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The effect of items in working memory on the deployment of attention and the eyes during visual search.

Paying attention to an object facilitates its storage in working memory. The authors investigate whether the opposite is also true: whether items in working memory influence the deployment of attention. Participants performed a search for a prespecified target while they held another item in working memory. In some trials this memory item was present in the search display as a distractor. Such a distractor has no effect on search time if the search target is in the display. In that case, the item in working memory is unlikely to be selected as a target for an eye movement, and if the eyes do land on it, fixation duration is short. In the absence of the target, however, there is a small but significant effect of the memory item on search time. The authors conclude that the target for visual search has a special status in working memory that allows it to guide attention. Guidance of attention by other items in working memory is much weaker and can be observed only if the search target is not present in the display.

Adolescent↗

Modulation of steroidal levels by adrenalectomy/castration and inhibition of neurosteroid synthesis enzymes affect sigma1 receptor-mediated behaviour in mice.

The interaction between neurosteroids and sigma1 (sigma1) receptors may be of therapeutic interest during physiological or pathological ageing, particularly concerning their neuromodulatory role on cognitive functions. Neurosteroids modulate memory processes through a mechanism involving interactions with GABAA, N-methyl-D-aspartate and/or sigma1 receptors. To measure the contribution of endogenous neurosteroid levels to the antiamnesic effects of sigma1 agonists, we investigated the effects of inhibitors of key enzymes involved in neurosteroid synthesis, in adrenalectomized/castrated (AdX/CX) mice to avoid the effect of circulating steroids. Trilostane, a 3beta-hydroxysteroid-deshydrogenase inhibitor, blocks the pregnenolone to progesterone conversion and leads to a decrease of progesterone. Finasteride, a 5alpha-reductase inhibitor, blocks the progesterone to 5alpha-pregnane-3,20-dione conversion and leads to an accumulation of progesterone. The in vivo binding of (+)-[3H]SKF-10 047 to sigma1 sites was measured in the mouse hippocampus and cortex. The attenuating effect of the selective sigma1 agonist PRE-084 (0.1-3 mg/kg) against dizocilpine (0.15 mg/kg)-induced learning impairment was examined using spontaneous alternation behaviour, step-down passive avoidance and place learning in the elevated plus-maze. The in vivo (+)-[3H]SKF-10 047 binding appeared significantly increased in AdX/CX mice and after trilostane treatment (10 mg/kg twice a day, 7 days), compared with sham-operated animals. The finasteride treatment (25 mg/kg, 7 days) significantly decreased binding levels. The learning deficits induced by dizocilpine were not affected by the treatments. The antiamnesic effect of PRE-084 was facilitated in AdX/CX mice and even more after trilostane treatment, as several parameters for animals treated with both PRE-084 and dizocilpine returned to control values. The PRE-084 effect was blocked after finasteride. These results confirmed that endogenous neurosteroidal levels modulate sigma1 receptor-mediated behaviour directly, and revealed that, among neurosteroids, progesterone may be the main modulator of sigma1 receptors.

Adrenalectomy↗

Behavioral testing does not exacerbate ischemic CA1 damage in gerbils.

BACKGROUND AND PURPOSE: Previous research studying ablative lesions has suggested that functional use may exacerbate brain injury. If true, this would have considerable ramifications not only for the mechanistic understanding of neuronal injury but also for the clinical use of physiotherapy. In this report the hypothesis that behavioral use of brain tissue exacerbates ischemic hippocampal injury was tested. METHODS: Gerbils were subjected to sham operation or 5 minutes of normothermic ischemia. To produce borderline hippocampal CA1 injury and enhance susceptibility to exacerbation, 2 of 3 ischemic groups were cooled (>48 hours) beginning at 6 hours after ischemia. Increased use of the hippocampus was produced by a battery of tests involving 3 novel small mazes, a T maze, and an open field. One hypothermic group was not tested and served as a control. RESULTS: Behavioral testing failed to worsen ischemic damage since neuronal loss in the behaviorally tested and untested hypothermic groups was 12% and 8%, respectively, while that in the untreated ischemic group was 81% at a 1-month survival. Accordingly, protected CA1 cells tolerated the neuronal activity associated with behavioral testing. Concomitant with marked CA1 neuroprotection, a significant reduction in behavioral deficits with the hypothermic treatment was observed. Importantly, behavioral testing was found to transiently elevate brain temperature. CONCLUSIONS: CA1 neuronal survival was unaffected by behavioral testing or the associated mild fever. Hypothermia delayed for 6 hours provided sustainable CA1 neuroprotection.

Animals↗

Hippocampal population activity during the small-amplitude irregular activity state in the rat.

The sleeping rat cycles between two well-characterized physiological states, slow-wave sleep (SWS) and rapid-eye-movement sleep (REM), often identified by the presence of large-amplitude irregular activity (LIA) and theta activity, respectively, in the hippocampal EEG. Inspection of the activity of ensembles of hippocampal CA1 complex-spike cells along with the EEG reveals the presence of a third physiological state within SWS. We characterize the hippocampal EEG and population activity of this third state relative to theta activity and LIA, its incidence relative to REM and LIA, and the functional correlates of its population activity. This state occurs repeatedly within stretches of SWS, occupying approximately 33% of SWS and approximately 20% of total sleep, and it follows nearly every REM episode; however, it never occurs just before a REM episode. The EEG during this state becomes low in amplitude for a few seconds, probably corresponding to "small-amplitude irregular activity" (SIA) described in the literature; we will call its manifestation during sleep "S-SIA." During S-SIA, a small subset of cells becomes active, whereas the rest remain nearly silent, with the same subset of cells active across long sequences of S-SIA episodes. These cells are physiologically indistinguishable from ordinary complex-spike cells; thus, the question arises as to whether they have any special functional correlates. Indeed, many of these cells are found to have place fields encompassing the location where the rat sleeps, raising the possibility that S-SIA is a state of increased alertness in which the animal's location in the environment is represented in the brain.

Action Potentials↗

Verbal conditioning of male and female schizophrenics as a function of experimenter proximity.

Verbal conditioning of male and female schizophrenics and nonschizophrenics was observed as Ss sat at different distances and orientations from an E who delivered a positive word/positive tone reinforcer ("Good"). Results indicated that the presence vs. absence of diagnostic differences in learning depended on (a) the sex of the Ss; and (b) the distance that Ss sat from the E. The absence of overall diagnostic group differences in learning and the finding that in some proxemic conditions schizophrenics learned more than nonschizophrenics are consistent with the view that under appropriate conditions schizophrenics emit behaviors that are incompatible with an assumption of schizophrenic deficit.

Conditioning, Classical↗

Effect of capsaicin on learning, retention and extinction of spatial and active avoidance tasks in adult rats neonatally treated.

The relationship between learning capability and neurological damage following neonatal treatment with capsaicin (50 mg/kg) was studied in adult Wistar rats of either sex using different experimental procedures. First of all, the reaction to a stress-inducing situation was evaluated by analysing the behavior of capsaicin and vehicle-treated rats in an open field situation. No differences were observed between these two groups. Moreover, the parameters considered were similar to those of untreated, age-matched animals. Rats treated with capsaicin showed a marked learning impairment of an appetitive task in a complex maze. On the contrary, no alterations were observed in both retention and extinction of this conditioned behavior. In spatial discrimination investigated using a different maze (8-arm radial maze) but with the same reinforcement (food), no difference was found between capsaicin-and vehicle-treated rats. In both groups a trial number-related increase of the responding efficiency and a decrease in the mean running time were observed. Neonatally treated rats behaved also similarly in aversive conditioning. However, their learning performances were much better than those of untreated rats. These results confirm that neonatal exposure to painful stimuli later improves active avoidance performance. Capsaicin treatment did not have any effect on the latency of nociceptive response in the hot-plate test.

Aging↗

Isradipine suppresses amphetamine-induced conditioned place preference and locomotor stimulation in the rat.

The locomotor activating and the reinforcing effects of psychomotor stimulants are considered to be correlated with and responsible for the development and maintenance of stimulant addiction. Experiments were conducted to examine the effects of isradipine, the L-type calcium channel inhibitor, on the d-amphetamine-induced (1 mg/kg IP) reinforcement (conditioned place preference) and locomotor stimulation. Isradipine dose-dependently (0.6, 1.2, 2.5 mg/kg IP) attenuated the reinforcing effect of amphetamine. Two higher doses completely blocked the induction of place preference. At these doses isradipine also prevented the increase in the number of intercompartment crosses that was observed in both amphetamine- and vehicle-treated controls. In an acute experiment, isradipine failed to affect locomotor activity on its own either in the place preference boxes or in the open field. Amphetamine increased the open field activity but did not change the number of crosses in the place preference boxes. Only the highest (2.5 mg/kg) dose of isradipine significantly suppressed amphetamine-induced hyperactivity in the open field. The present results suggest that isradipine interferes with amphetamine-derived reinforcement at doses lower than those needed to block the acute locomotor effects of amphetamine. Given the qualitatively similar, previously reported results with verapamil, we conclude that the antireinforcing effects of the L-type calcium channel blockers cannot be exclusively explained by the suppression of psychomotor stimulation. The present results further support the notion that the L-type calcium channel blockers may be effective against stimulant addiction.

Amphetamine↗

Entorhinal cortex lesions impair the use of distal but not proximal landmarks during place navigation in the rat.

Rats with entorhinal cortex lesions were trained in two versions of the place navigation task in the Morris water maze. In the distal condition, they had to locate the hidden platform on the basis of remote landmarks, while in the proximal condition, they had to rely only on a configuration of proximal objects, placed directly in the pool. Entorhinal rats were impaired in using distal landmarks but were able to use proximal landmarks to navigate toward the platform. These results suggest that the use of distal and proximal landmarks during navigation involves activation of different neural structures. They also suggest, in agreement with previous data, that there are two distinct landmark-processing systems, one devoted to the processing of proximal landmarks and the other to the processing of distal landmarks.

Animals↗

Environmental enrichment increases progenitor cell survival in the dentate gyrus following lateral fluid percussion injury.

Neurons in the hilus of the dentate gyrus are lost following a lateral fluid percussion injury. Environmental enrichment is known to increase neurogenesis in the dentate in intact rats, suggesting that it might also do so following fluid percussion injury, and potentially provide replacements for lost neurons. We report that 1 h of daily environmental enrichment for 3 weeks increased the number of progenitor cells in the dentate following fluid percussion injury, but only on the ipsilesional side. In the dentate granule cell layer, but not the hilus, most progenitors had a neuronal phenotype. The rate of on going cell proliferation was similar across groups. Collectively, these results suggest that the beneficial effects of environmental enrichment on behavioral recovery following FP injury are not attributable to neuronal replacement in the hilus but may be related to increased neurogenesis in the granule cell layer.

Animals↗

Nicotinic involvement in memory function in zebrafish.

Zebrafish are an emerging model for the study of the molecular mechanisms of brain function. To conduct studies of the neural bases of behavior in zebrafish, we must understand the behavioral function of zebrafish and how it is altered by perturbations of brain function. This study determined nicotine actions on memory function in zebrafish. With the methods that we have developed to assess memory in zebrafish using delayed spatial alternation (DSA), we determined the dose effect function of acute nicotine on memory function in zebrafish. As in rodents and primates, low nicotine doses improve memory in zebrafish, while high nicotine doses have diminished effect and can impair memory. This study shows that nicotine affects memory function in zebrafish much like in rats, mice, monkeys and humans. Now, zebrafish can be used to help understand the molecular mechanisms crucial to nicotine effects on memory.

Acetylcholine↗

Learning of landmark stability and instability by hippocampal place cells.

Place cells in the rat hippocampus fire whenever the animal is in a particular location. In a symmetrical environment, their receptive fields (place fields) are oriented by visual cues, and if these are unavailable they are oriented by movement-generated (idiothetic) cues. The present study tested the hypothesis that the cells would learn not to 'trust' a visual cue if the rat experienced it to be unstable (Knierim et al., 1995. Place cells, head direction cells and the learning of landmark stability. J. Neurosci. 15, 1648-1659). In an otherwise symmetrical environment, a visual cue was moved with respect to the idiothetic cues, either in sight or out-of-sight of the rat. When the visual cue was moved out-of-sight of the rat, place fields were initially oriented by this cue in preference to the idiothetic cues. However, if the cue was seen by the rat to be mobile, place fields ceased following the visual cue and became oriented by the idiothetic cues instead. If the cue was not seen to be mobile until the rat had had several days of experience in the environment, then the fields continued to be oriented by the (now visibly mobile) visual cue. It thus appears that the orienting influence of a visual cue on place fields can be either strengthened or weakened relative to the idiothetic cues, depending on the experience of the rat.

Animals↗

On the transience of egocentric working memory: evidence from testing the contribution of limbic brain regions.

Rats trained on a nonmatching-to-turn rule revealed that egocentric working memory is readily disrupted, hard to use, and transient. In Experiment 1, rats failed to acquire the rule in a plus-maze. Experiment 2 used 2 different plus-mazes to remove any intramaze cues. Task acquisition occurred only when rats could use direction cues (i.e., nonegocentric cues). In Experiments 3 and 4, a J maze was used to minimize the retention interval and eliminate handling rats within a trial. All rats acquired the nonmatching rule, although a 3-s retention delay severely impaired performance. Fornix lesions transiently disrupted performance of the J-maze task (Experiments 3 and 4), but neither fornix (Experiment 1) nor retrosplenial (Experiment 2) lesions impaired the plus-maze tasks.

Analysis of Variance↗

The effects of hippocampal lesions on response, direction, and place learning in rats.

Rats with hippocampal or sham lesions were trained to find food on a T maze located at 2 positions. Response rats were required to make a right or left turn. Direction rats were required to go in a consistent direction (east or west). Place rats were required to go to a consistent location, relative to room cues. One place group had distinguishable start points at the 2 maze positions, whereas another place group had start points facing the same side of the room. Controls took longer to solve a place problem than the response and direction problems when the start points were not distinguishable. Rats with hippocampal lesions were not different than controls on the response problem but were impaired on the direction and place problems.

Analysis of Variance↗

Metabolic alterations in the prefrontal and cingulate cortices are related to behavioral deficits in a rodent model of attention-deficit hyperactivity disorder.

Rats with a deficit in selective attention accompanied by impulsivity can be identified using a five-choice serial reaction time task (5-CSRT) and have been proposed to represent a rodent model of attention-deficit hyperactivity disorder (ADHD). The aim of the present study was to investigate which brain areas are important for visuospatial attention and to test the specific hypothesis that dysfunction of the frontal cortex is related to the behavioral deficits observed in poorly performing rats. Therefore, [(14)C]deoxyglucose (DG) uptake, an index of brain metabolic activity, was measured during the performance of a 5-CSRT task in two populations of rats (poorly and well-performing rats) to study the relationships between the regional brain activity and behavioral output. While performing a 5-CSRT task, poorly performing rats exhibited lower DG uptake in the cingulate and ventrolateral orbital cortices than did well-performing rats,. Moreover, there was a positive correlation between choice accuracy and DG uptake in several areas, especially in the frontal and parietal regions, whereas there was an inverse correlation between the percentage of premature responses and DG uptake in the ventrolateral orbital and cingulate cortices. These results, which demonstrated that the poorly performing rats exhibited metabolic dysfunction in the cingulate and prefrontal cortices, provide a basis for the face validity of the rodent model of ADHD. Moreover, they suggest that the neural network of attention in rats is remarkably analogous to that described in primates.

Animals↗

Galantamine-induced behavioral recovery after sublethal excitotoxic lesions to the rat medial septum.

Clinical trials show beneficial effects of acetylcholinesterase (AChE) inhibitors, including galantamine, on cognitive functions in patients with mild to moderate Alzheimer's disease. Galantamine shows a dual action profile by also acting as an allosteric modulator of nicotinic acetylcholine receptors. Nevertheless, its in vivo mechanism of action is only partly understood. Here, we first established a novel lesion model provoking significant functional impairment of the septo-hippocampal projection system without triggering massive neuronal death in the rat medial septum. Next, we studied whether galantamine, administered in doses of 1 and 3mg/kg post-lesion, promotes functional recovery of spatial navigation behaviors, and affects the output of septal cholinergic projections. Infusion of N-methyl-d-aspartate (NMDA; 30nmol/1microl) in the medial septum resulted in spatial learning deficits associated with significant shrinkage of cholinergic neurons and reduced AChE activity in the hippocampus at 7 days post-lesion. Galantamine treatment alone significantly increased the hippocampal acetylcholine concentration and attenuated the NMDA-induced spatial learning impairment. Galantamine post-treatment also affected NMDA-induced changes in AChE and choline-acetyltransferase activities. In conclusion, our data show that galantamine attenuates experimentally-induced cognitive impairments underscored by mild neuronal damage.

Acetylcholinesterase↗

Behavioral impairment in the rat after colchicine lesions of the hippocampus and nucleus basalis.

Rats were given bilateral injections of colchicine into the nucleus basalis (NBM; 1.0 or 2.0 micrograms/site), hippocampus (HPC; 1.25 or 2.5 micrograms/site), or both areas (COM; 1.0 NBM, 1.25 HPC) and examined for changes in locomotor activity, passive avoidance behavior, and spatial navigation in a water maze task. Colchicine injected into the HPC caused a dose-related increase in locomotor activity 7 days after treatment which declined with repeated testing. Motor activity in NBM-lesioned rats was not significantly different from control. Rats with the COM lesion were more active than controls 7 days after treatment and remained hyperactive over the 3 week testing period. Retention of a step-through passive avoidance task was examined 18 days after surgery. HPC lesions had no apparent effect on passive avoidance behavior. NBM lesions causes a dose-dependent decrease in step-through latencies, while latencies in the combined group were comparable to the low dose NBM group. In the spatial navigation task, HPC and COM lesions impaired acquisition, with little indication of learning in the combined group. NBM lesions had no effect in the water maze. These data suggest that combined lesions of the NBM and HPC cause lasting behavioral impairments and may be useful as a model for neurodegenerative disorders such as Alzheimer's disease.

Animals↗

A force-plate actometer for quantitating rodent behaviors: illustrative data on locomotion, rotation, spatial patterning, stereotypies, and tremor.

This report describes a new kind of actometer for recording the behavior of rodents or other small animals. The instrument, a force-plate actometer, uses a stiff, low-mass horizontal plate coupled to four supporting force transducers positioned at the corners of the plate. When an animal moves on the plate, its movements are sensed by the transducers whose signals are processed by computer to yield measurements of a wide range of behaviors or behavioral attributes, such as locomotor activity, rotation around the center, whole-body tremor, and amphetamine-induced stereotypies. Spatial resolution is less than 1 mm, and temporal resolution is 0.02 s. Sample data were presented comparing the locomotor activity of CD-1, BALB/c, and C57BL/6 mice before and after treatment with D-amphetamine sulfate. Rotational behavior was recorded in an amphetamine-treated rat that had sustained a unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal system. In the C57BL/6 mouse, harmaline-induced tremor was quantified. With rats as subjects, the force-plate actometer was used to quantify amphetamine-induced stereotypies, to demonstrate the development of sensitization to amphetamine's effects, and to quantitate the consistent 11-12 Hz rhythmicities that underlie the sterotypies. The performance of the force-plate actometer was compared with that of a variety of instruments reported in the literature on behavioral instrumentation. Finally, potential applications in neuroscience research other than those illustrated in this report were discussed.

Amphetamine↗

Behavioral effects of lesions of precommissural and postcommissural fornix.

Lesions which sever different parts of precommissural or postcommissural fornix were compared to the effects of control lesions in several behavioral tasks. Spatial learning and avoidance was impaired by lesions of the descending columns, or by lesions which sever the precommissural communications passing to and from medial septum. Damage to precommissural fibers through lateral septum produced a measurable change only on the avoidance task. This pattern of deficits, considered together with the anatomical relationship of the system, suggests a model in which the medial septum relays kinesthetic information to dorsal hippocampus, which in turn serves as a memory system in the performance of spatial habits. It is less clear what kind of information is relayed by lateral septum, but it may communicate with ventral hippocampus regarding the consequences of punishment, and thus serve as part of a system for defensive suppression of behavior.

Animals↗