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PubMed1979

Prenatal effects of alcohol on adult learning in rats.

In an initial study, the rate of blood alcohol disappearance was not significantly different in pregnant compared to nonpregnant rats, but blood alcohol levels were significantly different depending on dose. In a second study, pregnant rats received daily administrations (p.o.) of ethanol (30% w/v) in single doses throughout gestation. Pair-fed vehicle-treated, and nondrug-treated rats fed ad lib served as controls. All pups were removed from their biological mothers at birth and were raised by nondrug-treated surrogate mothers. At five months of age, both male and female offspring prenatally exposed to ethanol weighed less than controls and female offspring performed significantly worse than the offspring of vehicle-injected pair-fed control mothers, on a two-way shock-avoidance task. There were no significant group differences, however, for either sex in water-escape maze learning.

Animals↗
PubMed2003

Olfactory perceptual learning: the critical role of memory in odor discrimination.

The major problem in olfactory neuroscience is to determine how the brain discriminates one odorant from another. The traditional approach involves identifying how particular features of a chemical stimulus are represented in the olfactory system. However, this perspective is at odds with a growing body of evidence, from both neurobiology and psychology, which places primary emphasis on synthetic processing and experiential factors--perceptual learning--rather than on the structural features of the stimulus as critical for odor discrimination. In the present review of both psychological and sensory physiological data, we argue that the initial odorant feature extraction/analytical processing is not behaviorally/consciously accessible, but rather is a first necessary stage for subsequent cortical synthetic processing which in turn drives olfactory behavior. Cortical synthetic coding reflects an experience-dependent process that allows synthesis of novel co-occurring features, similar to processes used for visual object coding. Thus, we propose that experience and cortical plasticity are not only important for traditional associative olfactory memory (e.g. fear conditioning, maze learning, and delayed-match-to-sample paradigms), but also play a critical, defining role in odor discrimination.

Animals↗
PubMedDate not supplied

Maternal age as a factor in determining the reproductive and behavioral outcome of rats prenatally exposed to ethanol.

Nulliparous Long-Evans rats were bred at one of four different ages and assigned to one of three treatment groups within each age condition. Maternal ages were 9, 18, 32, and 36 weeks. Treatment groups were ethanol (E), administered by gavage as 8 g/kg in two divided doses on days 10-14 of gestation, pair-fed (PF) controls, administered as an isocaloric sucrose solution by gavage on days 10-14 of gestation, and ad lib fed controls (C). All offspring were surrogate fostered shortly after delivery to untreated recently parturient dams. Litter sizes were standardized to 8 on the day of birth. Offspring were assessed longitudinally for growth, mortality, and behavior (olfaction, locomotor activity, maze learning, avoidance acquisition and startle). Approximately 85% of the 36 week old dams did not produce viable litters. In the remaining maternal age conditions, ethanol delayed offspring olfactory orientation and increased locomotor activity, the latter dissipating after 50-60 days of age. These ethanol-related effects occurred independent of maternal age condition. Maternal age, independent of ethanol, was a factor which reduced litter size and offspring weight up to 50 days, but produced few effects on behavior. The combination of maternal age and prenatal ethanol interacted to increase pregnancy loss (oldest maternal age), reduce offspring weight up to day 99 (oldest and middle maternal age), alter olfactory orientation performance (oldest and middle maternal age), reverse the typical ethanol-induced increase in activity for males in the figure-8 test (oldest maternal age group), shift the pattern of open-field activity, and change errors in a complex water maze. Not all of these interactions turned out to be specific to the ethanol X old maternal age condition. Several of the interactions occurred in both the old and middle maternal age conditions. The only effect of old maternal age that interacted strongly with ethanol was in their combined effects on reproduction. Here the combination of the two factors increased maternal mortality, the number of early pregnancy losses, and the number of litters where all members were dead or resorbed. It was concluded that short-term prenatal ethanol combined with advanced maternal age produces additive interactions on pregnancy success without affecting longer-term outcomes, while young maternal age showed no clear detrimental effects compared to the middle maternal age reference group.

Aging↗
PubMed1999

Experience-dependent regulation of adult hippocampal neurogenesis: effects of long-term stimulation and stimulus withdrawal.

Exposure to an enriched environment has been shown to cause an increase in neurogenesis in the dentate gyrus of adult mice. In this study we examined how this experience-dependent response in adult hippocampal neurogenesis of C57BL/6 mice is modulated under the conditions of long-term stimulation and of withdrawal from the enriched environment. We found that a group which experienced withdrawal from the enriched environment 3 months earlier, had more than twice as many proliferating cells in the subgranular zone as controls and mice experiencing long-term stimulation. We propose that the greater number of proliferating cells after withdrawal reflects a survival-promoting effect on the dividing neuronal stem and progenitor cells during the earlier period of stimulation. No differences between the groups were observed in the number of surviving progeny or their phenotypes. Therefore, the existence of more dividing cells in the withdrawal group did not translate into a significant net increase in neurogenesis in the absence of continued stimulation. Similarly, the finding in the group experiencing long-term stimulation showing no clear benefit over controls could be interpreted as a diminished efficiency of continued environmental stimuli to elicit a neurogenic response. Thus, we propose as a working hypothesis that: 1) stimulation early in life may preserve the neurogenic potential in the dentate gyrus, and 2) the novelty of complex stimuli rather than simply continued exposure to complex stimuli elicits the environmental effects on adult hippocampal neurogenesis.

Adaptation, Psychological↗
PubMed2000

Functional reconstruction of the hippocampus: fetal versus conditionally immortal neuroepithelial stem cell grafts.

Late fetal CA1 hippocampal grafts and stem cell grafts from the conditionally immortal MHP36 clonal line derived from the H-2Kb-tsA58 transgenic mouse neuroepithelium both improved spatial deficits in rats with ischaemic CA1 damage induced by four-vessel occlusion (4VO). However, the distribution of fetal and MHP36 grafts differed. Fetal cells lodged in clumps around the implant sites and along the corpus callosum, whilst MHP36 grafts infiltrated the area of CA1 ischaemic damage, achieving apparent architectural reconstruction of the hippocampus. The migration of MHP36 cells is damage-dependent. Few cells were found in intact brain; after 15 min of 4VO cells repopulated only the discrete area of CA1 cell loss, whereas with more extensive damage after 30 min occlusion cells migrated to all hippocampal fields and to cortex. A higher proportion of grafted MHP36 cells differentiated into neurons in the host CA1 field than grafts of striatal or cortical expanded cell populations. Cortical population grafts were as effective as MHP36 grafts in improving water maze learning, whereas striatal or ventral mesencephalic cells were ineffective, indicating a degree of stem cell specificity. The efficacy of MHP36 cells extends to primates. In marmosets with profound impairments in conditional discrimination tasks after lesions of the CA1 field, MHP36 cells improved performance as effectively as fetal grafts and migrated evenly through the CA1 field, in contrast to clustered fetal cells. These findings suggest that MHP36 stem cell grafts are as effective as fetal grafts in functional repair of hippocampal damage, and that their preference for areas of cell loss and adoption of appropriate morphologies is consistent with a point-to-point repair mechanism.

Animals↗
PubMed1983

Cognitive changes with aging in schizophrenia.

Hospitalized, male chronic schizophrenics (N = 21) in their late sixties performed as well as those in their early forties when normal age effects were determined on measures of verbal fluency, picture anomaly recognition, tapping speed, and maze learning. The findings contraindicated the Kraepelinian view of schizophrenia as a deteriorative disorder and were more in accord with recent longitudinal evidence of clinical stabilization and amelioration of disruptive symptoms in chronic schizophrenia.

Adult↗
PubMed2002

Long-term monitoring of hippocampus-dependent behavior in naturalistic settings: mutant mice lacking neurotrophin receptor TrkB in the forebrain show spatial learning but impaired behavioral flexibility.

Previous behavioral studies (Minichiello et al., Neuron 1999;24:401-414) showed that mice deficient for the TrkB receptor in the forebrain were unable to learn a swimming navigation task with an invisible platform and were severely impaired in finding a visible platform in the same setup. Likewise, additional behavioral deficits suggested a malfunction of the hippocampus and proximally connected forebrain structures. In order to discriminate whether the behavioral impairment was caused either by deficits in spatial memory and learning, or alternatively by loss of behavioral flexibility, 8 trkB mutant, 13 wild-type, and 22 heterozygous mice were implanted with transponders and released for 21 days into a large outdoor pen (10 x 10 m). The enclosure contained 2 shelters and 8 computer-controlled feeder boxes, delivering food portions for every mouse only during their first visit. Every third day, mice received food ad libitum inside the shelters. All mice learned to patrol the boxes correctly within a few days. However, significant differences emerged during those days with free food available. Wild-type mice remained inside the shelters, while all homozygous mutants continued to patrol the boxes in their habitual way, the heterozygous mutants showing intermediate scores. These and previous data suggest that one of the natural functions of the mouse hippocampus is to comediate behavioral flexibility, and that TrkB receptors might play an essential role in maintaining the neuronal short-term plasticity necessary for this capacity.

Animals↗
PubMed2006

Is there a link between adult neurogenesis and learning?

During the past several years, evidence has accumulated suggesting a relationship between newly born cells in the hippocampus and various types of learning and memory. However, most of the evidence is correlational and some of it does not agree. This review discusses both sides of this issue, considering the effects of learning on the production of new neurons in the dentate gyrus and the question of whether newly born cells participate in learning and memory.

Animals↗
PubMed1994

Hippocampal mossy fibers and swimming navigation in mice: correlations with size and left-right asymmetries.

Individual differences in the extent of the infrapyramidal mossy fiber projection (IIP-MF) correlate with performance in tasks sensitive to hippocampal lesions, notably two-way avoidance, radial maze learning, and swimming navigation. Previous studies of swimming navigation suggested that the capacity of reversal learning and measures of directionality might also be related to asymmetries in the distribution of the IIP-MF. In order to verify these findings, the authors crossed the Collins High- and Low-lateralized mice (known to differ in mossy fiber morphology and brain asymmetries) and obtained a F2-generation characterized by strong individual differences in these traits. Twenty-three (13 females, 10 males) mice were tested during 3 days for acquisition of swimming navigation (16 trials) toward a central platform, and during two days (12 trials) for their capacity of reversal learning toward a shifted platform. Morphometry of Timm-stained hippocampi revealed several, partially independent correlations: Larger IIP-MF projections were associated with prolonged crossing over the former platform position during the entire reversal learning; larger IIP-MF projections on the left were correlated with more precise crossing of the former platform position during the first 45 seconds of reversal learning; both extent and asymmetry of IIP-MF correlated positively with overnight improvement of reversal learning; the size of the entire mossy fiber projection (CA4, suprapyramidal and IIP-MF) correlated positively with the time spent in the platform quadrant and measures of initial orientation during acquisition of the task; and the mice showed an ipsilateral turning bias (spin) toward the side with the larger mossy fiber projection. The authors conclude that an intact hippocampus mediates differential processes underlying swimming navigation, and that left and right subfields may have differential functions.

Animals↗
PubMed1982

Behavioural teratology: post-natal consequences of drug exposure in utero.

The effects of pre-natal exposure to drugs that subsequently affect the post-natal behaviour without apparently causing noticeable brain damage forms the subject of behavioural teratology. This review summarizes the experimental studies of several investigators who showed that pre-natal administration of such psychotropic drugs as meprobamate, isocarboxazid and reserpine reduced the maze-learning ability of the mature offspring. A more detailed survey of the effects of D-amphetamine and diazepam is then given. Both drugs were not foetotoxic and only caused appreciable changes in locomotor activity of the offspring at least 14 days after birth. With the amphetamine treated rats, these changes were biphasic (elevated at 15 days and reduced at 21 days) whereas the diazepam treated animals showed a reduction in locomotor activity for at least 21 days after birth. The results of our own studies, and those of others, do not enable a correlation to be made between the effects of the various drugs on the development of specific central neurotransmitters and the behavioural deficits noticed. The review concludes with an outline proposal for screening drugs for their potential as behavioural teratogens. The possible mechanisms whereby behavioural teratogens may cause subtle changes in the maturation of the brain are also outlined.

Amphetamines↗
PubMed1986

Behavioral effects of large and small lesions of the rat medial frontal cortex.

Rats with either sham operations, small medial frontal cortex lesions (SMF), or large medial frontal cortex lesions (LMF) were tested in the open field, for spatial alternation and for 8-arm maze learning. The behaviors of sham-operated and SMF rats were similar on the spatial learning tasks, while the LMF group performed poorly in relation to these two groups. In contrast, the two lesion groups differed from the sham group, but not from each other, on locomotor activity in the open field. The differences in performance between the SMF and LMF groups on the spatial learning measures suggest that medial frontal cortex lesion size and locus may be important factors underlying the variable results of previous studies evaluating spatially-oriented behaviors of rats with varying degrees of medial frontal cortex damage.

Animals↗
PubMed1978

Effects of ethanol on pregnant rats and their offspring.

Pregnant rats were intubated with either 1.0 or 2.0 g/kg of ethanol daily throughout gestation. Pair-fed vehicle-treated, and nontreated rats fed ad libitum, served as control groups for ethanol-treated animals. Ethanol treatment reduced food and water consumption and attenuated the gain in body weight of pregnant animals relative to nontreated animals fed ad libitum. Litter size, litter weight, and the mean weight per pup were reduced in both the ethanol-treated and pair-fed control groups. There was no evidence of gross malformations in any of the off-spring. Since the reduction in litter size and litter weights did not differ significantly between ethanol-treated and pair-fed controls, the effects of treatment with ethanol appeared to be related to a reduction in maternal intake of calories rather than to the direct effect of ethanol on the developing fetus. There were no significant differences between any of the groups of offspring on one-way shock avoidance learning, water maze escape learning, spontaneous alternation, or brightness discrimination learning in tests beginning at 75 days of age. Thus, at the doses of alcohol used in this study, there was no evidence of behavioral teratogenesis comparable to that reported for higher doses in animals or in man characterized by the fetal alcohol syndrome.

Animals↗
PubMed1982

Residual effects of prolonged cannabis administration on exploration and DRL performance in rats.

Chronic oral administration of cannabis extract to rats (daily delta 9-tetrahydrocannabinol dose 20 mg/kg) was examined for its residual effect on open field activity and DRL (differential reinforcement of low-rat responding) performance, following a 2-3 month drug-free period. Locomotor activity during the latter part of an open field test was markedly increased in rats previously treated for either 6 months or 3 months with the drug. The same treatments also produced a significant impairment on a DRL-20 task relative to control subjects' performance. These and other findings (impaired maze learning and facilitated two-way shuttle box avoidance) might mean that cannabis produces long-lasting hippocampal dysfunction in rats.

Animals↗
PubMed1976

Effects of antisera to S-100 protein and to synaptic membrane fraction on maze performance and EEG.

Topical cortical injection into rats of antiserum to the synaptic membrane fraction caused recurrent spiking activity as observed in the EEG; neither antiserum to S-100 protein nor antiserum to myelin caused any such abnormality. These same rats, when observed on a maze learning task (Lashley III) responded differently to the different antisera. Rats receiving injections of antiserum to the synaptic membrane fraction or antiserum to S-100 protein were inhibited in their performance, while rats injected with antiserum to myelin behaved like uninjected animals.

Animals↗
PubMed1986

Long-term effects of nerve growth factor and neural transplants on behavior of rats with medial septal lesions.

The present experiment investigated the interaction between exogenous nerve growth factor (NGF) and intrahippocampal septal grafts on the behavior of rats after a medial septum lesion. Young female rats received a bilateral injection of a fetal septal cell suspension into the dorsal hippocampus either immediately (immediate grafts) or 8 days after the lesion (delayed grafts). For delayed grafts, a higher concentration of endogenous neurotrophic factors can be assumed to be present in the deafferentated host tissue at the time of transplantation. One group of rats with lesions received NGF with the immediate grafts, another group received NGF alone. A sham-operated group and 3 groups with lesions (and given either immediate or delayed intrahippocampal saline injections, or no other treatment) constituted controls. The animals were tested for spontaneous alternation and for performance in a radial 8-arm maze, 1, 5 and 9 months postoperatively. Medial septal lesions reduced spontaneous alternation but, 9 months after surgery, recovery was observed in both lesion-control rats and in rats with delayed grafts (but not with immediate grafts). In the radial maze task, lesions produced a persistent impairment, although both immediate and delayed grafts reduced this deficit several months after surgery (more markedly and rapidly in the case of delayed grafts). NGF, however, increased the maze learning deficit especially 5 months postoperatively. These latter results are in contrast to findings of earlier studies showing transient beneficial effects of NGF administration. It is suggested that the effects of NGF in the present study might be due to an enhanced sprouting of sympathetic fibers into the hippocampal formation.

Animals↗
PubMed1987

Colchicine lesions in the rat hippocampus mimic the alterations of several markers in Alzheimer's disease.

An infusion of colchicine into the hippocampi of rats resulted in destruction of hippocampal cells. Twelve days after infusion, preoperative trained colchicine-treated rats showed a significant decrease in choice accuracy in a T-maze learning task. There was also local reduction in choline acetyltransferase (ChAT) activity and significant losses of 55-kDa protein in the soluble fraction and of 50-kDa protein in myelin and synaptosomal fractions in the hippocampi of colchicine-lesioned rats. There was a marked increase in [3H]glutamate binding in the hippocampus and cortex. In contrast, [3H]quinuclidinyl benzilate binding in the hippocampus was slightly reduced, whereas [3H]dihydroalprenolol binding was not affected by the colchicine treatment. Scatchard analysis revealed that the increase in glutamate binding is due to an increase in the number of glutamate receptors without significant change in their affinity. Some of the changes caused by hippocampal infusion of colchicine resemble those seen in Alzheimer's disease suggesting the use of such rats as one model for the disease.

Alzheimer Disease↗
PubMed1989

Dietary cis-fatty acids that increase protein F1 phosphorylation enhance spatial memory.

Activation of protein kinase C (PKC) facilitates long-term potentiation (LTP), a model of memory, and increases its substrate protein F1 (aka GAP43) phosphorylation in direct relation to synaptic enhancement. Unsaturated fatty acids (c-FAs) which activate purified PKC, when injected into hippocampus, enhance LTP. To determine if dietary c-FAs could alter memory itself as well as brain PKC substrate (F1) metabolism, rats were maintained for 10 weeks on fatty acid diets enriched in mono-unsaturated oleic acid (OA; 20% olive oil, w/w), or a mono- and di-unsaturated mixture of oleate/linoleate (O/L; 20% corn oil), or a saturated fatty acid diet of laurate/myristate (L/M; 20% hydrogenated coconut oil). The O/L diet group was superior to the OA and L/M groups in spatial memory performance after the first two weeks of acquisition and in later achievement of criterion performance. The O/L diet had a significantly higher hippocampal protein F1 in vitro phosphorylation than in both the OA and L/M in trained and non-trained animals. Significantly, animals that made fewer errors showed higher F1 phosphorylation (r = -0.70). Diet both increases brain PKC substrate phosphorylation and enhances maze learning, confirming the feasibility of enhancing learning and memory by dietary regimens derived from basic neurochemical studies of synaptic plasticity.

Animals↗
PubMed1992

Effects of septal and/or raphe cell suspension grafts on hippocampal choline acetyltransferase activity, high affinity synaptosomal uptake of choline and serotonin, and behavior in rats with extensive septohippocampal lesions.

At 31 days of age, Long-Evans female rats sustained aspirative lesions of the septohippocampal pathways and, 14 days later, received intrahippocampal suspension grafts prepared from the region including the medial septum and the diagonal band of Broca (Group S, n = 11), from the region including the mesencephalic raphe (Group R, n = 11) or from both regions together (Group S+R, n = 11). Sham-operated (Group Sham, n = 9) and lesion-only (Group Les, n = 11) rats served as non-grafted controls. Seven Sham, 7 Les and 8 rats from each transplant group were tested for home cage activity (6 months after grafting) and radial maze performance (between 7.5 and 8.5 months post-grafting). One month after completion of behavioral testing, the dorsal hippocampi of these rats were prepared for measuring choline acetyltransferase (ChAT) activity and high affinity synaptosomal uptake of both [3H]choline and [3H]serotonin. The remaining rats were used for histological verifications on brain sections stained for acetylcholinesterase (AChE). The lesions increased locomotor activity, impaired radial maze learning and, in the dorsal hippocampus, reduced AChE positive staining, decreased ChAT activity (-73%) as well as high affinity uptake of both choline (-81%) and serotonin (-82%). Neither type of transplant produced any significant behavioral recovery. However, septal transplants increased hippocampal AChE positivity, restored ChAT activity and enhanced choline uptake to 116% and 70% of the values found in sham-operated rats, respectively; they had no significant effect on uptake of serotonin. Transplants from the raphe region had weak effects on hippocampal AChE positivity, increased both the ChAT activity and the choline uptake to 70% ad 38% of the sham-operated rats, respectively, and produced an (over)compensation of the serotonin uptake which reached 324% of the values found in sham-operated rats. The co-transplantation of both regions resulted in restoration of ChAT activity (113% of sham-operated rats values), choline uptake (83% of sham-operated rats) and serotonin uptake (129% of sham-operated rats). Our neurochemical data show that after extensive denervation of the hippocampus, intrahippocampal grafts of fetal neurons may foster a neurotransmitter-specific recovery which depends upon the anatomical origin of the grafted cells: a graft rich in serotonergic neurons overcompensates the serotonergic deficit, a graft rich in cholinergic neurons attenuates the cholinergic deficit, whereas a mixture of both types of grafts produces recovery from both types of deficits. Thereby, both the feasibility and the interest of the co-grafting technique are confirmed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗