Maze Learning Deficits Research Articles

Swimming exercise is a promising early intervention for autism-like behavior in Shank3 deletion rats.

SHANK3 is an important excitatory postsynaptic scaffold protein, and its mutations lead to genetic cause of neurodevelopmental diseases including autism spectrum disorders (ASD), Philan McDermid syndrome (PMS), and intellectual disability (ID). Early prevention and treatment are important for Shank3 gene mutation disease. Swimming has been proven to have a positive effect on neurodegenerative diseases. Shank3 gene exon 11-21 knockout rats were intervened by a 40 min/day, 5day/week for 8-week protocol. After the intervention, the rats were tested to behavioral measures such as learning and memory, and the volume and H-spectrum of the brain were measured using MRI; hippocampal dendritic spines were measured using Golgi staining and laser confocal. The results showed that Shank3-deficient rats had significant deficits in social memory, object recognition, and water maze learning decreased hippocampal volume and number of neurons, and lower levels of related scaffold proteins and receptor proteins were found in Shank3-deficient rats. It is suggested that early swimming exercise has a positive effect on Shank3 gene-deficient rats, which provides a new therapeutic strategy for the prevention and recovery of neurodevelopmental disorders.

Prolonged methamphetamine exposure during a critical period in neonatal Sprague Dawley rats does not exacerbate egocentric and allocentric learning deficits but increases reference memory impairments.

Children exposed to methamphetamine (MA) in utero have cognitive deficits. MA administration in rats for 5-10days between postnatal days (P)6 and 20 produces cognitive deficits. The purpose of this study was to determine if extending MA administration by 5days within P6-20 would exacerbate allocentric (Morris water maze) and egocentric (Cincinnati water maze) learning deficits. Sprague Dawley female and male offspring (split-litter design) were administered saline (SAL) or MA (10mg/kg) four times daily from P6 to 20 to create four groups: (a) SAL from P6 to 20, (b) MA from P6 to 20 (MA6-20), (c) MA from P6 to 15 (MA6-15), or (d) MA from P11 to 20 (MA11-20); the latter groups received saline on days they did not receive MA. Egocentric, allocentric, and conditioned freezing tests began on P60. The MA6-15 and MA6-20 groups showed egocentric deficits, all MA groups had allocentric deficits but no differences in conditioned freezing compared with SAL controls. The MA6-15 and MA6-20 groups had similar deficits in learning and memory that were larger than in the MA11-20 group. Learning in both mazes was sex dependent, but no interactions with MA were found. The data demonstrate that extending the exposure period of MA beyond the sensitive periods (P6-15 and P11-20) did not exacerbate the cognitive deficits.

Learning and Memory Effects of Neonatal Methamphetamine Exposure in Sprague-Dawley Rats: Test of the Role of Dopamine Receptors D1 in Mediating the Long-Term Effects

Methamphetamine (MA) abuse is a worldwide issue that produces health and cognitive effects in the user. MA is abused by some women who then become pregnant and expose their developing child to the drug. Preclinical rodent models demonstrate cognitive deficits following developmental MA exposure, an effect observed in children exposed to MA in utero. To determine if the dopamine receptor D1 (DRD1) is involved in the learning and memory deficits following MA exposure, male Sprague-Dawley rats were treated 4 times daily at 2 h intervals with 0 (saline) or 10 mg/kg of MA from postnatal day (P)6–15, 30 min after 0.5, 1.0, or 2.0 mg/kg SCH23390. Cincinnati water maze testing began on P30, and the high dose of SCH23390 blocked the learning deficits induced by MA with no effect from the lower doses. Morris water maze (MWM) learning deficits following MA were not protected by SCH23390, although there was a non-dose dependent effect in the acquisition phase. Locomotor deficits induced by MA were reversed by all doses of SCH23390. There were no effects of MA on criterion to trial passive avoidance. Taken together, these data show that behaviors that are dependent on the striatum are better protected with the DRD1 antagonist during MA treatment than the hippocampally mediated spatial learning in the MWM. This suggests that multiple mechanisms exist for the deficits induced by neonatal MA administration.

Deleterious effects of prenatal exposure to morphine on the spatial learning and hippocampal BDNF and long-term potentiation in juvenile rats: Beneficial influences of postnatal treadmill exercise and enriched environment

Prenatal morphine exposure causes a variety of neurobehavioral alterations observed in later life. The present study investigated the effects of postnatal exercise and enriched environment (EE) on alterations in water maze learning and hippocampal long-term potentiation (LTP) and brain derived neurotrophic factor (BDNF) levels induced by exposure to morphine during prenatal period in rats. On gestation days 11–18, pregnant rats were injected twice daily with saline or morphine. Offspring were subjected to postnatal exercise and EE for 30 days and afterward, spatial learning and hippocampal LTP and BDNF levels were investigated. Prenatal morphine-exposure impaired the spatial learning and hippocampal LTP in both male and female offspring. Interestingly, postnatal exercise and EE increased performance in the water maze and improved LTP in both prenatally saline and morphine-exposed male and female rats. Prenatal morphine exposure also caused a reduction in the hippocampal BDNF levels in the female, but not male rats, and postnatal exercise and EE alleviated this deficit. Our results demonstrate that postnatal exercise and EE can improve deficits in water maze learning and hippocampal LTP and BDNF levels caused by prenatal morphine exposure.

Fear but not fright: re-evaluating traumatic experience attenuates anxiety-like behaviors after fear conditioning.

Fear allows organisms to cope with dangerous situations and remembering these situations has an adaptive role preserving individuals from injury and death. However, recalling traumatic memories can induce re-experiencing the trauma, thus resulting in a maladaptive fear. A failure to properly regulate fear responses has been associated with anxiety disorders, like Posttraumatic Stress Disorder (PTSD). Thus, re-establishing the capability to regulate fear has an important role for its adaptive and clinical relevance. Strategies aimed at erasing fear memories have been proposed, although there are limits about their efficiency in treating anxiety disorders. To re-establish fear regulation, here we propose a new approach, based on the re-evaluation of the aversive value of traumatic experience. Mice were submitted to a contextual-fear-conditioning paradigm in which a neutral context was paired with an intense electric footshock. Three weeks after acquisition, conditioned mice were treated with a less intense footshock (pain threshold). The effectiveness of this procedure in reducing fear expression was assessed in terms of behavioral outcomes related to PTSD (e.g., hyper-reactivity to a neutral tone, anxiety levels in a plus maze task, social avoidance, and learning deficits in a spatial water maze) and of amygdala activity by evaluating c-fos expression. Furthermore, a possible role of lateral orbitofrontal cortex (lOFC) in mediating the behavioral effects induced by the re-evaluation procedure was investigated. We observed that this treatment: (i) significantly mitigates the abnormal behavioral outcomes induced by trauma; (ii) persistently attenuates fear expression without erasing contextual memory; (iii) prevents fear reinstatement; (iv) reduces amygdala activity; and (v) requires an intact lOFC to be effective. These results suggest that an effective strategy to treat pathological anxiety should address cognitive re-evaluation of the traumatic experience mediated by lOFC.

Temporal and region-specific requirements of αCaMKII in spatial and contextual learning.

The α isoform of the calcium/calmodulin-dependent protein kinase II (αCaMKII) has been implicated extensively in molecular and cellular mechanisms underlying spatial and contextual learning in a wide variety of species. Germline deletion of Camk2a leads to severe deficits in spatial and contextual learning in mice. However, the temporal and region-specific requirements for αCaMKII have remained largely unexplored. Here, we generated conditional Camk2a mutants to examine the influence of spatially restricted and temporally controlled expression of αCaMKII. Forebrain-specific deletion of the Camk2a gene resulted in severe deficits in water maze and contextual fear learning, whereas mice with deletion restricted to the cerebellum learned normally. Furthermore, we found that temporally controlled deletion of the Camk2a gene in adult mice is as detrimental as germline deletion for learning and synaptic plasticity. Together, we confirm the requirement for αCaMKII in the forebrain, but not the cerebellum, in spatial and contextual learning. Moreover, we highlight the absolute requirement for intact αCaMKII expression at the time of learning.

2-Methyl-6-(phenylethynyl) pyridine (MPEP) reverses maze learning and PSD-95 deficits in Fmr1 knock-out mice

Fragile X Syndrome (FXS) is caused by the lack of expression of the fragile X mental retardation protein (FMRP), which results in intellectual disability and other debilitating symptoms including impairment of visual-spatial functioning. FXS is the only single-gene disorder that is highly co-morbid with autism spectrum disorder and can therefore provide insight into its pathophysiology. Lack of FMRP results in altered group I metabotropic glutamate receptor (mGluR) signaling, which is a target for putative treatments. The Hebb-Williams (H-W) mazes are a set of increasingly complex spatial navigation problems that depend on intact hippocampal and thus mGluR-5 functioning. In the present investigation, we examined whether an antagonist of mGluR-5 would reverse previously described behavioral deficits in fragile X mental retardation 1 knock-out (Fmr1 KO) mice. Mice were trained on a subset of the H-W mazes and then treated with either 20 mg/kg of an mGluR-5 antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP; n = 11) or an equivalent dose of saline (n = 11) prior to running test mazes. Latency and errors were dependent variables recorded during the test phase. Immediately after completing each test, marble-burying behavior was assessed, which confirmed that the drug treatment was pharmacologically active during maze learning. Although latency was not statistically different between the groups, MPEP treated Fmr1 KO mice made significantly fewer errors on mazes deemed more difficult suggesting a reversal of the behavioral deficit. MPEP treated mice were also less perseverative and impulsive when navigating mazes. Furthermore, MPEP treatment reversed post-synaptic density-95 (PSD-95) protein deficits in Fmr1 KO treated mice, whereas levels of a control protein (β-tubulin) remained unchanged. These data further validate MPEP as a potentially beneficial treatment for FXS. Our findings also suggest that adapted H-W mazes may be a useful tool to document alterations in behavioral functioning following pharmacological intervention in FXS.

P.1.g.017 Gender differences in rats: behavioural and electrophysiological aspects

Pfiesteria piscicida is an estuarine dinoflagellate involved with fish kills along the east coast of the United States. We previously documented a radial-arm maze learning deficit in rats exposed to Pfiesteria that may be related to cognitive deficits seen in humans after accidental Pfiesteria exposure. The current study elucidated important behavioral parameters of this deficit. There were six dose groups. Forty (10/group) adult female Sprague–Dawley rats were injected (SC) with a single dose of Pfiesteria taken from aquarium-cultured Pfiesteria (35,600, 106,800, or 320,400 Pfiesteria cells/kg of rat body weight or a cell-free filtrate of the 106,800 cells/kg dose). One control group (N = 10) was injected with saline and one (N = 10) with aquarium water not containing Pfiesteria. Half of the rats in each group were tested on an 8-arm radial maze in a standard test room, and the other half were tested on the radial maze in a sound-attenuating chamber. In the standard maze room, there was a significant effect of Pfiesteria (p < 0.05) impairing choice accuracy improvement over the first six sessions of training among rats administered 106,800, 320,400, and the 106,800 cells/kg filtered sample. In contrast, there was no indication of an effect of Pfiesteria when the rats were tested on the same configuration radial maze in the sound-attenuating chamber. After 18 sessions of training in one room, the rats were switched for six sessions of testing in the other room and finally were switched back to their original room for three sessions. There was a significant Pfiesteria-induced deficit when the rats were tested in the standard test room but not when they were tested in the sound-attenuating chamber. When the Pfiesteria-exposed rats were initially switched from the sound-attenuating chamber to the standard test room they performed significantly worse than controls, whereas Pfiesteria-treated rats switched from the standard test room to the sound-attenuating chamber did not perform differently from controls. These results suggest that the Pfiesteria-induced learning impairment may result from the negative impact of distracting stimuli. At the time of the learning impairment, no overt Pfiesteria-related effects were seen using a functional observational battery and no overall response latency effects were seen, indicating that the Pfiesteria-induced choice accuracy deficit was not due to generalized debilitation. In the initial use of the figure-8 maze in this line of research, the rats in the same Pfiesteria treatment groups that showed significant deficits in the radial-arm maze showed greater declines in activity rates in a 1-h figure-8 locomotor activity test. Both the 106,800 and 320,400 Pfiesteria cells/kg groups showed significantly greater linear trends of activity decline relative to tank water-treated controls. This reflected an initial slight hyperactivity in the Pfiesteria-treated animals followed by a decrease to control levels. Pfiesteria effects in the figure-8 maze and in early radial-arm maze training may be useful in a rapid screen for identifying the critical toxin(s) of Pfiesteria in future studies. Published by Elsevier Science Inc.

Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits

Fragile X syndrome (FXS) is a common cause of inherited intellectual disability and a well-characterized form of autism spectrum disorder. As brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of FXS we examined the effects of reduced BDNF expression on the behavioral phenotype of an animal model of FXS, Fmr1 knockout (KO) mice, crossed with mice carrying a deletion of one copy of the Bdnf gene (Bdnf(+/-)). Fmr1 KO mice showed age-dependent alterations in hippocampal BDNF expression that declined after the age of 4 months compared to wild-type controls. Mild deficits in water maze learning in Bdnf(+/-) and Fmr1 KO mice were exaggerated and contextual fear learning significantly impaired in double transgenics. Reduced BDNF expression did not alter basal nociceptive responses or central hypersensitivity in Fmr1 KO mice. Paradoxically, the locomotor hyperactivity and deficits in sensorimotor learning and startle responses characteristic of Fmr1 KO mice were ameliorated by reducing BNDF, suggesting changes in simultaneously and in parallel working hippocampus-dependent and striatum-dependent systems. Furthermore, the obesity normally seen in Bdnf(+/-) mice was eliminated by the absence of fragile X mental retardation protein 1 (FMRP). Reduced BDNF decreased the survival of newborn cells in the ventral part of the hippocampus both in the presence and absence of FMRP. Since a short neurite phenotype characteristic of newborn cells lacking FMRP was not found in cells derived from double mutant mice, changes in neuronal maturation likely contributed to the behavioral phenotype. Our results show that the absence of FMRP modifies the diverse effects of BDNF on the FXS phenotype.

Exercise is not beneficial and may accelerate symptom onset in a mouse model of Huntington’s disease

Exercise benefits both general health and brain function in rodents and humans. However, it is less clear whether physical activity prevents or ameliorates neurodegenerative diseases. The aim of the present study was to determine whether voluntary wheel running can delay the onset or reduce the severity of Huntington’s disease (HD) in a mouse model. To investigate whether running may delay HD symptoms lifespan, disease onset, locomotor activity, glucose levels, weight, striatal volume, inclusions, cognition and hippocampal neurogenesis were studied in male N171-82Q transgenic HD mice. Running started in pre-symptomatic (44±1 days old) male HD mice, did not improve function and appeared to accelerate disease onset. In particular, HD runners had an earlier onset of disease symptoms (shaking, hunched back and poor grooming), reduced striatal volume and impaired motor behavior, including a shorter latency to fall from the rotarod compared to sedentary controls. Furthermore, weight loss, reduced lifespan, hyperglycemia, Morris water maze learning deficits, diminished hippocampal neurogenesis, deficits in immature neuronal morphology, intranuclear inclusions and decreased dentate gyrus volume were refractory to physical activity. Taken together our research indicates that exercise is not beneficial, and may be detrimental to a vulnerable nervous system.

Cognitive impairment in Gdi1-deficient mice is associated with altered synaptic vesicle pools and short-term synaptic plasticity, and can be corrected by appropriate learning training

The GDI1 gene, responsible in human for X-linked non-specific mental retardation, encodes alphaGDI, a regulatory protein common to all GTPases of the Rab family. Its alteration, leading to membrane accumulation of different Rab GTPases, may affect multiple steps in neuronal intracellular traffic. Using electron microscopy and electrophysiology, we now report that lack of alphaGDI impairs several steps in synaptic vesicle (SV) biogenesis and recycling in the hippocampus. Alteration of the SV reserve pool (RP) and a 50% reduction in the total number of SV in adult synapses may be dependent on a defective endosomal-dependent recycling and may lead to the observed alterations in short-term plasticity. As predicted by the synaptic characteristics of the mutant mice, the short-term memory deficit, observed when using fear-conditioning protocols with short intervals between trials, disappeared when the Gdi1 mutants were allowed to have longer intervals between sessions. Likewise, previously observed deficits in radial maze learning could be corrected by providing less challenging pre-training. This implies that an intact RP of SVs is necessary for memory processing under challenging conditions in mice. The possibility to correct the learning deficit in mice may have clinical implication for future studies in human.

Accelerated cognitive aging in diabetic rats is prevented by lowering corticosterone levels

Diabetes and normal aging are both characterized by increases in levels of glucocorticoids. Because long-term exposure to elevated glucocorticoids can be detrimental to hippocampal function, we evaluated the performance of young diabetic rats in the 14-unit T-maze, a task that is sensitive to hippocampal deficits. To assess the contribution of diabetes-induced elevations in corticosterone levels, we examined maze learning in diabetic rats that had levels of corticosterone ‘clamped’ through adrenalectomy and low-dose corticosterone replacement. For comparison, we also tested a separate group of young and aged rats in the maze. Adrenally intact diabetic rats learned poorly in the 14-unit T-maze. Preventing the increases in corticosterone levels that accompanies the onset of experimental diabetes also prevented deficits in complex maze learning. The pattern of errors made by adrenally intact diabetic rats was similar to the pattern of errors made by aged rats, suggesting that the cognitive profiles of diabetic and aged rats share common features.

Neonatal lesions of the entorhinal cortex induce long-term changes of limbic brain regions and maze learning deficits in adult rats

We here investigated the effects of neonatal lesions of the entorhinal cortex (EC) in rats on maze learning and on structural alterations of its main projection region, the hippocampus, as well as other regions with anatomical connections to the EC that are involved in maze learning. Since early brain damage is considered to be involved in certain neuropsychiatric diseases, this approach sought to model certain aspects of this etiopathogenesis.Bilateral neonatal lesions were induced on postnatal day 7 by microinjection of ibotenic acid (1.3 μg/0.2 μl phosphate-buffered saline (PBS)) into the EC. Naive and sham-lesioned rats served as controls. Rats were trained and tested on an eight-arm radial maze for allocentric and egocentric learning. Subsequently, gold-chloride staining and immunohistochemical staining for the microtubule-associated protein MAP-2 was used to assess myelination and dendritic density in the hippocampus, striatum and medial prefrontal cortex (mPFC) of these rats. Additionally, parvalbumin-expressing, presumably GABAergic interneurons, were evaluated in these regions.Performance in both the allocentric and the egocentric strategy was disturbed after neonatal EC lesion as shown by an increase of repeated arm entries, which indicates disturbed working memory. Histological evaluation revealed that the density of parvalbumin-immunopositive neurons and myelin sheaths was reduced in the hippocampus but not in the striatum and mPFC in neonatally lesioned rats. Density of MAP-2 staining did not differ between groups in all regions tested.Since structural alterations were only found in the EC and hippocampus our findings support their eminent role in working memory and show that no functional restoration occurs after neonatal lesions.

Effects of glucocorticoids on age-related impairments of hippocampal structure and function in mice.

Effects of glucocorticoids (GCs) on maze-learning performances and hippocampal morphology were observed in male C57BL/6Cr mice. Correlations between aging, GCs and maze-learning performances were also studied. (2) Eight-arm radial maze was used in maze-learning tests. Learning performance was assessed by the parameters of time of getting all the bait, number of reentry errors into the already-entered arm with bait, and number of missed entries into an unbaited arm. Brain sections, 8 mum thick, were Nissl-stained with cresyl violet or stained immunocytochemically with antibodies against neurofilaments. (3) With aging, normal pyramidal cells decreased gradually in amount, and degenerating cells increased since the age of 18 months, accompanied with the maze-learning deficit. Here we have suggested that these changes were associated with the age-related deficits in adaptation tolerance of neurons to stress. In addition, the age-related deficits in plasticity of hippocampal neurons to GCs in young mice (3 months of age) resulted in an increase in plasma corticosterone (CORT) concentrations, degeneration of hippocampal pyramidal cells, as well as maze-learning deficits. (4) In conclusion, our data indicated that CORT caused the degeneration of hippocampal pyramidal cells and the impairment of memory.

Profiling psychomotor and cognitive aging in four-way cross mice

In part due to their genetic uniformity and stable characteristics, inbred rodents or their F1 progeny are frequently used to study brain aging. However, it is recognized that focus on a single genotype could lead to generalizations about brain aging that might not apply to the species as a whole, or to the human population. As a potential alternative to uniform genotypes, genetically heterogeneous (HET) mice, produced by a four-way cross, were tested in the current study to determine if they exhibit age-related declines in cognitive and psychomotor function similar to other rodent models of brain aging. Young (4months) and older (23months) CB6F1 × C3D2F1 mice were administered a variety of tests for cognitive, psychomotor, and sensory/reflexive capacities. Spontaneous locomotion, rearing, and ability to turn in an alley all decreased with age, as did behavioral measures sensitive to muscle strength, balance, and motor coordination. Although no effect of age was found for either startle response amplitude or reaction time to shock stimuli, the old mice reacted with less force to low intensity auditory stimuli. When tested on a spatial swim maze task, the old mice learned less efficiently, exhibited poorer retention after a 66-h delay, and demonstrated greater difficulty learning a new spatial location. In addition, the older mice were less able to learn the platform location when it was identified by a local visual cue. Because there was a significant correlation between spatial and cued discrimination performance in the old mice, it is possible that age-related spatial maze learning deficits could involve visual or motor impairments. Variation among individuals increased with age for most tests of psychomotor function, as well as for spatial swim performance, suggesting that four-way cross mice may be appropriate models of individualized brain aging. However, the analysis of spatial maze learning deficits in older CB6F1 × C3D2F1 mice may have limited applicability in the study of brain aging, because of a confounding with visually cued performance deficits.

Protein tyrosine phosphatase alpha (PTPα) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety

Receptor PTPα is a widely expressed transmembrane enzyme enriched in brain. PTPα knockout (PTPα −/−) mice are viable and display no gross abnormalities. Brain and embryo derived fibroblast src and fyn activity is reduced to <50% in PTPα −/− mice. These protein kinases are implicated in multiple aspects of neuronal development and function. However, the effect of the loss of function of the PTPα gene on behavior has yet to be investigated. PTPα −/− and WT mice were tested for anxiety, swimming ability, spatial learning, cued learning, locomotor activity, and novel object recognition (NOR). PTPα −/− mice were indistinguishable from WT in swimming ability, cued learning and novel object recognition. Knockout mice showed decreased anxiety without an increase in head dips and stretch-attend movements. During Morris water maze (MWM) learning, PTPα −/− mice had increased latencies to reach the goal compared to WT on acquisition, but no memory deficit on probe trials. On reversal learning, knockout mice showed no significant effects. PTPα −/− mice showed decreased exploratory locomotor activity, but responded normally to a challenge dose of d-methamphetamine. The data suggest that PTPα serves a regulatory function in learning and other forms of neuroplasticity.

Neurobehavioural deficits following postnatal iron overload: II Instrumental learning performance.

Three experiments reporting instrumental learning deficits following postnatal iron overload in rodents are described. In Experiment I, NMRI mice were given different doses of iron succinate (0.0, 3.7 or 37.0 mg Fe2+/kg b.w., p.o.) on different postnatal days (PD). In the PD 10–12 group, there were marked disruptions of radial arm maze learning performance in the 37.0 mg Fe2+/kg dose grup, and to a lesser extent in the 3.7 mg Fe2+/kg dose group. In Experiment II, newborn NMRI mice were administered Fe2+ (7.5 mg/kg, b.w.) at either PD 3–5, PD 10–12, or PD 19–21, or vehicle (saline). Marked deficits in radial arm maze performance were obtained in the mice administered iron during PD 10–12, and to a much lesser extent PD 3–5. In Experiments III and IV, rats were administered two different dose regimes: (i)Experiment III: 2.5, 7.5, 15.0 or 30 mg Fe2+/kg b.w., p.o., at PD 10–12, or (ii)Experiment IV: 2.5, 7.5 or 22.5 mg Fe2+/kg b.w., p.o., at PD 10–12, followed 3 months later by behavioural testing. All four dose groups in Experiment III demonstrated marked deficits in radial arm maze learning and retention performance but only the 30 mg/kg group showed hypoactivity. In Experiment IV, deficits in inhibitory conditioning were obtained in the 7.5 and 15.0, but not the 2.5, mg/kg dose groups. The analysis of enzymes involved in oxidative stress indicated that: (1) Formation of thiobarbiturate acid reactive species (TBARS) concentration was elevated in the substantia nigra by both the 7.5 and 15.0 mg Fe2+/kg doses whereas in the striatum there was a decrease. (2) Superoxide dismutase activity was decreased in a dose-related fashion in the substantia nigra but was elevated in the cerebellum. Iron-overload during the immediate postnatal period incorporating critical synaptogenesis seems detrimental for several aspects of functional and neurobiological development.

Ameliorative Effects of Azaindolizinone Derivative ZSET845 on Scopolamine-Induced Deficits in Passive Avoidance and Radial-Arm Maze Learning in the Rat

Effects of ZSET845 (3,3-dibenzylimidazo[1,2-a]pyridin-2-(3H)-one), a newly synthesized cognitive enhancer, and donepezil and tacrine on the scopolamine-induced cognitive deficits in rats were examined in passive avoidance and radial-arm maze tasks. ZSET845 (0.01 mg /kg) showed a greater ameliorative effect than donepezil (0.1 mg/kg) or tacrine (1 mg/kg) in the passive avoidance task. In the radial-arm maze task, ZSET845 (0.1 mg /kg) also showed a greater effect than donepezil (10 mg /kg) or tacrine (10 mg/kg). ZSET845 induced an increase in the choline acetyltransferase (ChAT) activity in the hippocampus, suggesting that the ameliorative effects of ZSET845 are related to the increase in the ChAT activity in the hippocampus.

Role of maternal biochemistry in fetal brain development: effect of maternal thyroidectomy on behaviour and biogenic amine metabolism in rat progeny.

Few studies have addressed the role of biochemicals of maternal origin on fetal neurodevelopment and behavioural outcome. Thyroid deficiency in the thyroidectomized pregnant rat provides an excellent model to study fetal effects of maternal chemistry, as this condition is known to be associated with deficits in motor and cognitive behaviour in human offspring. Based on evidence that thyroid hormone of maternal origin may be an important determinant in regulating these behaviours, we assessed neurobehaviours and regional brain biogenic amine levels in offspring of rats thyroidectomized (Tx) prior to conception. Cross-fostering techniques were used to isolate fetal effects of maternal thyroid deficiency from possible neonatal effects during nursing by thyroid-deficient dams. The progeny of Tx dams showed significant deficits in maze learning, were less cautious in emotionality testing, and were more active in open-field exploration. Tx females appeared to be more vulnerable to the effects on learning. Learning in Tx males was only slightly impaired. Serotonin and dopamine metabolism was also affected in a brain region-specific manner in Tx progeny. Levels of 5-HIAA were reduced in the olfactory tubercle and cortex. HVA levels were lower in olfactory tubercle, but were elevated in the hippocampus. As these neurotransmitters play a functional role in activity, mood and learning, the findings may be pertinent to the observed behavioural impairments. The results are consistent with the hypothesis that an adequate in utero thyroid hormone environment may be essential for early fetal neurodevelopment even if the fetus is euthyroid.

Maze learning and motor activity deficits in adult mice induced by iron exposure during a critical postnatal period

Newborn mice were administered Fe 2+ (iron succinate: 7.5 mg/kg, b.wt) on either Days 3–5, 10–12 or 19–21, or vehicle (saline) at the same times, postnatally. Spontaneous motor behaviour and radial arm maze learning were tested at the age of 3 months. It was found that mice treated with Fe 2+ during postnatal Days 10–12 were markedly hypokinetic during the 1st 20-min test period and hyperkinetic during the 3rd and final 20-min test period. These mice showed an almost complete lack of habituation of spontaneous motor activity parameters to the test chambers. In the radial arm maze, the Days 10–12 treatment group evidenced significantly both more errors in arm choices and longer latencies to acquire all eight pellets; these mice showed also a severe trial-to-trial retention deficit as indexed by retention quotients. These behavioural deficits were observed also in animals treated with Fe 2+ during postnatal Days 3–5, but the effects were less pronounced, indicating the higher susceptibility of the brain for Fe 2+-induced damage during Days 10–12 postpartum. Treatment with Fe 2+ on Days 19–21 did not induce behavioural alterations in comparison with its respective control (vehicle) group. Analysis of total brain iron content indicated significantly more iron (μg/g) accumulation in the basal ganglia, but not frontal cortex, of mice from the Days 3–5 and 10–12 Fe 2+ (7.5 mg/kg) treatment groups. The contribution of iron overload during the immediate postnatal to later functional deficits seems to implicate symptoms of Parkinsonism but the kinetics of iron uptake to the brain and its regional distribution at this critical period of development awaits elucidation.