadrants than did the FPI plus VCP-injected group. Neurologic evaluations 24 hours postinjury revealed differences in sensorimotor function between groups. The results suggest that in a mild injury model, VCP influences neurologic outcome and offers some enhancement in spatial memory and learning.

Animals↗
PubMed1993

Hippocampal function in the rat: cognitive mapping or vicarious trial and error?

The most prominent hypothesis of hippocampal function likens the hippocampus to a "cognitive map," a term used by a famous learning theorist, E. C. Tolman, to explain maze learning. The usual application of this concept of cognitive map, as it applies to the hippocampus, is to what is called spatial learning, mainly in the radial-arm maze of Olton and the Morris water maze. In a recent Hippocampus Forum, evidence for the cognitive map hypothesis was reviewed in a lead article by Nadel, followed by a series of commentaries by leading investigators of hippocampal function. This speculative commentary offers an alternative not represented in the forum--that the function of the hippocampus in spatial learning is not as a cognitive map, but that it subserves another function proposed by Tolman in his work on simple discrimination learning, vicarious trial and error, based on incipient, conflicting dispositions to approach and avoid.

Animals↗
PubMed2000

Intact negative patterning in rats with fornix or combined perirhinal and postrhinal cortex lesions.

It has been proposed that the hippocampal formation is necessary for the acquisition of tasks that require the use of configural representations for their solution, including spatial learning and negative patterning. Tests of this influential view have, however, yielded conflicting results. For example fornix or hippocampal lesions, which reliably impair spatial learning, do not reliably impair negative patterning. A problem in interpreting these results has been the lack of controls for factors such as over-responding, excitatory effects of reward, and the possibility of non-configural solutions. At the same time, other studies have pointed to a role in configural learning for parahippocampal regions such as the perirhinal cortex. The present experiments controlled for the above factors and revealed that neither lesions of the fornix nor of the perirhinal/postrhinal cortex in the rat had any effect on negative patterning, although subsequent tests of object and spatial memory demonstrated the functional efficacy of the lesions.

Amygdala↗
PubMed1988

Deficits in spontaneous behavior and cognitive function following systemic administration of kainic acid.

Recurrent seizures leading to status epilepticus were induced in rats by a 10 mg/kg subcutaneous injection of kainic acid (KA). After a 4-day recovery period, the KA-treated animals showed a syndrome of increased activity in an open field, hyperreactivity in response to handling, and deficits in acquisition of both passive avoidance and spatial learning tasks. The second experiment demonstrated that KA also caused deficits in learning to approach a visible platform in a water maze. Two months after the initial treatment, the animals were still hyperactive and deficient in passive avoidance acquisition; however, they performed normally on the spatial learning task. These results reflect both the convulsive effects of KA, which produce transient retardation, and the brain damage to limbic system structures, which accounts for the permanent deficits.

Animals↗