Maze Learning Research Articles

Improvements in concentration, working memory and sustained attention following consumption of a natural citicoline–caffeine beverage

This study examined the neurocognitive and electrophysiological effects of a citicoline–caffeine-based beverage in 60 healthy adult participants enrolled in a randomized, double-blind, placebo-controlled trial. Measures of electrical brain activity using electroencephalogram (EEG) and neuropsychological measures examining attention, concentration and reaction time were administered. Compared to placebo, participants receiving the citicoline–caffeine beverage exhibited significantly faster maze learning times and reaction times on a continuous performance test, fewer errors in a go/no-go task and better accuracy on a measure of information processing speed. EEG results examining P450 event-related potentials revealed that participants receiving the citicoline–caffeine beverage exhibited higher P450 amplitudes than controls, suggesting an increase in sustained attention. Overall, these findings suggest that the beverage significantly improved sustained attention, cognitive effort and reaction times in healthy adults. Evidence of improved P450 amplitude indicates a general improvement in the ability to accommodate new and relevant information within working memory and overall enhanced brain activation.

SLEEP-RELATED FEATURES AND PERFORMANCE ON A COMPUTERIZED COGNITIVE BATTERY: THE MAYO CLINIC STUDY OF AGING

Several sleep disorders are associated with cognitive impairment and dementia. However, the association between sleep and cognitive function in phenotypically normal individuals in population-based samples has been inadequately characterized. We conducted a cross-sectional study derived from the population-based Mayo Clinic Study of Aging. Subject informants completed the Mayo Sleep Questionnaire, in which an affirmative response to a history of repeatedly “acting out dreams” represents probable REM sleep behavior disorder (pRBD), and the level of alertness was queried on a scale from 0 (poorly alert) to 10 (fully alert). Informants also rated the subject's degree of sleepiness using the Epworth Sleepiness Scale (ESS). The following Cogstate tests were administered: Detection (DET) - measuring simple reaction time, Identification (IDN) - measuring choice reaction time, One Card Learning (OCL) - measuring visual learning, One Back test (ONB) - measuring working memory and attention, and the Graded Maze Learning Test (GMLT) - measuring spatial working memory. Multivariate linear regression analyses were conducted to compute associations corrected for age, sex, education, depression, and obstructive sleep apnea. Among the 599 participants (median age 63.8, range 51-71, 59% male), those rated as more alert took less time to complete the 4 card tasks and the GMLT (p < 0.05) but accuracy measures were not affected. Having a higher sleepiness score was associated with a greater time to complete the IDN task (p<0.05). pRBD was not associated with performance on Cogstate measures in this age group. These findings suggest that alertness and daytime sleepiness are associated with cognitive performance in cognitively-normal individuals. Longitudinal analyses are needed to determine if these sleep related features are predictive of future cognitive decline in this age group. Study supported by: U01 AG06786, P50 Ag016574, K01 AG028573, K01 MH068351, R01 AR0305082, Harold Amos Medical Faculty Development Program (RWJ Foundation), Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program.

The effects of moderate alcohol concentrations on driving and cognitive performance during ascending and descending blood alcohol concentrations.

Alcohol has an adverse effect on driving performance; however, the effects of moderate doses on different aspects of the driving task are inconsistent and differ across the intoxication curve. This research aimed to investigate driving and cognitive performance asymmetries (acute tolerance and acute protracted error) accompanying the onset and recovery from moderate alcohol consumption. Sixty-one participants received a placebo, medium (target blood alcohol concentration [BAC] 0.05 mg/ml) or high (target BAC 0.08 mg/ml) dose of alcohol. Participants completed a simulated drive, cognitive tests and subjective rating scales five times over a 3.5 h period. When ascending and descending BACs (0.05 and 0.09 mg/ml) were compared participants' self-ratings of intoxication and willingness to drive showed acute tolerance. Acute protracted errors were observed for response speed, maze learning errors, time exceeding the speed limit and exaggerated steering responses to hazards. Participants' estimates of their level of intoxication were poorly related to their actual BAC levels (and hence degree of impairment), and various aspects of driving and cognitive performance worsened during descending BACs. This indicates that drivers are not good at judging their fitness to drive after drinking only moderate amounts of alcohol and suggests an important focus for public education regarding alcohol and driving.

Sex differences in learning and memory following short-term dietary restriction in the rat

IntroductionAcute or prolonged dietary restriction has been shown to have significant effects on learning and memory, and also on the food seeking behaviour in animals. AimThis study investigated whether or not there are sex differences in spatial learning and memory following short-term dietary restriction in the rat. MethodsTwo month-old male (n=24) and female (n=24) Sprague-Dawley rats were randomly assigned to either (1) male or female control (i.e. normal diet regimen); (2) male or female 40% dietary restriction for either 2hours (2h-DR) or 2 weeks (2 wks-DR) duration. Following the restriction paradigm (i.e. either 2h or 2 weeks), animals were weighed, and learning and memory was assessed daily for a total of 5 days by Morris Water Maze. ResultsDietary restriction for 2h provoked high speed swimming in female rats compared to controls. However the females performance in water maze was inferior to the control animals. Two weeks after 40% DR resulted in reduction of male's body weight by 20% compared to their control group. However, both males and females showed difficulties in water maze learning and memory test after the 2 weeks 40% DR. The animals swam longer distance and took longer time to reach the platform when compared to their age-matched controls. ConclusionIn fully developed brain, adult animal's cognitive performance is shown to be affected by acute and prolonged stress in the form of food restriction. Interestingly, the impact of this stress was different according to the sex of the animals. In female rats, dietary restriction has a negative effect on learning and memory after 2h and 2 weeks intervals. In male rats, 2h of DR has a positive effect on learning and memory; however this effect is not maintained and by 2 weeks there is a negative effect similar to that seen in female animals.

The impact of postnatal iron administration on memory and levels of serotonin and gaba in hippocampus of adult male rats

Objectives Excess iron in the brain has been implicated in the pathogenesis of neurodegenerative disorders. The present study was designed to investigate the effect of postnatal iron administration on memory, hippocampal serotonin (5HT) and γ-aminobutyric acid (GABA) levels and oxidative stress markers in adult male rats. Methods Thirty pups at age of 7 days weighting 50-52 grams were randomly divided equally into two groups : control (normal pups) and iron overload group treated with ferrous sulphate (3 mg/kg/day,intraperitoneally) for consecutive 21 days. Spatial and avoidance memories were tested using radial arm maze and passive avoidance tests. Hippocamapl levels of 5HT, GABA, serum total antioxidant capacity (TAC), and total peroxide (TP) were determined. Histopathological studies using H&E and Prussian blue stains were done. Results Iron overloaded rats showed impaired working memory in radial arm maze and impaired avoidance learning in passive avoidance test compared to the controls. Iron overload induced a significant decrease in the hippocampal levels of both 5HT and GABA. Levels of TAC were decreased and total peroxide was increased in iron overload group as compared to control group. Moreover, in contrast to the control group, positive iron depositions in the form of blue particles were detected in different areas of the hippocampus of iron overload group. Conclusion postnatal iron administration resulted in memory impairment possibly through alternation in hippocampal 5HT and GABA levels and oxidative stress

Effect of Temperature and Maze Learning on Simple Muscular Activity of White Rats

The paper discusses the effects of temperature variation on the simple muscular activity of white rats. Two groups of white rats were selected. Members of one group were trained to run a proteus maze prior to the experiment. Muscular activity of both the groups was compared when subjected to temperature variation. The results show a superiority of trained rats over the others in respect of their muscular activity.

Effects of intrahippocampal GABAB receptor antagonist treatment on the behavioral long-term potentiation and Y-maze learning performance

GABAB receptor is present at pre- and post-synaptic sites and participates in many brain functions including cognition, reward and anxiety. Although a lot of research has shown that activation or blockade of GABAB receptor may produce different even opposing effects on long-term potentiation (LTP) and cognitive function, there is little information available concerning the effect of GABAB receptor on behavioral LTP, a learning-induced LTP model. Herein, we firstly examined the effects of 2-OH saclofen, a GABAB receptor antagonist, on the induction of behavioral LTP and Y-maze learning performance. In addition, GABAB receptor has been reported to be present on cholinergic terminals and to regulate the ACh release. Therefore, we also investigated the effect of 2-OH saclofen on the impairments in behavioral LTP and cognitive function induced by scopolamine, an acetylcholine receptor antagonist. We found that intrahippocampal application of 2-OH saclofen could significantly enhance the population spike (PS) amplitude with a dose–response relationship, and 20μM 2-OH saclofen evidently facilitated the formation of behavioral LTP in the perforant pathway to the dentate gyrus (PP-DG) and led to an obvious improvement in maze learning performance. Furthermore, intrahippocampal 20μM 2-OH saclofen administration could markedly reverse the scopolamine-induced impairments in behavioral LTP and maze performance. Our data demonstrate that blockade of GABAB receptor displays a facilitatory role in the induction of behavioral LTP and maze learning task, and the antagonist of GABAB receptor seems to exert the potentially therapeutic value in the cognitive defect induced by cholinergic dysfunction.

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.

Rationality and Novelty of Instrumental Use in Neuropsychological Research Evaluations: Taking Infinity to Singularity

Background: Few studies address the rationality of utilization of instrumental tasking and maze learning in neuropsychological research evaluations; this is apparent from the literature search in biomedical databases with appropriate keywords yielding nil hits for rationality of such usage. Furthermore, how could such rationality be interpreted and used for scientific benefits of the researcher? What is the scope of applicability of such research in neuropsychology to patient care? This systematic review addresses such key issues and focuses on ways to appraise such research articles using rationality as the key criterion in such appraisals and interpretations. Objectives & scope: The systematic review focuses on deciphering the rationality and novelty of instrumental usage in neuropsychological research and patient care, from a thorough literature search in a seven month period from January 2013 to July 2013 in the medline database. The review was a pilot initiative to give a recommended harmonized validated checklist to best search, select, appraise, and apply such research for two purposes - psychological research and patient care. Methods: To this end, this meta-analysis uses medline index and pubmed database to establish a list of the pre-clinical and clinical research articles using instrumental tasks and maze learning in the last seven months. Then, quantitative analysis of these included articles are performed using MS Excel 2013 with Daniel XL-add in. Qualitative analysis of the selected articles has been performed using a pilot checklist validation, provided in this article; the same can be used for appraising and applying such research to the benefits of researcher and patients. The last seven months has been chosen appropriately since this is a pilot attempt to fulfilling the objective that it intends to do so. Conclusions & limitations: This meta-analysis will be useful in giving recommendation about how to select and critically appraise and interpret such neuropsychological evaluations in research using maze and neurological instrumentation. The study has not considered in-depth the methodologies of each individual research study. Although novelty was one of the objectives, it could not be met with appropriately due to the diverse nature of methodologies followed in each of the included research articles. Nonetheless, this pilot meta-analysis must encourage more explorations in this research area from a broader perspective in the future.

Microdosing of scopolamine as a “cognitive stress test”: Rationale and test of a very low dose in an at-risk cohort of older adults

BackgroundAbnormal β-amyloid (Aβ) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal “microdose” of scopolamine for the development of a “cognitive stress test.” MethodsHealthy older adults (n = 26, aged 55–75 years) with two risk factors for AD, but with low cortical Aβ burden, completed the Groton Maze Learning Test (GMLT) at baseline and then received scopolamine (0.20 mg subcutaneously). Participants were reassessed at 1, 3, 5, 7, and 8 hours postinjection. ResultsThere were significant differences, of a moderate magnitude, in performance between baseline and 3 hours postinjection for total errors, rule break errors, and the GMLT composite (d ≈ 0.50) that were all unrelated to body mass. ConclusionsA very low dose of scopolamine leads to reliable cognitive impairment at 3 hours postdose (Tmax) and full cognitive recovery within 5 hours, supporting its use as a prognostic test paradigm to identify individuals with potential preclinical AD. This paradigm is being implemented in a larger cohort of healthy adults, with high or low Aβ, to identify pharmacodynamic differences between groups.

Prospective associations between dietary patterns and cognitive performance during adolescence

The aim of the study was to investigate prospective associations between dietary patterns and cognitive performance during adolescence. Participants were sourced from the Western Australian Pregnancy Cohort (Raine) Study that includes 2868 children born between 1989 and 1992 in Perth, Western Australia. When the children were 17years old (2006-2009), cognitive performance was assessed using a computerized cognitive battery of tests (CogState) that included six tasks. Using a food frequency questionnaire administered when the children were 14years old (2003-2006), 'Healthy' and 'Western' dietary patterns were identified by factor analysis. Associations between dietary patterns at 14years of age and cognitive performance at 17years of age were assessed prospectively using multivariate regression models. Dietary and cognitive performance data were available for 602 participants. Following adjustment for the 'Healthy' dietary pattern, total energy intake, maternal education, family income, father's presence in the family, family functioning and gender, we found that a longer reaction time in the detection task (β=.016; 95% CI: 0.004; 0.028; p=.009) and a higher number of total errors in the Groton Maze Learning Test - delayed recall task (β=.060; 95% CI: 0.006; 0.114; p=.029) were significantly associated with higher scores on the 'Western' dietary pattern. The 'Western' dietary pattern was characterized by high intakes of take-away food, red and processed meat, soft drink, fried and refined food. We also found that within the dietary patterns, high intake of fried potato, crisps and red meat had negative associations, while increased fruit and leafy green vegetable intake had positive associations with some aspects of cognitive performance. Higher dietary intake of the 'Western' dietary pattern at age 14 is associated with diminished cognitive performance 3years later, at 17years.

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

Apolipoprotein E4 (apoE4) allele is the major genetic risk factor for sporadic Alzheimer disease (AD) due to the higher prevalence and earlier onset of AD in apoE4 carriers. Accumulating data suggest that the interaction between the N- and the C-terminal domains in the protein may be the main pathologic feature of apoE4. To test this hypothesis, we used Arg-61 mice, a model of apoE4 domain interaction, by introducing the domain interaction feature of human apoE4 into native mouse apoE. We carried out hippocampus-dependent learning and memory tests and related cellular and molecular assays on 12- and 3-month-old Arg-61 and age-matched background C57BL/6J mice. Learning and memory task performance were impaired in Arg-61 mice at both old and young ages compared with C57BL/6J mice. Surprisingly, young Arg-61 mice had more mitotic doublecortin-positive cells in the subgranular zone; mRNA levels of brain-derived neurotrophic factor (BDNF) and TrkB were also higher in 3-month-old Arg-61 hippocampus compared with C57BL/6J mice. These early-age neurotrophic and neurogenic (proliferative) effects in the Arg-61 mouse may be an inadequate compensatory but eventually detrimental attempt by the system to "repair" itself. This is supported by the higher cleaved caspase-3 levels in the young animals that not only persisted, but increased in old age, and the lower levels of doublecortin at old age in the hippocampus of Arg-61 mice. These results are consistent with human apoE4-dependent cognitive and neuro-pathologic changes, supporting the principal role of domain interaction in the pathologic effect of apoE4. Domain interaction is, therefore, a viable therapeutic/prophylactic target for cognitive impairment and AD in apoE4 subjects.

Lesions of the dorsomedial striatum delay spatial learning and render cue-based navigation inflexible in a water maze task in mice

The dorsal striatum is involved in cue-based navigation strategies and in the development of habits. It has been proposed that striatum-dependent cued navigation competes with hippocampus-dependent spatial navigation in some circumstances. We have previously shown that large lesions of the dorsal striatum, as well as impairment of corticostriatal synaptic plasticity in transgenic mice, can enhance spatial learning in a water maze task, presumably by the disruption of competitive interference. However, the dorsal striatum is not a homogeneous structure; both anatomical considerations and experimental studies in various paradigms show that dorsomedial and dorsolateral striatum are functionally distinct, although there is no precise anatomical or neurochemical boundary between them. Here we investigated the effect of restricted excitotoxic lesions of dorsomedial striatum (DMS) on cued and spatial water maze learning. We find that dorsomedial striatal lesions delay spatial learning but permit cued learning. After cued learning, lesioned animals showed inflexible search, resulting in repeated visits to the escape platform-associated cue. These results support a role for the DMS in behavioral flexibility rather than in cue-based navigation.

Adolescent binge ethanol treatment alters adult brain regional volumes, cortical extracellular matrix protein and behavioral flexibility

Adolescents binge drink more than any other age group, increasing risk of disrupting the development of the frontal cortex. We hypothesized that adolescent binge drinking would lead to persistent alterations in adulthood. In this study, we modeled adolescent weekend underage binge-drinking, using adolescent mice (post-natal days [P] 28–37). The adolescent intermittent binge ethanol (AIE) treatment includes 6 binge intragastric doses of ethanol in an intermittent pattern across adolescence. Assessments were conducted in adulthood following extended abstinence to determine if there were persistent changes in adults. Reversal learning, open field and other behavioral assessments as well as brain structure using magnetic imaging and immunohistochemistry were determined. We found that AIE did not impact adult Barnes Maze learning. However, AIE did cause reversal learning deficits in adults. AIE also caused structural changes in the adult brain. AIE was associated with adulthood volume enlargements in specific brain regions without changes in total brain volume. Enlarged regions included the orbitofrontal cortex (OFC, 4%), cerebellum (4.5%), thalamus (2%), internal capsule (10%) and genu of the corpus callosum (7%). The enlarged OFC volume in adults after AIE is consistent with previous imaging studies in human adolescents. AIE treatment was associated with significant increases in the expression of several extracellular matrix (ECM) proteins in the adult OFC including WFA (55%), Brevican (32%), Neurocan (105%), Tenacin-C (25%), and HABP (5%). These findings are consistent with AIE causing persistent changes in brain structure that could contribute to a lack of behavioral flexibility.

Reliability and Validity of the CogState Battery Chinese Language Version in Schizophrenia

BackgroundCognitive impairment in patients with schizophrenia is a core symptom of this disease. The computerized CogState Battery (CSB) has been used to detect seven of the most common cognitive domains in schizophrenia. The aim of this study was to examine the reliability and validity of the Chinese version of the CSB (CSB-C), in Chinese patients with schizophrenia.Methodology/Principal FindingsSixty Chinese patients with schizophrenia and 58 age, sex, and education matched healthy controls were enrolled. All subjects completed the CSB-C and the Repeated Battery for the Assessment of Neuropsychological Status (RBANS). To examine the test-retest reliability of CSB-C, we tested 33 healthy controls twice, at a one month interval. The Cronbach α value of CSB-C in patients was 0.81. The test-retest correlation coefficients of the Two Back Task, Gronton Maze Learning Task, Social Emotional Cognition Task, and Continuous Paired Association Learning Task were between 0.39 and 0.62 (p<0.01) in healthy controls. The composite scores and all subscores for the CSB-C in patients were significantly (p<0.01) lower than those of healthy controls. Furthermore, composite scores for patients on the RBANS were also significantly lower than those of healthy controls. Interestingly, there was a positive correlation (r = 0.544, p<0.001) between the composite scores on CSB-C and RBANS for patients. Additionally, in the attention and memory cognitive domains, corresponding subsets from the two batteries correlated significantly (p<0.05). Moreover, factor analysis showed a two-factor model, consisting of speed, memory and reasoning.Conclusions/SignificanceThe CSB-C shows good reliability and validity in measuring the broad cognitive domains of schizophrenia in affected Chinese patients. Therefore, the CSB-C can be used as a cognitive battery, to assess the therapeutic effects of potential cognitive-enhancing agents in this cohort.

CogState computerized testing is associated with amyloid and FDG-PET: Implications for secondary preventive trials

Inexpensive and non-invasive screening tools of significant brain amyloidosis and neurodegeneration are needed for secondary preventive Alzheimer's disease (AD) trials enrolling cognitively normal (CN) individuals. We examined the association between performance on the CogState computerized neuropsychological battery and MR, FDG-PET, and PiB-PET. We studied 153 Mayo Clinic Study of Aging participants who were cognitively normal (CN) (aged 51–70) and had undergone MRI (n=152), FDG PET (n=120), and/or PiB PET (n=121) and the CogState computerized assessment within a 5 month period. The following CogState tests were administered: Detection (DET) - measuring simple reaction time, Identification (IDN) - measuring choice reaction time, One Card Learning (OCL) - measuring visual learning, One Back test (ONB) - measuring working memory and attention, and the Groton Maze Learning Test (GMLT) - measuring spatial working memory. Linear regression was used to assess the relationship between each test (average reaction time for all tests and also accuracy on OCL and ONB) and continuous measures of PiB PET SUVR, FDG PET metabolism in an “AD signature region”, and hippocampal atrophy, controlling for age. A slower reaction time for DET (p=0.005), IDN (p=0.02), and OCB (p=0.02) was associated with lower FDG PET metabolism. A faster response time (i.e., more moves per second) on the GMLT (p=0.009) was the only test associated with larger hippocampal volumes. While elevated amyloid (PIB SUVR>1.5) was uncommon in this age range, an intriguing finding that needs to be borne out by additional data was that high amyloid trended towards an association with slower reaction times for ONB (p=0.08), OCL (p=0.05), and GMLT (p=0.002). There were no associations between accuracy on the OCL or ONB and neuroimaging measures. These results suggest that the CogState computerized assessment may be a useful indicator of neurodegenerative pathology among young CN individuals. While additional data are needed, especially among persons with higher amyloid burden, there were also trends between slower reaction times on memory-related measures and higher amyloid. CogState is brief (∼15 minutes), can be administered in the home without the need for an in-person visit, and may be a useful screening tool for enhancing clinical trial enrollment of persons harboring preclinical AD biomarkers.

Increased hippocampal cell density and enhanced spatial memory in the valproic acid rat model of autism

Autism is characterized by behavioral impairments in three main domains: social interaction; language, communication and imaginative play; and the range of interests and activities. However, neuronal processing studies have suggested that hyper-perception, hyper-attention, and enhanced memory, which may lie at the heart of most autistic symptoms. Pregnant Wistar rats were administered by either Valproic Acid (VPA, 500mg/kg) or Phosphate Buffer Saline (PBS) during fetal neural tube development on embryonic day 12.5. All offspring were subjected to various tests. The present study examined social interaction, repetitive behaviors, nociception and tactile threshold, anxiety as well as spatial memory. Histological analyses of cells in five regions of the hippocampus were done to determine neuronal density in both groups. A single intra-peritoneal injection of VPA to pregnant rats produced severe autistic-like symptoms in the offspring. The results showed significant behavioral impairments such as a lower tendency to initiate social interactions, enhanced stereotyped, repetitive behaviors, increased nociception threshold and anxiety at postnatal day (PND) 30 and PND 60. The Morris water maze learning paradigm revealed enhanced spatial memory at PND 60. Furthermore, histological analysis showed that the neuronal density in five separate regions of hippocampus (CA1, CA2, CA3, Dentate gyrus and Subiculum) were increased at PND 67. This work suggests that early embryonic exposure to VPA in rats provides a good model for several specific aspects of autism and should help to continue to explore pathophysiological and neuroanatomical hypotheses. This study provides further evidence to support the notion that spatial memory and hippocampal cell density are increased in this animal model of autism.

Heterozygosity for nuclear factor one x affects hippocampal-dependent behaviour in mice.

Identification of the genes that regulate the development and subsequent functioning of the hippocampus is pivotal to understanding the role of this cortical structure in learning and memory. One group of genes that has been shown to be critical for the early development of the hippocampus is the Nuclear factor one (Nfi) family, which encodes four site-specific transcription factors, NFIA, NFIB, NFIC and NFIX. In mice lacking Nfia, Nfib or Nfix, aspects of early hippocampal development, including neurogenesis within the dentate gyrus, are delayed. However, due to the perinatal lethality of these mice, it is not clear whether this hippocampal phenotype persists to adulthood and affects hippocampal-dependent behaviour. To address this we examined the hippocampal phenotype of mice heterozygous for Nfix (Nfix +/−), which survive to adulthood. We found that Nfix +/− mice had reduced expression of NFIX throughout the brain, including the hippocampus, and that early hippocampal development in these mice was disrupted, producing a phenotype intermediate to that of wild-type mice and Nfix−/− mice. The abnormal hippocampal morphology of Nfix +/− mice persisted to adulthood, and these mice displayed a specific performance deficit in the Morris water maze learning and memory task. These findings demonstrate that the level of Nfix expression during development and within the adult is essential for the function of the hippocampus during learning and memory.

Distinct long-term neurocognitive outcomes after equipotent sevoflurane or isoflurane anaesthesia in immature rats

Many anaesthetics when given to young animals cause cell death and learning deficits that persist until much later in life. Recent attempts to compare the relative safety or toxicity between different agents have not adequately controlled for the relative dose of anaesthetic given, thereby making direct comparisons difficult. Isoflurane or sevoflurane were given at 1 minimum alveolar concentration (MAC) for 4 h to postnatal day 7 (P7) rat pups. Beginning at P75 these animals underwent fear conditioning and at P83 Morris water maze testing to assess working memory, short-term memory and early long-term memory using delays of 1 min, 1 h, and 4 h. No difference between groups was seen in fear conditioning experiments. Morris water maze learning was equivalent between groups, and no difference was seen in working memory. Sevoflurane-treated animals had a deficit in early long-term memory, and isoflurane-treated animals had a deficit in both short-term and early long-term memory. Both isoflurane and sevoflurane delivered at 1 MAC for 4 h to immature rats caused a deficit in long-term memory. Isoflurane also caused a deficit in short-term memory. Isoflurane might be more detrimental than sevoflurane in very young animals.

A randomized, double-blind, placebo-controlled crossover study of α4β2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder

Stimulation of nicotinic cholinergic systems has been shown to alleviate ADHD symptoms and to improve cognitive performance. AZD1446 is a selective α4β2* nicotinic acetylcholine receptor agonist with potential effect on the symptoms of ADHD. The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AZD1446 in adults with ADHD treated for 2 weeks. This was a randomized, double-blind, placebo-controlled crossover trial. Participants were 79 adults with ADHD, grouped according to their use of nicotine-containing products. Nicotine non-users received placebo and two of three AZD1446 treatment regimens (80 mg tid, 80 mg qd, 10 mg tid). Nicotine users received placebo, AZD1446 80 mg tid and 80 mg qd. Efficacy measures included the Conners' Adult ADHD Rating Scale and cognitive measures of immediate and delayed verbal episodic memory, learning, attention, working memory, executive functioning, and spatial problem solving (CogState computerized test battery). There was no significant effect of AZD1446 on any of the clinical scores irrespective of dose, schedule, or concomitant use of nicotine products. A statistically significant improvement was seen on the Groton Maze Learning Task, a measure of executive functioning, in nicotine non-users after treatment with AZD1446 80 mg qd. AZD1446 was well tolerated, but did not significantly improve ADHD symptoms after 2 weeks of treatment compared to placebo. While the present study does not support the therapeutic utility of AZD1446 in ADHD, its potential pro-cognitive effects remain to be explored in other neuropsychiatric disorders.