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The primary function of a brain is to produce adaptive behavioral choices by selecting the right action at the right time. In humans, attention determines action selection as well as memory formation, whereas memories also guide which external stimuli should be attended to (Chun and Turk-Browne, 2007). The complex codependence of attention, memory, and action selection makes approaching the neurobiological basis of these interactions difficult in higher animals. Therefore, a successful reductionist approach is to turn to simpler systems for unraveling such complex biological problems. In a constantly changing environment, even simple animals have evolved attention-like processes to effectively filter incoming sensory stimuli. These processes can be studied in the fruit fly, Drosophila melanogaster, by a variety of behavioral and electrophysiological techniques. Recent work has shown that mutations affecting olfactory memory formation in Drosophila also produce distinct defects in visual attention-like behavior (van Swinderen, 2007; van Swinderen et al., 2009). In this study, we extend those results to describe visual attention-like defects in the Drosophila memory consolidation mutant radish(1). In both behavioral and brain-recording assays, radish mutant flies consistently displayed responses characteristic of a reduced attention span, with more frequent perceptual alternations and more random behavior compared with wild-type flies. Some attention-like defects were successfully rescued by administering a drug commonly used to treat attention-deficit hyperactivity disorder in humans, methylphenidate. Our results suggest that a balance between persistence and flexibility is crucial for adaptive action selection in flies and that this balance requires radish gene function.

Gaboxadol is a selective extrasynaptic GABA(A) receptor agonist previously in development for the treatment of insomnia. Due to its short half-life (1.5-2 h) it is expected to be free from residual effects the next morning. The present study assessed the residual effects of evening and middle-of-the-night administration of 15 mg of gaboxadol on cognitive, psychomotor and driving performance. Twenty-eight healthy volunteers entered the study with 25 (12 women; mean age 31.4 years) completing a double-blind, placebo-controlled, active-referenced five-way cross-over study. Each treatment night subjects ingested one capsule at 23:00 hours and one at 04:00 hours. Treatments were placebo at both times, 15 mg gaboxadol or 7.5 mg zopiclone followed by placebo, and placebo followed by 15 mg gaboxadol or 10 mg zolpidem. Effects on cognition and psychomotor performance were assessed between 07:30 and 08:30 hours and on driving between 09:00 and 10:00 hours. Driving, as measured by standard deviation of lateral position in an on-the-road driving test, was almost significantly (P < 0.07) impaired after evening administration of gaboxadol for the all-subjects-completed set (n = 25) but significantly (P < 0.05) in the full analysis set (n = 28). Effects of all other active treatments on driving were significant. Evening administration of gaboxadol had minor effects on divided attention only, whereas middle-of-the-night administration impaired performance significantly in all tests except memory. Zolpidem and zopiclone impaired performance significantly in every test except tracking after zopiclone; 15 mg of gaboxadol can produce minor residual effects on driving after evening administration. Administration later at night is associated with moderately impairing residual effects on driving and psychomotor performance but not on memory.

Ketamine-acepromazine-xylazine (KAX) has long been a popular combination of injectable anesthetics for use in laboratory rodents. These drugs are compounded extemporaneously at research facilities because a commercial mixture is not available. This study was designed to determine an appropriate period of use for this mixture by examining its safety, stability, and efficacy at 30-d intervals over an aging period of 270 d. For as long as 270 d after compounding, most of the data collected (chemical stability, sterility, pH, particulate formation, times to loss of righting reflex in injected mice and rats, and histopathology from these animals) supported the finding that the component drugs do not change or degrade. However, mice and rats did show significant differences in anesthetic responses after injection with KAX mixtures of different ages. In light of these findings, we suggest that KAX remains safe, stable, and efficacious for at least 180 d after mixing, and that 180 d constitutes an appropriate period of use for this drug combination when stored in a dark, room-temperature environment.

In many insects, mate finding is mediated by volatile sex pheromones, but evidence for this phenomenon in triatomines (Heteroptera: Reduviidae) is still fragmentary. Recently, it was shown that metasternal glands (MGs) are involved in producing signals related to the sexual communication of Triatoma infestans and Rhodnius prolixus. Based on this, we tested whether MG volatiles could be involved in the sexual communication of Triatoma brasiliensis. Odor-mediated orientation responses were studied by using a T-tube olfactometer. These tests showed that males exhibit positive anemotaxis when confronted with adult odor-laden air currents. Moreover, females that had their metasternal glands occluded did not elicit significant orientation by males. Compounds produced by the MGs of T. brasiliensis females were identified by means of SPME, GC-FID, and GC-MS, with achiral and chiral columns. All substances identified were ketones and alcohols, and similar compound profiles were found in the secretions produced by both sexes. The most abundant compounds identified were 3-pentanone, followed by (4R)-methyl-1-heptanol, 3-pentanol, and (2S)-methyl-1-butanol. In addition, GC-EAD recordings showed that the antennae of males responded to several of the main components of female MG secretions. Our results showed that compounds produced by the MGs of T. brasiliensis females are involved in the sexual communication of this species.

The present study systematically investigated the effects of agmatine administered i.p. in several commonly used behavioral tasks. In Experiment 1, pre-test treatment of agmatine (1 and 40 mg/kg) appeared to improve animals' performance in the water maze probe test conducted 24 h, but not 120 s, after training, when the effect was evaluated within subjects. In Experiment 2, pre-test agmatine treatment (40 mg/kg) did not affect animals' performance in the open field, and the place navigation, probe tests (1-4 and 6), reversal test and cued navigation in the water maze, but significantly facilitated performance in probe 5 which was conducted 96 h after training. In Experiment 3, rats with pre-test agmatine treatment (40 mg/kg) were less anxious relative to the controls, with no performance changes in the open field. In the water maze task, post-training agmatine treatment (40 mg/kg) did not affect place and cued navigation, but significantly improved animals' performance in the probe test conducted 24 h after training and the reversal test. In the working memory version of the task, agmatine treated rats took significantly less time and generated markedly shorter path length to reach the platform at the 180 s, but not 30 s, delay relative to the controls. In the object recognition task, rats with pre-test agmatine treatment (40 mg/kg) spent significantly more time exploring displaced objects, but not novel object, as compared to the controls. In Experiment 4, pre-test agmatine treatment (40 mg/kg) had no effect on the task acquisition in the delayed non-match to position task in the T-maze, but significantly facilitated performance at the 600 s delay. These results suggest that the behavioral effects of agmatine are task- and delay-dependent, and agmatine facilitates memory particularly when the task difficulty is increased due to memory trace decay and/or greater interference.

Background and Purpose: Recent neuroimaging studies in narcolepsy discovered significant gray matter loss in the right prefrontal and frontomesial cortex, a critical region for executive processing. In the present study, event-related potential (ERP) low-resolution brain electromagnetic tomography (LORETA) was used to investigate cognition before and after modafinil as compared with placebo., Patients and Methods: In a double-blind, placebo-controlled cross-over design, 15 patients were treated with a 3-week fixed titration scheme of modafinil and placebo. The Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT) and auditory ERPs (odd-ball paradigm) were obtained before and after the 3 weeks of therapy. Latencies, amplitudes and LORETA sources were determined for standard (N1 and P2) and target (N2 and P300) ERP components., Results: The ESS score improved significantly from 15.4 (+/- 4.0) under placebo to 10.2 (+/- 4.1) under 400mg modafinil (p=0.004). In the MWT, latency to sleep increased nonsignificantly after modafinil treatment (11.9+/-6.9 versus 13.3+/-7.1 min). In the ERP, N2 and P300 latencies were shortened significantly. While ERP amplitudes showed only minor changes, LORETA revealed increased source strengths: for N1 in the left auditory cortex and for P300 in the medial and right dorsolateral prefrontal cortex., Conclusion: LORETA revealed that modafinil improved information processing speed and increased energetic resources in prefrontal cortical regions, which is in agreement with other neuroimaging studies.

Aims: This study investigated the role of the cannabinoid CB1 receptor agonist, WIN 55,212-2, on motor activity. Subsequently, the effects of a low, stimulatory dose of WIN 55,212-2 and cocaine, as a positive control, were evaluated using a conditioned place preference (CPP) procedure. Upon completion of CPP, in rats that had been treated with WIN 55,212-2, dopaminergic status and spontaneous and d-amphetamine-induced motor activity were assessed., Main Methods: Sprague-Dawley rats were evaluated for habituated motor activity following WIN 55,212-2 (0, 0.1, 0.3, 1 mg/kg, i.p.) administration. A stimulatory dose of WIN 55,212-2 (0.1 mg/kg, i.p.) and cocaine (20 mg/kg, i.p.) was selected to assess CPP behaviour. Upon completion of CPP, in one group, tissue levels of dopamine and its metabolites were measured in distinct brain regions (dorsal striatum, nucleus accumbens, prefrontal cortex, amygdala, hippocampus) using High Performance Liquid Chromatography with electrochemical detection. In another group, spontaneous and D-amphetamine-induced motor activity was evaluated in an open-field apparatus., Key Findings: The lowest dose of WIN 55,212-2 increased motor activity but did not produce CPP. As expected, cocaine induced clear CPP. Dopaminergic status was increased in a region-specific way and motor activity was enhanced following a challenge of D-amphetamine in rats that had been administered with WIN 55,212-2 during conditioning., Significance: A stimulatory effect of WIN 55,212-2 on motor activity was not accompanied by place preference. Upon completion of the CPP procedure, this dose was found to induce region-specific hyperdopaminergia along with a greater sensitivity to a subsequent challenge dose of D-amphetamine.

Large unilateral visual cortex lesions produce enduring contralesional visual orientation deficits. To examine whether glutamate excitotoxicity is involved in establishing these deficits, cats were pretreated with the NMDA receptor antagonist dizocilpine (MK-801) 30 min before unilateral visual cortex ablation. Pretreated MK-801 animals were trained first in an orientation task in which they were required to fixate directly ahead and then orient to stimuli introduced at various eccentricities throughout the visual field. They did not display the characteristic ipsilesional head and neck asymmetries and/or spontaneous ipsiversive rotational behaviors or show the profound contralesional visual neglect seen postoperatively in nonpretreated control animals. Rather, pretreated animals were able to orient to visual stimuli in the contralesional hemifield immediately following surgical recovery. Postmortem histology revealed severe retrograde degeneration of the ipsilesional lateral geniculate nucleus in both experimental groups, suggesting that postlesion visuomotor behavioral competencies in pretreated animals are attributable to preserved function in nongeniculocortical visual pathways. These observations are consistent with the hypothesis that visual cortex lesions normally induce secondary alterations via NMDA-mediated excitotoxicity in these other pathways that prevents them from supporting visuomotor behaviors. The similar behavioral competencies of MK-801-pretreated animals and those whose lesion-induced deficits are ameliorated by removing basal ganglia afferents to the ipsilesional superior colliculus are consistent with this hypothesis and highlight the normal functional capabilities of this circuit. It is likely that MK-801 pretreatment acts, at least in part, by preserving the normal interhemispheric control dynamics with which the basal ganglia influence superior colliculus-mediated orientation behaviors.

Although many studies have focused on trace metals accumulation, investigations of talitrid amphipods as biomarkers are rare. This study explores the possibility of using the solar orientation capacity of Talitrus saltator as a behavioural marker of exposure to two essential (Cu and Zn) and two non-essential (Cd and Hg) metals. LC(50) analyses performed before the solar orientation tests showed that the 72 h LC(50) for Hg was 0.02 ppm while the 96 h LC(50) values for Cu, Cd and Zn were 13.28 ppm, 27.66 ppm, and 62.74 ppm, respectively. The presence of metals in seawater affects the solar orientation capacity of T. saltator in a concentration-dependent manner and according to the toxicity ranking of the metals (Hg > Cu > Cd > Zn). Therefore, the solar orientation capacity of T. saltator seems to be a promising behavioural marker for exposure to trace metals.

To separate the direct pharmacological effects of cocaine from those associated with active drug self-administration we employed a yoked control-operant paradigm and investigated the expression of well established markers of the rapid action of cocaine, i.e. the inducible early genes Arc and Zif268 and trophic factors, i.e. brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (FGF-2), in rats after a single intravenous (i.v.) cocaine self-administration session. Animals self-administering cocaine (SA, 0.25 mg/0.1 ml saline per infusion, 2-h session) did more active lever-presses than yoked-cocaine (YC) and yoked-vehicle (YV) animals. This goal-oriented behaviour was accompanied by a selective increase in Arc mRNA levels in the medial prefrontal cortex (mPFC). There were no changes in the expression of the other genes in this brain region. mRNA levels of Arc and Zif268 in striatum and Zif268 in the nucleus accumbens markedly increased both in SA and YC animals; but there was no change in the expression of FGF-2 and BDNF. No changes were observed in hippocampus, hypothalamus, frontal cortex, and midbrain in SA and YC animals compared to YV animals in any of the genes. These findings demonstrate that a single session of cocaine i.v. self-administration is sufficient to shape rat behaviour towards goal-directed behaviours and selectively up-regulate Arc expression in mPFC (of SA animals), providing the first evidence that the mPFC's function is already profoundly influenced by the first voluntary cocaine exposure.

Effects of a local compression brain injury and the preventive application of cyclopentyladenosine (CPA) on the behavior of rats in the open field test was investigated. It is established that the local injury of a parietal cortex causes intensification of the orientation--research behavior and an increase in the emotional stress in rats. A protective action of CPA was manifested by a decrease in the expressiveness and duration of disturbances in the emotional and orientation--research behavior of animals in the open field test.

Study Objectives: To evaluate the effect of ramelteon on middle-of-the-night balance, mobility, and memory in older insomniacs., Methods: Thirty-three older adults (age > or = 65 years) with insomnia were enrolled in a single-dose, 3-way crossover study of balance after bedtime administration of ramelteon, 8 mg; zolpidem, 10 mg (positive control); or placebo. Subjects were administered study medication 30 minutes before bedtime and were awakened 2 hours after dosing to evaluate balance (Sensory Organization Test), turning speed and stability, memory (immediate and delayed word recall), and adverse events. There was a 4- to 10-day washout between treatments., Results: Ramelteon or zolpidem (positive control) was compared with placebo. There were no differences between placebo and ramelteon on the Sensory Organization Test (p = 0.837), turn time (p = 0.776), or turn sway (p = 0.982). The positive control (zolpidem) did reveal significant impairments on the Sensory Organization Test, turn time, and turn sway (p < 0.001, all). Immediate and delayed memory recall were not significantly different with ramelteon (p = 0.683 and p = 0.650, respectively). Immediate recall declined significantly with zolpidem (p = 0.002). Adverse events were infrequent (ramelteon, n = 7; placebo, n = 7; zolpidem, n = 13); none were serious., Conclusion: In older adults, ramelteon did not impair middle-of-the night balance, mobility, or memory relative to placebo.

Female insect pheromone blends induce robust tracking responses in males and direct them into traps. In vertebrates, pheromones that induce strong and precise tracking responses in natural habitats have rarely been described. Here, we show in the sea lamprey (Petromyzon marinus), a vertebrate invader of the Laurential Great Lakes, that a synthesized component of the male mating pheromone, 7alpha, 12alpha, 24-trihydroxy-5alpha-cholan-3-one 24-sulfate (3kPZS), when released into a stream to reach concentrations of 10(-14), 10(-13), 10(-12), 10(-11), or 10(-10) M, triggers robust upstream movement in ovulated females drawing approximately 50% into baited traps. Experiments conducted in diverse stream segments demonstrate the level of behavioral response was not affected by habitat conditions and is effective over hundreds of meters. 3kPZS is equally effective at luring ovulated females as the whole pheromone blend released by males between 10(-14) and 10(-11) M. 3kPZS diverts ovulated females away from and disrupts orientation to male washings when applied at concentrations higher than washings. Indeed, a single pheromone compound is able to redirect female sea lampreys away from a natural pheromone source and lure them into traps, which should be more effective than targeting males when applied in population control. Our findings may spur the discovery of other potent and environmentally benign agents to combat biological invasion, a process accelerated by globalization, exacerbated by climate change, and costing the global economy US$ 1.4 trillion of damage annually.

Increasing evidence suggests that the pathophysiology of movement disorders in Parkinson's disease (PD) includes deficits in sensory processing and integration. However, the exact nature of these deficits and the ability of dopamine medication to correct them have not been thoroughly examined in previous studies. For instance, it remains unclear whether PD patients have globally impaired sensorimotor integration functions or selective deficiencies in processing proprioception. We evaluated the specific deficits of PD patients in sensorimotor integration and proprioceptive processing by testing their ability to perform three-dimensional (3D) reaching movements in four conditions in which the sensory signals defining target and hand positions (visual and/or proprioceptive) varied. Ten healthy subjects and 11 PD patients, ON dopamine medication and in the OFF state, were tested. PD patients in the OFF state showed a greater mean level of 3D errors relative to controls when the only available sensory information about target and hand position came from proprioception, but this difference did not reach significance. This indicates that deficient proprioception is not an early key feature of PD. Interestingly, the inaccuracies of a number of PD subjects further increased in the ON medicated state relative to healthy controls when reaching to proprioceptively-defined targets, and this between group difference was statistically significant. However, dopamine medication did not consistently degrade the reaching accuracy of PD patients, with both negative and positive effects on accuracy of reaching to proprioceptive-defined targets. Together, these findings indicate that dopamine replacement therapy not only did not normalize sensorimotor performance to the level of controls, but also induced deficits in the processing of proprioceptive information in some of the PD patients tested. Furthermore, the diversity of effects of medication on accuracy of reaching to proprioceptively-defined targets supports the idea that dysfunction of dopaminergic circuits within the basal ganglia is not primarily responsible for the proprioceptive processing deficits of PD patients.

Activity-dependent and sustained alterations in synaptic efficacy are widely regarded as the cellular correlates underlying learning and memory. Metabotropic glutamate receptors (mGluRs) are intrinsically involved in both hippocampal synaptic plasticity and spatial learning. Group II mGluRs are required for persistent hippocampal long-term depression (LTD), but are not required for long-term potentiation (LTP) in the hippocampal CA1 region in vivo. The role of these receptors in spatial learning, and in synaptic plasticity in the dentate gyrus in vivo has not yet been the subject of close scrutiny. We investigated the effects of group II mGluR antagonism on LTP and LTD in the adult rat, at medial perforant path-dentate gyrus synapses, and on spatial learning in the eight-arm radial maze. Daily application of the group 2 mGluR antagonist (2S)-alpha-ethylglutamic acid (EGLU) resulted in impairment of long-term (reference) memory with effects becoming apparent 6 days after training and drug-treatment began. Short-term (working) memory was unaffected throughout the 10-day study. Acute injection of EGLU did not affect either LTD or LTP in the dentate gyrus in vivo. Following six daily applications of EGLU a clear impairment of LTD but not LTP was apparent however. These data support that prolonged antagonism of group II mGluRs results in an impairment of LTD that parallels the appearance of spatial memory deficits arising from group II mGluR antagonism. These findings support the importance of group II mGluRs for spatial memory formation and offer a further link between LTD and the encoding of spatial information in the hippocampus.

We studied the relationship between vertical and lateral movements during free flight odor plume tracking by male moths, Manduca sexta, in a wind tunnel with the "horizon" set at different altitudes. Three-dimensional recordings revealed that the plume tracking males generated roughly equivalent movements vertically and laterally regardless of horizon height. We hypothesized that the moths' tracks would be narrower in the vertical plane when they were presented with visual patterns on the tunnel's side walls. Instead, we discovered that their tracks tended to be wider in the horizontal plane. Anecdotal observations of other moth species describe plume tracking flight in three dimensions as "spiraling", suggesting a specific predictable relationship between vertical and lateral movements. However, we found that the relative phase, frequency, and amplitude of the vertical versus lateral movements vary on a maneuver-by-maneuver basis with no predictable temporal or spatial relationship. Our analyses suggest that a moth's trajectory in 3D can best be described as progressing upwind toward the source while cutting through the plume from all directions with loops of different radii. This is a more precise description than the terms "zigzagging" and "counter-turning" which were derived from 2D analyses of this behavior.

Orientation selectivity of primary visual cortical neurons is an important requisite for shape perception. Although numerous studies have been previously devoted to a question of how orientation selectivity is established and elaborated in early life, how the susceptibility of orientation plasticity to visual experience changes in time remains unclear. In the present study, we showed a postnatal sensitive period profile for the modifiability of orientation selectivity in the visual cortex of kittens reared with head-mounted goggles for stable single-orientation exposure. When goggle rearing (GR) started at P16-P30, 2 weeks of GR induced a marked over-representation of the exposed orientation, and 2 more weeks of GR consolidated the altered orientation maps. GR that started later than P50, in turn, induced the under-representation of the exposed orientation. Orientation plasticity in the most sensitive period was markedly suppressed by cortical infusion of NMDAR antagonist. The present study reveals that the plasticity and consolidation of orientation selectivity in an early life are dynamically regulated in an experience-dependent manner.

Background: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. Furthermore, dopaminergic neurotransmission plays an important role in the physiology of visual contrast sensitivity (CS). To test the hypothesis that altered dopaminergic neurotransmission plays a role in major depression we measured contrast sensitivity in patients with major depression and in healthy control subjects., Methods: Twenty-eight patients diagnosed with major depressive disorder were compared to 21 age-matched control subjects on their ability to detect a Gabor target with slightly elevated luminance contrast embedded in seven equi-contrast distracters., Results: Contrast discrimination thresholds were significantly elevated in unmedicated and medicated patients with major depression compared to control subjects, at all pedestal contrast levels tested., Conclusions: Contrast discrimination performance is reduced in depressive patients and might reflect a state of altered dopaminergic neurotransmission.

Aims/objectives: A growing body of evidence suggests that regular 'ecstasy' (3,4-methylenedioxymethamphetamine) use causes lasting changes to central serotonergic functioning in humans, including in the occipital lobe. Serotonin may play a role in visual orientation processing, mediated in the occipital lobe, via lateral inhibition. The tilt aftereffect is an illusion apparent following adaptation to stimuli angled 5-50 degrees from vertical and thought to be affected by lateral inhibition between occipital neurons. A recent study identified an enhanced tilt aftereffect among ecstasy users, but only in a subset that were recently abstinent from amphetamines. The current study examined the effects of ecstasy use, cannabis use and their interacting effect on the magnitude of the tilt aftereffect among participants with no recent history of amphetamine consumption., Materials and Methods: Eleven ecstasy users, 15 cannabis users, 15 ecstasy plus cannabis users and 15 drug-naïve controls were compared on the magnitude of the tilt aftereffect elicited following adaptation to stimuli angled 15, 30, 40 or 60 degrees from vertical., Results: At a 40 degrees adaptation condition, ecstasy users had a greater magnitude of the tilt aftereffect compared to those that had not taken the drug. Additionally, the extent of ecstasy use was positively associated with the magnitude of the tilt aftereffect generated following 15, 30 and 40 degrees adaptation conditions, but not at 60 degrees., Conclusions: Given that lateral inhibition mediates the tilt aftereffect following adaptation to 5-50 degrees , the findings of a relationship between ecstasy use and tilt magnitude at the 15-40 degrees but not 60 degrees adaptation conditions support a role for serotonin in visual orientation processing via lateral inhibition., (Copyright 2009 S. Karger AG, Basel.)

Typical N-methyl-D-aspartate (NMDA) receptor antagonists exhibit anticonvulsant action and unwanted effects, even in developing rats. Therefore, we studied the actions of the low-affinity, noncompetitive antagonist memantine and the NR2B-specific antagonist ifenprodil. Seizures (minimal clonic and generalized tonic-clonic) were elicited with pentylenetetrazol (100mg/kg subcutaneously) in rats 7, 12, 18, and 25 days old pretreated with memantine (2.5-40 mg/kg intraperitoneally) or ifenprodil (10-60 mg/kg intraperitoneally). The effects of both drugs were studied in open field and motor performance tests in 12-, 18-, and 25-day-old rats. Memantine suppressed generalized tonic-clonic seizures in all age groups; minimal seizures were potentiated. Ifenprodil abolished the tonic phase of generalized tonic-clonic seizures in 7-, 12-, and 18-day-old rats only; minimal seizures remained untouched. Memantine induced locomotor hyperactivity and compromised motor performance in all age groups. Ifenprodil exerted these effects only in 12-day-old rats; older animals were less active in open field tests. Memantine exhibits both anti- and pro-convulsant and behavioral effects typical of NMDA antagonists. Ifenprodil exerted the same effects in 12-day-old rats, but its anticonvulsant action in 18-day-old rats was accompanied by a decrease in locomotion.

In the Morris water maze (MWM) task, proprioceptive information is likely to have a poor accuracy due to movement inertia. Hence, in this condition, dynamic visual information providing information on linear and angular acceleration would play a critical role in spatial navigation. To investigate this assumption we compared rat's spatial performance in the MWM and in the homing hole board (HB) tasks using a 1.5 Hz stroboscopic illumination. In the MWM, rats trained in the stroboscopic condition needed more time than those trained in a continuous light condition to reach the hidden platform. They expressed also little accuracy during the probe trial. In the HB task, in contrast, place learning remained unaffected by the stroboscopic light condition. The deficit in the MWM was thus complete, affecting both escape latency and discrimination of the reinforced area, and was thus task specific. This dissociation confirms that dynamic visual information is crucial to spatial navigation in the MWM whereas spatial navigation on solid ground is mediated by a multisensory integration, and thus less dependent on visual information.

Head direction (HD) cells have been speculated to be part of a network mediating navigational behavior. Previous work has shown that combined administration of serotonergic and muscarinic antagonists eliminates hippocampal theta activity and produces navigational deficits more severe than blockade of either neurotransmitter system alone. The authors sought to assess this effect on the directional characteristics of HD cells. HD cells were recorded from the anterior dorsal thalamus of Long-Evans rats before and after administration of the serotonergic antagonist methiothepin, the muscarinic antagonist scopolamine, both drugs, or saline. Combined drug administration produced HD cells with preferred directions that drifted within recording sessions. In addition, cells showed shifts in the preferred directions at the start of a session relative to the position of the major landmarks, suggesting that combined drug administration led to deficits in landmark control of the HD system. Single drug exposures to methiothepin or scopolamine did not noticeably affect the directional characteristics of HD cells. This finding that navigation-impairing drugs can disrupt the HD signal provides further evidence that this network plays an important role in navigational behavior.

Humanin (HN) and its analogues have been shown to protect cells against death induced by various Alzheimer's disease (AD) genes and amyloid-beta-peptides in vitro; the analogues [Gly(14)]-HN and colivelin have also been shown to be potent in reversing learning and memory impairment induced by scopolamine or quinuclidinyl benzilate (QNB) in mice or rats in vivo using the Y-maze or multiple T-maze tests. This paper describes the activity of new peptides of the HN family, after i.p. administration, on QNB-induced impairment of spatial memory in the multiple T-maze test in rats. The following peptides have been studied: HN analogues truncated either on the C- or N-terminus, or analogues having a tert-Leu in place of Leu in the central part of the molecule, the active HN core PAGASRLLLLTGEIDLP (RG-PAGA) and its analogues having three or five leucines instead of four, and finally the recently described hybrid peptide colivelin (i.e. a peptide having the activity-dependent neurotrophic factor SALLRSIPA attached to the N-terminus of the active RG-PAGA) and its des-Leu- and plus-Leu-analogues. While the truncated analogues and most of the tert-Leu containing analogues were devoid of activity, the analogues of the RG-PAGA were active, i.e. they reversed the impairment of spatial memory irrespective of the number of Leu present in their sequence. The highest activity was shown by colivelin and its des-Leu-analogue. These results demonstrate the potential of HN analogues in the modulation of the cholinergic system, which plays an important role in the cognitive deficits associated with AD and other neurodegenerative diseases.

In field O(3)-enrichment experiments increased herbivore densities have been reported, which could be due to negatively affected host location behavior of natural enemies. We addressed the impact of doubling background O(3) on the host location of the parasitoid Cotesia plutellae by conducting 24-h trials in an open-air O(3)-fumigation system during two consecutive years. Two circles (radii 1.40 and 4.00 m) of Plutella xylostella-infested potted cabbage plants were placed in the O(3) and ambient plots. Female wasps were released into each plot from the center, and observed 5 times over a 24-h period to assess their host location capability. Thereafter, plants were kept in laboratory conditions until larvae pupation to determine parasitism rates. No significant differences were detected between ambient and O(3)-enriched environments either in the number of wasps found in the field, or in the percentages of parasitized larvae. This suggests that moderately elevated O(3) will not affect the behavior of this parasitoid.

Objective: To examine attention bias toward threat faces in a large sample of anxiety-disordered youths using a well-established visual probe task., Method: Study participants included 101 children and adolescents (ages 7-18 years) with generalized anxiety disorder, social phobia, and/or separation anxiety disorder enrolled in a multisite anxiety treatment study. Nonanxious youths (n = 51; ages 9-18 years) were recruited separately. Participants were administered a computerized visual probe task that presents pairs of faces portraying threat (angry), positive (happy), and neutral expressions. They pressed a response key to indicate the spatial location of a probe that replaced one of the faces on each trial. Attention bias scores were calculated from response times to probes for each emotional face type., Results: Compared to healthy youths, anxious participants demonstrated a greater attention bias toward threat faces. This threat bias in anxious patients did not significantly vary across the anxiety disorders. There was no group difference in attention bias toward happy faces., Conclusions: These results suggest that pediatric anxiety disorders are associated with an attention bias toward threat. Future research may examine the manner in which cognitive bias in anxious youths changes with treatment.

In this article, the literature examining the relationship between testosterone and various cognitive domains in elderly men is reviewed. The review focuses on the role of endogenous testosterone levels and the effects of androgen depletion and replacement. The cognitive domains most commonly linked to testosterone include memory and visuospatial function. Indeed, the literature suggests that in certain conditions (ie, hypogonadism, cognitive impairment) testosterone levels may be significantly associated with memory and visuospatial function, but not other cognitive functions. Studies with larger sample sizes and more sensitive cognitive measures are indicated, as questions remain about the potential role of testosterone as a cognitive enhancer.

The mammalian tachykinins are a family of closely related peptides including substance P, neurokinin A, neurokinin B and, recently, also hemokinin-1. They are present in the peripheral and central nervous systems, and bind to three known neurokinin (NK) receptors, the NK(1)-, NK(2)- and NK(3) receptors. In both rodents and humans, NK(3) receptors are expressed in brain structures which have been associated with learning and memory. Evidence for a role of NK(3) receptors in learning and memory has been found in NK(3) receptor knockout mice. Here, we investigated the influence of the NK(3) receptor agonist, senktide (0.1, 0.2 and 0.4 mg/kg), on the performance of C57BL/6 mice in a recently developed episodic-like memory task. Since a promnestic effect of senktide was expected, we employed an experimental protocol that provided sub-optimal learning conditions for episodic-like memory. The results indicate that senktide promotes episodic-like memory in mice in a dose-dependent manner, providing, for the first time, evidence for an involvement of NK(3) receptors in episodic-like memory.

The purpose of the present study was to examine the role of the dorsal striatum, and more specifically, the patch region of the dorsal striatum, in mediating spatial learning and memory. To this end, male, Long Evans rats were bilaterally implanted with cannula aimed at the dorsal striatum. Rats were injected with different doses (0, 0.05, 0.5 or 5 microg/0.5 microl) of [3H]-[D-Ala2,MePhe4,Gly-ol5]-enkephalin (DAMGO) into the dorsal striatum daily (Exp. 1) before training on a hidden platform version of the water maze task or during a reversal water maze spatial task (Exp. 2). In both experiments, probe retention tests were given drug free. Results from Exp. 1 showed that intra-striatal injection of the low DAMGO dose (0.05) resulted in enhanced spatial acquisition while the high dose (5.0) produced impairments compared to controls. During the probe test, the low dose group showed better retention of the platform location than controls as well as an enhanced ability to alter their search strategy. In Exp. 2, pretraining alleviated the high dose impairment found in Exp. 1 suggesting a motoric impairment in this group. The low dose group continued to show an enhanced ability to alter their search strategy during the probe test compared to all other groups. The data suggest that the low dose of DAMGO, when injected into the dorsal striatum, eliminates competition with the hippocampus thereby leading to enhanced spatial processing. Alternatively, inhibition of patch-striatal neurons may attenuate a memory decay process. Both alternatives are discussed.

3-nitropropionic acid (3-NP)-induced neurotoxicity causes a cellular energy deficit and oxidative stress via an irreversible inhibition of the mitochondrial enzyme succinate dehydrogenase (SDH). Systemic administration of 3-NP causes motor and cognitive deficits, particularly those associated with excessive free radical generation. Recently, carvedilol has been implicated as a neuroprotectant in the treatment of various neurological disorders. The present study was designed to investigate the neuroprotective effects of carvedilol against 3-NP-induced cognitive impairment and oxidative damage in rats. Intraperitoneal administration of 3-NP (20 mg/kg for 4 days) caused significant body weight reduction, impaired motor function (locomotor activity, movement pattern), induced vacuous chewing movements, led to poor retention of memory in the Morris water maze, and elevated plus maze task paradigms. Chronic treatment with carvedilol (1 and 2 mg/kg, po), once daily for a period of 8 days beginning 4 days before 3-NP administration, significantly reversed 3-NP-induced motor impairment and cognitive deficits. However, carvedilol (1 and 2 mg/kg, po) treatment significantly attenuated oxidative damage (reduced lipid peroxidation and nitrite levels, and restored depleted reduced glutathione and succinate dehydrogenase enzyme activity) in the rat brain. The results of the present study suggest that carvedilol has a neuroprotective effect against 3-NP-induced behavioral alterations and oxidative damage.

Recent studies in patients with hippocampal lesions have indicated that the degree of memory impairment is proportional to the extent of damage within the hippocampus. Particularly, patients with damage restricted to the CA1 field demonstrate moderate to severe anterograde amnesia with only slight retrograde amnesia. Comparable results are also seen in other species such as non-human primates and rats; however, the effect of selective damage to CA1 has not yet been characterized in mice. In the present study, we investigated the effects of excitotoxic (NMDA) lesions of dorsal CA1 on several aspects of learning and memory performance in mice. Our data indicate that dorsal CA1 lesioned mice are hyperactive upon exposure to a novel environment, have spatial working memory impairments in the Y-maze spontaneous alternation task, and display deficits in an 8-arm spatial discrimination learning task. Lesioned mice are able to acquire an operant lever-press task but demonstrate extinction learning deficits in this appetitive operant paradigm. Taken together, our results indicate that lesions to dorsal CA1 in mice induce selective learning and memory performance deficits similar to those observed in other species, and extend previous findings indicating that this region of the hippocampus is critically involved in the processing of spatial information and/or the processing of inhibitory responses.

Orientation selectivity is an important emergent property of neurons in the primary visual cortex, and inhibition is thought to play an important role in establishing this selectivity. But the relationship between strength of inhibition and orientation selectivity is unclear. To investigate this relationship, we electrophoretically applied the inhibitory transmitter GABA and the GABA(A) antagonist bicuculline on the same individual area 17 neurons in anesthetized cats. Neurons were classified as weakly orientation-selective, moderately orientation-selective, or strongly orientation-selective, according to the values of an orientation bias index. Orientation bias, half-width of the tuning curve at half-height and an orientation-specificity index (orthogonal to optimal ratio) were compared with or without GABA and bicuculline administration. GABA improved orientation selectivity with the greatest effects on weakly orientation-selective cells, smaller effects on moderately orientation-selective cells, and minimal effects on strongly orientation-selective cells; bicuculline diminished orientation selectivity the most on moderately and strongly orientation-selective cells, with minimal effects on weakly orientation-selective cells. We also found that orientation selectivity correlated with the level of neurons' spontaneous activity. These results suggest that the degree of orientation selectivity of an area 17 neuron correlates with its endogenous inhibition strength, and that GABAergic inhibition can bi-directionally regulate orientation selectivity. This correlation indicates that GABA-mediated inhibition plays an important role in establishing sharp orientation selectivity of individual neurons.

The present study examined the effects of acute progesterone administration on hippocampal-dependent memory consolidation in ovariectomized middle-aged (16 months old) and aged (22 months old) female mice. Spatial memory was tested in a 2-day Morris water-maze task and object memory was tested using an object recognition task with 24- and 48-h delays. Immediately after water-maze training, mice received i.p. injections of vehicle, or 5.0, 10.0, or 20.0 mg/kg of water-soluble progesterone. Twenty-four hours later, retention of the platform location was tested. No overnight forgetting of the platform location was observed in middle-aged vehicle-treated mice. Acute progesterone administration had no effect on spatial memory in middle-aged mice. However, aged vehicle-treated mice demonstrated impaired memory for the platform location on Day 2 relative to Day 1. Twenty mg/kg, but not 5 or 10 mg/kg, progesterone reversed these deficits, suggesting that 20 mg/kg progesterone can improve spatial memory in aged females. In the object recognition task, mice explored two identical objects and then immediately received vehicle or progesterone injections. In middle-aged mice, 10 and 20 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24-h, but all doses were ineffective after 48-h. In aged mice, 10 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24 h, whereas both 5 and 10 mg/kg progesterone enhanced memory after 48 h. Together, these results indicate that acute progesterone differentially enhances hippocampal-dependent memory in middle-aged and aged females.

Two pulses of 17beta-estradiol (10 microg) are commonly used to increase hippocampal CA1 apical dendritic spine density and alter spatial performance in ovariectomized (OVX) female rats, but rarely are the measures combined. The goal of this study was to use this two-pulse injection protocol repeatedly with intervening wash-out periods in the same rats to: 1) measure spatial ability using different tasks that require hippocampal function and 2) determine whether ovarian hormone depletion for an extended 10-week period reduces 17beta-estradiol's effectiveness in elevating CA1 apical dendritic spine density. Results showed that two injections of 10 microg 17beta-estradiol (72 and 48 h prior to testing and timed to maximize CA1 apical spine density at behavioral assessment) corresponded to improved spatial memory performance on object placement. In contrast, two injections of 5 microg 17beta-estradiol facilitated spatial learning on the water maze compared to rats given two injections of 10 microg 17beta-estradiol or the sesame oil vehicle. Neither 17beta-estradiol dose altered Y-maze performance. As expected, the intermittent two-pulse injection protocol increased CA1 apical spine density, but 10 weeks of OVX without estradiol treatment decreased the effectiveness of 10 microg 17beta-estradiol to increase CA1 apical spine density. Moreover, two pulses of 5 microg 17beta-estradiol injected intermittently failed to alter CA1 apical spine density and decreased basal spine density. These results demonstrate that extended time without ovarian hormones reduces 17beta-estradiol's effectiveness to increase CA1 apical spine density. Collectively, these findings highlight the complex interactions among estradiol, CA1 spine density/morphology, and task requirements, all of which contribute to behavioral outcomes.

Involvement of hippocampal cannabinoid receptors in short-term memory was investigated in rats using spontaneous object and place recognition memory tasks. Rats were allowed to explore the field in which two identical objects were presented. Then after a delay period, they were placed again in the same field in which one of the two objects was replaced by another object (object recognition task) or moved to another place (place recognition task), and their exploration behavior to these objects were analyzed. Activation of hippocampal cannabinoid receptors by an agonist WIN 55,212-2 (1-2 microg/side) dose-dependently decreased the exploration of object in a new place, while it did not affect the exploration of a new object. Disruptive effect of WIN 55,212-2 on place recognition was antagonized by the pretreatment with a cannabinoid receptor antagonist AM 281 (2mg/kg, i.p.). Results suggest that hippocampal cannabinoid receptors play an important role in place recognition or spatial memory.

Young (2-4 months) and aged (14-16 months) male Swiss-Webster albino mice (n = 7 per group) were subcutaneously injected with 20 mg/kg/day dehydroepiandrosterone sulfate (DHEAS), progesterone (P), DHEAS + P, or vehicle control and trained over a 5-day period in a Morris water maze. The subjects were tested 48 hr after training for memory recall as measured by latencies to locate the hidden platform, and trunk blood was collected immediately thereafter. As expected, latency to platform decreased for all groups over the 6 testing days, with aged mice taking longer to reach platform than did young mice. However, results did not support the hypotheses that DHEAS-treated mice would exhibit shorter latencies and that P-treated mice would show longer latencies to platform in comparison with age-matched controls. These results raise doubts about the effectiveness of commercially available supplements claiming to promote enhanced memory in humans.

Rationale: One of the adaptive abilities of the brain is the generation of a strategy to optimize acquisition of information, i.e., learning. In this study, we explored the role of environmental conditions (the light-dark cycle) and of the endocannabinoid anandamide in rats to select a strategy to solve the Barnes maze (BM)., Objectives: To determine the effects of manipulating the cannabinergic system on a spatial task in relation to the light-dark cycle., Materials and Methods: Rats received an intrahippocampal or intrastriatal administration of anandamide, AM251, or their combination at two different points of the light-dark cycle (1300 and 0100 hours), and their performance in the BM was evaluated. In addition, we determined the expression of the cannabinoid 1 receptor (CB1R) in the hippocampus and striatum throughout the light-dark cycle., Results: Results indicate that rats solved the BM by using a spatial strategy during the light phase and a procedural (serial) strategy during the dark phase of the cycle. CB1R expression varied in the hippocampus, being higher at 1300 hours and lower at 0100 hours, whereas its expression remained unchanged in the striatum., Conclusions: Changes in the brain, which include changes in the endocannabinoid system, prompt it to use different strategies (spatial and procedural, or others not evaluated in this study) to cope with the environmental demands. These cerebral changes are adaptive responses to the light-dark cycle.

Rationale: Many studies have reported deficits of mismatch negativity (MMN) in schizophrenic patients. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN after ketamine (N-methyl-D-aspartate acid [NMDA] antagonist model) but not after psilocybin (5HT2A agonist model)., Objectives: The aim of the present study was to directly compare the two models of psychosis using an intraindividual crossover design., Materials and Methods: Fifteen healthy subjects participated in a randomized, double-blind, crossover study with a low and a high dose of the 5HT2A agonist dimethyltryptamine (DMT) and the NMDA antagonist S-ketamine. During electroencephalographic recording, the subjects were performing the AX-version of a continuous performance test (AX-CPT). A source analysis of MMN was performed on the basis of a four-source model of MMN generation., Results: Nine subjects completed both experimental days with the two doses of both drugs. Overall, we found blunted MMN and performance deficits in the AX-CPT after both drugs. However, the reduction in MMN activity was overall more pronounced after S-ketamine intake, and only S-ketamine had a significant impact on the frontal source of MMN., Conclusions: The NDMA antagonist model and the 5HT2A agonist model of psychosis display distinct neurocognitive profiles. These findings are in line with the view of the two classes of hallucinogens modeling different aspects of psychosis.

Schizophrenia is widely thought to involve deficits of attention. However, the term "attention" can be defined so broadly that impaired performance on virtually any task could be construed as evidence for a deficit in attention, and this has slowed cumulative progress in understanding attention deficits in schizophrenia. To address this problem, we divide the general concept of attention into two distinct constructs: input selection, the selection of task-relevant inputs for further processing; and rule selection, the selective activation of task-appropriate rules. These constructs are closely tied to working memory, because input selection mechanisms are used to control the transfer of information into working memory and because working memory stores the rules used by rule selection mechanisms. These constructs are also closely tied to executive function, because executive systems are used to guide input selection and because rule selection is itself a key aspect of executive function. Within the domain of input selection, it is important to distinguish between the control of selection--the processes that guide attention to task-relevant inputs--and the implementation of selection--the processes that enhance the processing of the relevant inputs and suppress the irrelevant inputs. Current evidence suggests that schizophrenia involves a significant impairment in the control of selection but little or no impairment in the implementation of selection. Consequently, the CNTRICS (Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia) participants agreed by consensus that attentional control should be a priority target for measurement and treatment research in schizophrenia.

Heavy use of marijuana is claimed to damage critical skills related to short-term memory, visual scanning and attention. Motor skills and driving safety may be compromised by the acute effects of marijuana. The aim of this study was to investigate the acute effects of 13 mg and 17 mg Delta 9-tetrahydrocannabinol (THC) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana. Fourteen regular users of marijuana were enrolled. Each subject was tested on two separate days. On each test day, subjects smoked two low-nicotine cigarettes, one with and the other without THC. Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day. The sequence of cigarette types was unknown to the subject. During smoking, heart rate and blood pressure were monitored, and the subjects performed a virtual reality maze task requiring attention and motor coordination, followed by 3 other cognitive tasks (Wisconsin Card Sorting Test (WCST), a "gambling" task and estimation of time and distance from an approaching car). After smoking a cigarette with 17 mg THC, regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC; this effect was not seen in patients after they smoked cigarettes with 13 mg THC. Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC. Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC, but not with 13 m THC. Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction, drug "effect" and drug "high". These findings imply that smoking of 17 mg THC results in impairment of cognitive-motor skills that could be important for coordinated movement and driving, whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana.

Marijuana is the most widely used illicit substance among teenagers, yet little is known about the possible neural influence of heavy marijuana use during adolescence. We previously demonstrated an altered functional magnetic resonance imaging (fMRI) activity related to spatial working memory (SWM) among adolescents who were heavy users of after an average of 8 days of abstinence, but the persisting neural effects remain unclear. To characterize the potentially persisting neurocognitive effects of heavy marijuana use in adolescence, we examined fMRI response during SWM among abstinent marijuana-using teens. Participants were 15 MJ teens and 17 demographically similar non-using controls, ages 16-18. Teens underwent biweekly urine toxicology screens to ensure abstinence for 28 days before fMRI acquisition. Groups performed similarly on the SWM task, but MJ teens demonstrated lower activity in right dorsolateral prefrontal and occipital cortices, yet significantly more activation in right posterior parietal cortex. MJ teens showed abnormalities in brain response during a SWM task compared with controls, even after 1 month of abstinence. The activation pattern among MJ teens may reflect different patterns of utilization of spatial rehearsal and attention strategies, and could indicate altered neurodevelopment or persisting abnormalities associated with heavy marijuana use in adolescence.

Spatial tasks are widely used to determine the function of limbic system structures in rats. The present study used a new task designed to evaluate spatial behavior, the ziggurat task (ZT), to examine the performance of rats with widespread hippocampal damage induced by N-methyl-d-aspartic acid (NMDA). The task consisted of an open field containing 16 identical ziggurats (pyramid shaped towers) arranged at equal distances. One of the ziggurats was baited with a food reward. The task required rats to navigate through the open field by using a combination of distal and/or proximal cues in order to locate the food reward. The ability to acquire and recall the location of the goal (baited) ziggurat was tested in consecutive training sessions of eight trials per day for 10 days. The location of the goal ziggurat was changed every second day, requiring the rats to learn a total of five different locations. Several parameters, including latency to find the target, distance traveled, the number of visits to non-baited ziggurats (errors), and the number of returns were used as indices of learning and memory. Control rats showed a significant decrease in distance traveled and reduced latency in locating the goal ziggurat across trials and days, suggesting that they learned and remembered the location of the goal ziggurat. Interestingly, the hippocampal-damaged group moved significantly faster, and traveled longer distances compared to the control group. Significant differences were observed between these groups with respect to the number of errors and returns on test days. Day 11 served as probe day, in which no food reward was given. The controls spent more time searching for the food in the previous training quadrant compared to the hippocampal group. The findings demonstrate that the ZT is a sensitive and efficient dry task for measuring hippocampus-dependent spatial performance in rats requiring little training and not associated with some of the disadvantages of water tasks.

Rationale: Experimental studies have investigated the effects of chronic donepezil treatment on the behavioral deficits elicited by reduced activity or the loss of cholinergic neurons that occurs in aging or in models of dementia. However, few studies have analyzed the effects of chronic donepezil treatment on the cognitive functions of intact animals., Objectives: The cognitive functions of healthy young rats treated chronically with the acetylcholinesterase inhibitor donepezil were evaluated using a wide behavioral test battery., Results: Chronic treatment with donepezil ameliorated memory functions and explorative strategies, speeded up the acquisition of localizing knowledge, augmented responsiveness to the context, and reduced anxiety levels. However, it did not affect spatial span, modify motivational levels, or influence associative learning., Conclusions: The present findings show the specific profile of donepezil action on cognitive functions in the presence of unaltered cholinergic neurotransmission systems.

Background: Problems with the voluntary control of behavior, such as those leading to increased antisaccade errors, are accepted as evidence of prefrontal dysfunction in schizophrenia. We previously reported that speeded prosaccade responses, i.e., shorter response latencies for automatic shifts of attention to visual targets, were associated with higher antisaccade error rates in schizophrenia. This suggests that dysregulation of automatic attentional processes may contribute to disturbances in prefrontally mediated control of voluntary behavior., Methods: Twenty-four antipsychotic-naïve schizophrenia patients and 30 healthy individuals completed three tasks: a no-gap prosaccade task in which subjects shifted gaze toward a peripheral target that appeared coincident with the disappearance of a central fixation target and separate prosaccade and antisaccade tasks in which a temporal gap or overlap of the central target offset and peripheral target onset occurred. Sixteen patients were retested after 6 weeks of antipsychotic treatment., Results: Patients' prosaccade latencies in the no-gap task were speeded compared with healthy individuals. While patients were not atypical in the degree to which response latencies were speeded or slowed by the gap and overlap manipulations, those patients with diminished attentional engagement on the prosaccade task (i.e., reduced overlap effect) had significantly elevated antisaccade error rates. This effect persisted in patients evaluated after antipsychotic treatment., Conclusions: This study provides evidence that a reduced ability to engage attention may render patients more distracted by sensory inputs, thereby further compromising impaired executive control during antisaccade tasks. Thus, alterations in attentional and executive control functions can synergistically disrupt voluntary behavioral responses in schizophrenia.

Rationale: In Western societies, a considerable percentage of young people expose themselves to 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"). Commonly, ecstasy is used in combination with other substances, in particular alcohol (ethanol). MDMA induces both arousing as well as hallucinogenic effects, whereas ethanol is a general central nervous system depressant., Objective: The aim of the present study is to assess the acute effects of single and co-administration of MDMA and ethanol on executive, memory, psychomotor, visuomotor, visuospatial and attention function, as well as on subjective experience., Materials and Methods: We performed a four-way, double-blind, randomised, crossover, placebo-controlled study in 16 healthy volunteers (nine male, seven female) between the ages of 18-29. MDMA was given orally (100 mg) and blood alcohol concentration was maintained at 0.6 per thousand by an ethanol infusion regime., Results: Co-administration of MDMA and ethanol was well tolerated and did not show greater impairment of performance compared to the single-drug conditions. Impaired memory function was consistently observed after all drug conditions, whereas impairment of psychomotor function and attention was less consistent across drug conditions., Conclusions: Co-administration of MDMA and ethanol did not exacerbate the effects of either drug alone. Although the impairment of performance by all drug conditions was relatively moderate, all induced significant impairment of cognitive function.

Lead (Pb2+) exposure in children can induce long lasting deficits in cognitive function and has been modeled in experimental animals. Based on previous studies which demonstrated that learning impairments resulting from developmental Pb2+ exposure were reversible if the animals were provided with an enriched environment, here, we asked if environmental enrichment (EE) could also reverse long-term potential (LTP) impairment induced by lead. Rats drank 1,500 ppm lead acetate (PbAc) solution or distilled water throughout gestation and lactation. After weaning at postnatal Day 22, one half of the control and lead-exposed male offspring were given the environmental enrichment treatment through all the experiments until tested. Electrophysiological and Morris water maze test were performed at 8 weeks of age. The result showed that the impaired learning ability induced by lead could be reversed by EE. Furthermore, our results revealed that EPSP LTP and PS LTP impairments induced by lead were also reversible by EE experience.

Rationale: The interest for acetylcholinesterase inhibitors in the treatment of Alzheimer's disease has been greatly renewed owing to the discovery of a broad range of additional cholinergic and non-cholinergic effects, exploitable to maximize the efficacy of these drugs beyond merely improving intellectual functions at the symptomatic level., Objectives: The age-dependent cognitive decline in the valid APP23 transgenic mouse model for Alzheimer's disease was employed to evaluate disease-modifying efficacy of chronic treatment with donepezil., Materials and Methods: At age 6 weeks, heterozygous APP23 mice and control littermates were subcutaneously implanted with osmotic pumps delivering saline or donepezil (0.27 or 0.58 mg/kg per day). After 2 months of treatment, a 3-week wash-out period was allowed to prevent bias from sustained symptomatic effects before cognitive evaluation in the Morris water maze commenced., Results: Donepezil (0.27 mg/kg per day)-treated APP23 mice performed significantly better than their sham-treated counterparts during the Morris water maze acquisition phase and the subsequent probe or retention trial. Chronic donepezil (0.27 mg/kg per day) treatment improved spatial accuracy in APP23 mice as to reach the same level of performance as wild-type control animals on this complex visual-spatial learning task., Conclusion: This is the first study reporting disease-modifying efficacy of donepezil at the level of cognitive performance in transgenic mice modeling Alzheimer's disease.

We investigated the effects of an enriched environment and/or basic fibroblast growth factor (bFGF) on recovery from neonatal frontal injury in rats. Rats received medial frontal lesions, or sham surgery, on postnatal day (P) 2/3. In the first set of experiments (Experiments 1 and 2), rats were housed in enriched environments that consisted of a large enclosure with multiple objects (or standard housing) for 90 days beginning at weaning (P22) or in adulthood (P110). In Experiment 3, the rats either received 7 days of subcutaneous bFGF beginning on the day after surgery or bFGF plus enriched housing beginning at weaning. After the 90-day housing period, the animals were tested on a spatial navigation task and a skilled reaching task. Early lesions of the medial frontal cortex caused severe impairments in spatial learning but this deficit was markedly reduced with enriched housing, bFGF, or a combination of both, with the latter being most effective. The housing effects varied with age, however: the earlier the experience began, the better the outcome. Enriched housing increased dendritic length in cortical pyramidal neurons, an effect that was greater in the lesion than the control animals, and enriched housing reversed the lesion-induced decrease in spine density. Enriched environment increased the thickness of the cortical mantle in both lesion and controls whereas bFGF had no effect. Experience thus can affect functional and anatomical outcome after early brain injury but the effects vary with age at experience and may be facilitated by treatment with bFGF., ((c) 2008 Wiley Periodicals, Inc.)

Rationale: Pyrilamine, a selective histamine H(1) antagonist, impaired spatial memory, and decreased hippocampal theta activity during a radial maze task., Objective: We investigated the ameliorative effects of glutamatergic drugs on pyrilamine-induced spatial memory deficit and the decrease in hippocampal theta activity in rats., Materials and Methods: Drug effects were measured using an eight-arm radial maze with four arms baited. Hippocampal theta rhythm during the radial maze task was also recorded with a polygraph system using a telemetric technique., Results: Intraperitoneal injection of pyrilamine (35 mg/kg) resulted in impaired reference and working memory in the radial maze task and a decrease in the amplitude and power of hippocampal theta waves. The working memory deficit and the decrease in hippocampal theta power were antagonized by intrahippocampal injection of D: -cycloserine (1 microg/side), spermidine (10 microg/side), spermine (10 microg/side), aniracetam (1 microg/side), and 1-(1,3-benzodioxol-5-ylcarbonyl) piperidine (1-BCP) (1 microg/side), but not concanavalin A., Conclusion: These results clearly indicate that H(1) antagonist-induced working memory deficit, and the decrease in hippocampal theta activity was closely associated with hippocampal glutamatergic neurotransmission mediated by N-methyl-D: -aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

Background: Although methamphetamine abuse has been associated with cognitive deficits, few studies have investigated the acute effects of the drug on complex cognitive performance. This study evaluated the acute effects of intranasal methamphetamine on a computerized task measuring metacognition of agency., Procedure: Ten nontreatment seeking methamphetamine abusers (2F, 8M) completed this four-session, within-participant, double-blind laboratory study; during each session, participants received one of four doses (0, 12, 25, or 50 mg/70 kg) and completed the metacognition of agency task. In this task, participants were instructed to "catch" falling targets with a mouse and then provide metacognitive judgments about their feelings of control., Results: Following placebo, judgments of agency were greater under optimal task conditions compared with less than optimal task conditions. Relative to placebo, the 12-mg dose improved task performance, increased judgments of agency under the optimal condition, and decreased judgments of agency under the less than optimal condition. By contrast, the larger doses (25 and 50 mg) increased judgments of agency only under the optimal condition but disrupted performance under the less than optimal condition., Conclusion: These data show that a low intranasal methamphetamine dose enhanced judgments of agency and performance, while larger doses produced limited effects.

Background: Although large-scale, randomized trials involving children have been completed and their results demonstrate an absence of neurobehavioral effects from clinical exposure to mercury amalgam, neurological findings from such studies have not been reported., Methods: The authors conducted a randomized, prospective trial examining the safety of dental amalgam in which 507 children aged 8 through 12 years were assigned to treatment with either amalgam or resin-based composite. During seven years of follow-up, the authors performed annual clinical neurological examinations, including an evaluation of neurological hard signs (NHSs), presence of tremor and neurological soft signs (NSSs)., Results: The authors found no significant differences between treatment groups in any of the neurological measures. Groups did not differ with respect to the presence or absence of NHSs or tremor, nor the presence or absence or severity of NSSs at any point. As expected, NSS severity scores diminished with increasing age., Conclusions: Even at the levels of amalgam exposure in this study (a mean of 7.7-10.7 amalgam surfaces per subject across the seven years of follow-up), the authors conclude that exposure to mercury from dental amalgam does not adversely affect neurological status., Clinical Implications: The current evidence is that potential neurobehavioral or neurological effects from dental amalgam mercury exposure in children are inconsequential.