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PubMed2002

Thyroid hormones, brain function and cognition: a brief review.

In addition to their role in cellular metabolic activity, thyroid hormones (THs), also regulate neural development; the central nervous system is particularly dependent on TH for normal maturation and function. Specifically, there appears to be extensive inter-reliance between TH and acetylcholine (Ach), nerve growth factor and hippocampal function. These associations led us to investigate the possible effects of thyroxine (L-T4) on performance of a spatial learning task, where cholinergic activity and hippocampal function are known to be important. Groups of rats (n=20) received saline (controls) or L-T4 at 2.5 or 5mg/kg daily for 4 days as a sub-chronic treatment, or 0, 5 or 10mg/kg doses administered every third day for 28 days prior to testing as a chronic regimen. Rats were assessed in a water maze for their ability to find a submerged or visible platform. Forty minutes prior to water maze testing, half the animals in each group received 1mg/kg scopolamine to elicit a cognitive deficit. Following testing, rats were decapitated, blood samples taken, and the frontal cortex and hippocampus were dissected out for acetylcholinesterase (AChE) assay. The results showed that L-T4 treatment, administered both sub-chronically and chronically, significantly enhanced the ability of rats to learn a spatial memory task, compared with controls. Moreover, both short-term and long-term L-T4 treatment reduced the cognitive-impairing effects of scopolamine. Improvements in performance were shown to occur alongside significantly increased cholinergic activity in frontal cortex and in the hippocampus of treated animals. These findings demonstrate an augmentative effect of L-T4 upon cognitive function, possibly mediated by an enhancement of cholinergic activity. The results support previous findings of a relationship between L-T4 and acetylcholine, and underscore possible mechanisms by which disorders of thyroid function may be associated with cognitive decline.

Animals↗
PubMed2002

Contact with maternal parent and siblings affects hunting behavior, learning, and central nervous system development in spiderlings of Hogna carolinensis (Araeneae: Lycosidae).

The purpose of this study was to determine the effects of early experience (rearing conditions) on the central nervous system (CNS) and behavior of spiderlings of Hogna carolinensis (Lycosidae). We were interested in whether or not spiderlings that were allowed to remain in contact with their maternal parent and siblings (enriched condition, EC) would exhibit differences in CNS development or subsequent behavior when compared with those reared in isolation (improverished condition, IC). Spiderlings emerged from their egg sacs and climbed onto the dorsal surface of their mother's abdomen where they remained until their yolk supply was depleted (5 days). They dispersed on day 6 after emergence. We compared the ability of 16-day-old EC and IC spiderlings to capture prey in a linear runway and to learn a complex maze (spatial learning). We also compared certain aspects of CNS development (brain weight, total number of brain cells, volume of central body and protocerebral neuropil) in EC and IC spiderlings. Results indicated that EC subjects are more efficient at capturing moving prey (crickets) and exhibited improved performance (significantly fewer blind alley errors) in the maze. The volume of the protocerebral neuropil in 6-day-old EC animals increased 30% over a 5-day period after emergence as compared to IC animals of the same age. The volume of the central body of EC animals increased 34.8% over the same time period. On day 6 after emergence, the weight of the protocerebrum was significantly greater in EC versus IC subjects. There were no significant effects of rearing condition (EC vs IC) or age (1- and 6-day-old spiderlings) on the total number of nerve cells in the protocerebrum, suggesting that the difference in protocerebral weight was due primarily to differences in supporting glial tissues and neuropil matrix. In conclusion, the data suggest that early contact with the maternal parent and siblings is of vital importance to CNS development in lycosid spiderlings and can influence the capacity for spatial learning as well as the ability to capture prey.

Animals↗
PubMed1994

Differential effects of serotonin and raphe grafts in the hippocampus and hypothalamus: a combined behavioural and anatomical study in the rat.

Combined with a partial cholinergic deficiency, serotonergic lesions induce severe spatial learning deficits. Serotonergic lesions, however, have additional effects, such as reduced body weight and disruption of thermoregulation, which may be the cause of the observed learning deficits. Restoration of the serotonergic innervation of the hippocampus by raphe grafts reduces these learning deficits. The effects of the grafts may result from a direct support of spatial learning but may also be an indirect result of preventing some of the other effects of serotonergic lesions. In the present study we used raphe grafts to examine the selectivity and specificity of the effects of serotonergic lesions in the rat, and used the behavioural effects as an indication of successful transplantation in order to examine the fine details of such grafts. Raphe grafts in the hippocampus did not prevent the effects of the lesions on body weight, thermoregulation and exploratory behaviour but did minimize the effects of the lesions on spatial learning. In contrast, raphe grafts in the hypothalamus reduced the effects of the lesions on thermoregulation but failed to support learning. The grafted fibres showed termination specificity with the interneurons, which is typical of the serotonergic innervation of the normal hippocampus. The results indicate that the serotonergic innervation of the hippocampus functions locally to support spatial learning. This role of serotonin is independent of its involvement in modulation of body weight, thermoregulation or exploratory behaviour. The results confirm that the modes of serotonergic action in the hippocampus include the selective innervation of specific interneuron subpopulations.

5,7-Dihydroxytryptamine↗
PubMedDate not supplied

Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons.

Prion protein (PrP(C)) is a constituent of most normal mammalian cells and plays an essential role in the pathogenesis of transmissible spongiform encephalopathies (TSE). However, the normal cellular function of PrP(C) remains unclear. Here, we document that mice with a selective deletion of PrP(C) exhibited deficits in hippocampal-dependent spatial learning, but non-spatial learning remained intact. mPrP-/- mice also showed reduction in paired-pulse facilitation and long-term potentiation in the dentate gyrus in vivo. These deficits were rescued in transgenic mPrP-/- mice expressing PrP(C) in neurons under control of the neuron-specific enolase (NSE) promoter indicating that they were due to lack of PrP(C) function in neurons. The deficits were seen in mPrP-/- mice with a homogeneous 129/Ola background and in mPrP-/- mice in the mixed (129/Ola x C57BL/10) background indicating that these abnormalities were unlikely due to variability of background genes or alteration of the nearby Prnd (doppel) gene.

Amyloid↗
PubMed1984

Selective reminding in normal and demented aged people: auditory verbal versus visual spatial task.

A new test of visual spatial learning (VS) which uses the rationale of selective reminding and evaluates memory and learning of spatial positions of objects was presented. This was compared with the auditory verbal selective reminding (AV) in regard to normal aging and dementia. The results showed that the performance of VS declines with age more steeply than those of AV. Factor analyses showed that the performance of VS to be factorially independent of that of AV, and showed that VS can account for most of the decline in performance of normal aged people. The performance on VS of demented patients correlated well with the serverity of dementia. The comparison between multi-infarct dementia and Alzheimer type dementia indicated that severe impairment of VS with relative preservation of AV is a distinctive pattern of Alzheimer type. These results suggest that VS is a useful tool to evaluate memory decline with aging and that it can be useful in the clinical diagnosis of dementia.

Aged↗
PubMed2002

Progressive impairment of constructional abilities: a visuospatial sketchpad deficit?

The case of a patient, PC, with an impairment of constructional abilities due to a progressive degenerative disease is described. Ideomotor apraxia was also present. PC showed difficulties in all tasks requiring a "manipulation" of a visual model or requiring a visual model to address a specific movement or a choice among alternatives. The spatial component of mental imagery was also severely impaired. The conclusion was that the patient presented a deficit of the rehearsal component of the visuospatial sketchpad (VSSP). This produced an impairment of spatial learning, but spatial retrograde memory was preserved, as well as object recognition. The most prominent sites of atrophy were located in the parietal lobe bilaterally. A 3-year follow-up is reported, showing a progressive impairment of verbal abilities.

Aphasia↗
PubMed2002

A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning.

We have investigated a potential mechanism by which a diet, similar in composition to the typical diet of most industrialized western societies rich in saturated fat and refined sugar (HFS), can influence brain structure and function via regulation of neurotrophins. We show that animals that learn a spatial memory task faster have more brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus. Two months on the HFS diet were sufficient to reduce hippocampal level of BDNF and spatial learning performance. Consequent to the action of BDNF on synaptic function, downstream effectors for the action of BDNF on synaptic plasticity were reduced proportionally to BDNF levels, in the hippocampus of rats maintained on the HFS diet between 2 and 24 months. In particular, animals maintained on the HFS diet showed a decrease in levels of: (i) synapsin I mRNA and protein (total and phosphorylated), important for neurotransmitter release; (ii) cyclic AMP-response element-binding protein (CREB) mRNA and protein (total and phosphorylated); CREB is required for various forms of memory and is under regulatory control of BDNF; (iii) growth-associated protein 43 mRNA, important for neurite outgrowth, neurotransmitter release, and learning and memory. Diet-related changes were specific for the hippocampus consequent to its role in memory formation, and did not involve neurotrophin-3, another member of the neurotrophin family. Our results indicate that a popularly consumed diet can influence crucial aspects of neuronal and behavioral plasticity associated with the function of BDNF.

Animals↗
PubMed2002

Hippocampal dysfunction and behavioral deficit in the water maze in mice: an unresolved issue?

Dysfunction of the hippocampal formation manifests as impaired relational learning and memory in humans and animals. One of the most frequently applied relational learning paradigms in animals is the Morris water maze (MWM), in which the subject is required to learn complex spatial relationships of visual cues. MWM has been employed as a diagnostic tool to investigate effects of drugs and mutations. However, the validity of this test and its ability to properly detect hippocampal dysfunction have been questioned. In order to corroborate the role of hippocampus in spatial learning, we employed ibotenic acid lesioning and ablated the hippocampus bilaterally or unilaterally in mice, as ascertained by magnetic resonance imaging. We found a significant impairment in response to hippocampal disruption that was more pronounced in mice with bilateral lesion than with unilateral lesion. However, the results also indicated that even the mice with bilateral lesion could improve their performance, which confirms the notion that the MWM has an important non-hippocampal component. It is thus possible that experimental alteration of brain function does not manifest as modified performance in MWM, even when hippocampal function is modified (false-negative finding), or manifest as altered performance without varying hippocampal function (false-positive finding), possibilities that have important implications for studies using genetic and pharmacological manipulation of the brain.

Animals↗
PubMed1992

Inhibition of nitric oxide synthesis impairs two different forms of learning.

Nitric oxide (NO), an intercellular messenger in the central nervous system of vertebrates, plays an important role in the establishment of synaptic plasticity. In order to investigate the role of NO and synaptic plasticity in learning, we injected rats and rabbits with the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME) prior to training on two tests of learning. Rats treated with L-NAME were impaired in learning a spatial learning task, while rabbits given the NO synthase inhibitor demonstrated learning deficits in the conditioned eyeblink response. The results support the hypothesis that NO plays a critical role in acquisition of two different forms of learning.

Animals↗
PubMed1994

Primary amnesia of insidious onset with subsequent stabilisation.

A patient had a slowly developing amnesic syndrome that remained substantially unchanged during the two and a half years of observation. Intellectual skills were excellent and there was no language, perception, praxis, or calculation deficit. The memory impairment involved verbal and visual learning, sparing spatial learning and, to a large extent, retrograde memory. Magnetic resonance imaging was normal, but PET showed a hypometabolism of the left temporal mesial region and thalamus. This case extends the spectrum of monosymptomatic cognitive disorders, previously reported in the area of language, praxis, and visual recognition, to amnesia.

Aged↗
PubMed1987

Effects of alpha-MSH, TRH and AVP on learning and memory, pain threshold, and motor activity: preliminary results.

The effect of daily peripheral administration of various peptides on learning and memory performance was studied in male albino rats. Groups of rats were treated with either TRH (1.0 mg/kg) alpha-MSH (1.0 mg/kg), or saline for three days. Other groups were treated either with vasopressin (1.0 microgram/kg) or saline. All treatments were 30 min before testing in a Morris Water Task apparatus. This type of learning is spatial learning which requires integration of environmental cues. Only alpha-MSH treated rats exhibited improved learning on Day 1 and Day 3 of the training period. One month later all rats were retested with no difference between the experimental groups. Single doses of these peptides caused a nonsignificant increase in pain threshold. The body weight gain of vasopressin-treated rats was significantly reduced as well as their motoric behavior. Therefore, the alpha-MSH effect on learning cannot be explained by nonspecific effects on body weight, pain threshold, or motor activity level.

Animals↗
PubMed2001

3,4-methylenedioxymethamphetamine (ecstasy)-induced learning and memory impairments depend on the age of exposure during early development.

Use of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) has increased dramatically in recent years, yet little is known about its effects on the developing brain. Neonatal rats were administered MDMA on days 1-10 or 11-20 (analogous to early and late human third trimester brain development). MDMA exposure had no effect on survival but did affect body weight gain during treatment. After treatment, body weight largely recovered to 90-95% of controls. MDMA exposure on days 11-20 resulted in dose-related impairments of sequential learning and spatial learning and memory, whereas neonatal rats exposed on days 1-10 showed almost no effects. At neither stage of exposure did MDMA-treated offspring show effects on swimming ability or cued learning. Brain region-specific dopamine, serotonin, and norepinephrine changes were small and were not correlated to learning changes. These findings suggest that MDMA may pose a previously unrecognized risk to the developing brain by inducing long-term deleterious effects on learning and memory.

3,4-Methylenedioxyamphetamine↗
PubMed2003

Refining the critical period for methamphetamine-induced spatial deficits in the Morris water maze.

RATIONALE: Neonatal administration of methamphetamine (MA) to rats from postnatal day (P) 11 to 20, but not from P1 to P10, produces lasting deficits in spatial learning and memory. The preweaning period of development in the rat corresponds to human third trimester hippocampal development and because of the increased use of MA in women of childbearing age, there is a greater likelihood that fetuses will be exposed to this drug. Development of the hippocampus is dependent upon many factors, including an optimal level of corticosterone (CORT). We have demonstrated that the CORT response of animals on P11 to MA is protracted relative to administration on P15 or P20. Interestingly, the P11 animals are still in the stress hyporesponsive period. OBJECTIVES: We postulated that because of the prolonged CORT response on P11, the effects of MA on spatial learning and memory may be confined to a shorter period of exposure. METHODS: Neonatal rats were administered MA (10 mg/kg) 4 times daily from either P11 to P15 or from P16 to P20, raised to adulthood and tested against animals only administered saline (SAL) from P11 to P20 for anxiety, swimming ability, and spatial learning and memory. RESULTS: Animals exposed to MA, regardless of exposure period, tended to be less anxious in the Zero maze relative to SAL animals. No differences were noted for swimming ability. Only animals exposed to MA from P11 to P15 demonstrated deficits in spatial learning and memory during acquisition as well as during a shifted platform phase where learning a new position was required. CONCLUSIONS: The results demonstrate that spatial learning and memory deficits produced by MA administration are dependent upon when the exposure of the animal occurs and appears to be during the period of development in the rat when the response to threatening environments, stressors, is greatly reduced.

Animals↗
PubMed2006

Conditional associative learning of spatial and object information in children with attention deficit/hyperactivity disorder.

The present study assessed frontostriatal mediated memory functions in children with ADHD (N=12) and healthy control participants (N=12) using two tests of conditional associative learning (i.e., object and spatial) that shared similar stimulus-response association structures but that differed in terms of the demands placed upon strategic processes. Children with ADHD displayed normal performance on the object learning task but were impaired on the spatial learning task that placed greater demands on internally derived strategic processes. Secondary analyses further indicated that this strategic processing impairment cannot be attributed specifically to perseverative or working memory errors but rather appears to be related to a more general inability to maintain a high degree of consistency in responding across trials. Although the results of this study must be interpreted in light of the small sample sizes, they suggest that ADHD does not produce a basic deficit in acquiring stimulus-response associations previously shown to be associated with basal ganglia dysfunction. Rather, these findings suggest that the impaired conditional associative learning performance of children with ADHD is attributable to deficits in strategic processes previously been found to be dependent upon the integrity of the prefrontal cortex.

Association Learning↗
PubMed2002

A spatial memory task appropriate for electrophysiological recordings.

We developed a novel method for assessing spatial learning that is compatible with the requirements of electrophysiological recording of multiple single neurons. The behavioral task utilized a rectangular track with 8 reward boxes of which a subset contained available food (bait). Errors were scored whenever the rat investigated a non-baited box location (commission), failed to investigate a baited box location (omission), or hesitated in front of a non-baited box location (hesitation). Several controls encouraged the animal to solve the task through allocentric cues rather than through procedural strategies or simple local cue pairing. The learning curve for this task (3-5 d to criterion) was comparable to that of other spatial learning tasks when adequately motivated. The types of errors varied as the animal learned the task. Unlike other spatial learning tasks, the multi-box track allows many repeated samples of the same spatial coordinates within a short period of time to allow, for example, reliable determination of place fields while recording from hippocampal cells. Multiple trials per session also allow for high intensity training important for many learning assessments such as the timing and type of sleep involved in learning and memory.

Analysis of Variance↗
PubMed1995

A single intraseptal injection of nerve growth factor facilitates radial maze performance following damage to the medial septum in rats.

Rats were trained on a radial maze and then given electrolytic lesions of the MS followed by a single intraseptal injection of 5 micrograms of NGF. Three days later they were re-tested on the maze. They were also post-operatively tested for hyperemotionality. MS lesions severely impaired performance on the radial maze and produced increased emotionality. MS lesions also produced a general decrease in hippocampal high affinity choline transport and acetylcholinesterase staining, which was not affected by NGF administration. NGF treatment ameliorated the behavioral deficit in the radial maze but had no effect on the hyperemotionality. In order to determine whether the NGF was working to restore previously learned spatial abilities, the type of learning strategy used by the animals was also assessed. NGF treatment did not restore previously learned spatial strategies but facilitated recovery of alternative learning strategies. The reduction in cognitive deficit was also paralleled by reduced ventricular enlargement in the NGF treated rats. The present results suggest that a single injection of NGF can produce a long-lasting improvement on a cognitive task and reduce some of the injury-induced, secondary reactive changes that occur following electrolytic MS lesions.

Analysis of Variance↗
PubMed1998

Monkeys with rhinal cortex damage or neurotoxic hippocampal lesions are impaired on spatial scene learning and object reversals.

Rhesus monkeys (Macaca mulatta) with lesions of the rhinal cortex or parahippocampal gyrus (made by aspiration) or hippocampus (made with ibotenic acid) and unoperated controls were tested on object discrimination and reversal, place discrimination and reversal, and spatial scene learning to determine the contribution of these temporal lobe structures to these forms of learning and memory. Rhinal cortex lesions produced a severe deficit in object reversal learning; hippocampal lesions produced a milder deficit. Monkeys with rhinal cortex removals and those with hippocampal lesions were equally impaired on spatial scene learning. None of the lesions impaired place discrimination or reversal. These results argue against the idea that the mnemonic contributions of the rhinal cortex and hippocampus are limited to object and spatial domains, respectively.

Animals↗
PubMed2000

Gene-experience interaction alters the cholinergic septohippocampal pathway of mice.

Spatial learning requires the septohippocampal pathway. The interaction of learning experience with gene products to modulate the function of a pathway may underlie use-dependent plasticity. The regulated release of nerve growth factor (NGF) from hippocampal cultures and hippocampus, as well as its actions on cholinergic septal neurons, suggest it as a candidate protein to interact with a learning experience. A method was used to evaluate NGF gene-experience interaction on the septohippocampal neural circuitry in mice. The method permits brain region-specific expression of a new gene by using a two-component approach: a virus vector directing expression of cre recombinase; and transgenic mice carrying genomic recombination substrates rendered transcriptionally inactive by a "floxed" stop cassette. Cre recombinase vector delivery into transgenic mouse hippocampus resulted in recombination in 30% of infected cells and the expression of a new gene in those cells. To examine the interaction of the NGF gene and experience, adult mice carrying a NGF transgene with a floxed stop cassette (NGFXAT) received a cre recombinase vector to produce localized unilateral hippocampal NGF gene expression, so-called "activated" mice. Activated and control nonactivated NGFXAT mice were subjected to different experiences: repeated spatial learning, repeated rote performance, or standard vivarium housing. Latency, the time to complete the learning task, declined in the repeated spatial learning groups. The measurement of interaction between NGF gene expression and experience on the septohippocampal circuitry was assessed by counting retrogradely labeled basal forebrain cholinergic neurons projecting to the hippocampal site of NGF gene activation. Comparison of all NGF activated groups revealed a graded effect of experience on the septohippocampal pathway, with the largest change occurring in activated mice provided with repeated learning experience. These data demonstrate that plasticity of the adult spatial learning circuitry can be robustly modulated by experience-dependent interactions with a specific hippocampal gene product.

Animals↗