Effects of the NMDA antagonists CPP and MK-801 on delayed conditional discrimination

N-methyl-D-aspartate (NMDA) receptor/channel antagonists have previously been shown to impair spatial working memory and hippocampal long-term potentiation. The present experiment investigated the effects of a variety of doses of NMDA antagonists on a working memory task in rats involving an auditory delayed conditional discrimination. Signal detection analysis and an exponential memory decay model were used to extract independent measures of stimulus discriminability and rate of forgetting. A competitive NMDA antagonist, (CPP, 0.33, 1.0, 10.0 mg/kg, IP) produced a reduction in discriminability which was linearly related to log dose, but which was only clear at the 10 mg/kg dose. Rate of forgetting was not increased by any dose. Similar results were obtained with a non-competitive antagonist (MK-801, 0.1, 0.33 mg/kg, IP). These data suggest that doses of NMDA receptor channel antagonists sufficient to disrupt hippocampal long-term potentiation and radial arm maze performance will also disrupt delayed conditional discrimination. The effect on delayed conditional discrimination is due to a disruption of stimulus discriminability and not to an increased rate of forgetting. The extent to which these effects relate to the reported changes in hippocampal long-term potentiation and radial arm maze performance remains to be determined.     

Hemicholinium-3 impairs spatial learning and the deficit is reversed by cholinomimetics

The effects of hemicholinium-3 (HC-3) on spatial discriminaton learning were studied. Rats were equipped with indwelling cannulae in the right lateral ventricle and, following recovery, were trained on a two platform spatial discrimination task in a water maze. In this task a visible escape platform remains in a fixed position in the pool during a single training session, whilst the location of an identical float (which affords no escape) is randomly varied. For each session the location of the fixed escape platform was changed and the rats were retrained to criterion following pretreatment either with artificial cerebrospinal fluid (CSF) or HC-3 (2.5, 5.0 g/rat/ICV) 1 h before training. Each rat received every treatment according to a latin square design. The results showed that spatial learning was dose dependently impaired by HC-3, choice accuracy being reduced to chance levels by the higher dose. There was no evidence of motoric difficulty, as choice latencies were not significantly increased. Experiments were then conducted to test for reversal of the deficit using a range of psychotropic drugs. Rats were treated with CSF or HC-3 (5 g/rat ICV) 60 min prior to testing and test drugs were injected 15 min before testing. Some doses of physostigmine (46–460 g/kg/SC) and tetrahydroaminoacridine (THA) (2.2–10 mg/kg/SC) reversed the spatial learning deficit. The muscarinic agonists arecoline (0.046–1 mg/kg/SC), aceclidine (1–10 mg/kg/SC), oxotremorine (30–100 g/kg/SC) and RS-86 (0.46, 1.0 g/kg/SC) were also effective. Pilocarpine (0.22–2.2 mg/kg/SC) showed marginal activity and isoarecoline (4.6–10 mg/kg/SC) was inactive. Nicotine (0.32, 1, 3.2 mg/kg/SC) and piracetam (10, 30, 100 mg/kg IP) were also inactive. The ₂ agonist, clonidine (46, 100 g/kg SC) and the antagonist idazoxan (32, 100 g/kg SC) were also inactive. Learning deficits were not reversed by haloperidol (20, 60 g/kg), amphetamine (0.1, 0.46 mg/kg), the selective 5-HT_1A agonist 8-OH-DPAT (30, 100 g/kg) or by the benzodiazapine antagonist ZK 93426 (1, 3.2, 10 mg/kg). The results show that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and these deficits are reversed by cholinesterase inhibitors and some muscarinic receptor agonists. Some degree of pharmacological selectivity is indicated by the failure of a range of other drugs to reverse the impairments.     

Trajectory of contact region on the fingerpad gives the illusion of haptic shape

When one explores a solid object with a fingertip, a contact region is usually defined. When the trajectory of this region on the fingerpad is artificially controlled so as to resemble the trajectory that is normally present while exploring a real object, the experience of shape is created. In order to generate appropriate local deformation trajectories, we built a servo-controlled mechanism that rolled a flat plate on the fingerpad during the manual exploration of virtual surfaces so that the plate was kept tangent to a virtual shape at the point of virtual contact. An experiment was then designed to test which mode of exploration maximized the shape information gain: active versus semi-active exploration, where semi-active exploration is when one hand touches passively and the other moves the target object, and the use of single versus multiple points of contact. We found that subjects were able to perform curvature discrimination at levels comparable to those achieved when using direct manual contact with real objects, and that the highly simplified stimulus provided by the device was a sufficient cue to give the illusion of touching three-dimensional surfaces.     

Interaction of sensory and cognitive processes during visual recognition: The role of the associative areas of the cerebral cortex

The first part of the present study used a model of Alzheimers disease in two groups of animals (three monkeys in each), given injections of neurotoxins (monkeys of group I) and physiological saline (monkeys of group II). Before injections, all monkeys were trained to discriminate stimuli containing different types of information (spatial frequency grids and geometrical figures of different colors and with different spatial relationships between objects) and to perform spatial selection. The dynamics of impairments in the characteristics of working memory were identified using delayed differentiation tasks in monkeys of both groups before injections and every two months after injections. Quantitative measures of impairments were made using the entropy of visual recognition, which characterizes uncertainty in decision-taking. The development of Alzheimers disease in rhesus macaques was characterized by a deficit of working memory, resulting from lesions to the two component processes of memory. Impairments of the first of these in monkeys of group I were manifest as a significant increase in entropy, which is associated with correct decision-taking. The magnitude of the increase depended on the type of visual information. Impairments of the second component were characterized by increases in entropy associated with refusals to take decisions and were independent of the delay duration and the type of visual information. Monkeys given injections of physiological saline showed no significant changes in these characteristics. The features of working memory were also studied in the second part of the investigation, using four groups of Rhesus macaques: intact, those with bilateral extirpation of the sulcus principalis or field 7 or both: degradation again identified two components. Entropy associated with this was increased significantly for most of the stimuli tested on monkeys of all extirpation groups as compared with intact animals. Significant differences were found in these characteristics for a number of stimuli, which depended on the location of the structures removed. The characteristics of impairments of the components of working memory resulting in the development of Alzheimers disease showed that the cholinergic mechanisms responsible for sensory processing differ from those involved in decision-taking. The structural-functional organization of the interaction of sensory and cognitive processes controlled by the motivation and attention systems is discussed, as is the role of the associative areas of the cortex.Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 89, No. 10, pp. 1226–1239, October, 2003.     

Developmental characteristics of topographic EEG in the newborn using an autoregressive model

Summary Autoregressive topographic EEG analysis was used to determine topographic EEGs of the total power in quiet and active sleep stages in 33 healthy premature infants of 34 to 40 weeks conceptional age. The developmental characteristics were also examined by simultaneously referring to the autoregressive pattern discrimination of topographic EEGs between different conceptional age groups in both sleep stages. Treating 10.24 seconds of EEG as one segment, the topographic EEG of 10 segments in each of the quiet and active sleep stages as well as their mean were obtained. In both sleep stages the results showed a small peak in total power in the frontal region and a large peak in the occipital region, but total power was greater in the quiet sleep. Total power decreased with increasing conceptional age. Topographic pattern discrimination between different conceptional age groups showed significant differences mainly in the frontal, temporal and occipital regions. It was concluded that regional differences in the development of EEG in premature infants could be clarified by means of topographic EEG analysis and the pattern discrimination method using the autoregressive model.This study was supported by a Scientific Research Grant (No. 02670450) from the Japanese Ministry of Education.     

Spontaneous recognition of object configurations in rats: effects of fornix lesions

The effects of fornix lesions were examined in an object recognition memory test based on spontaneous exploration. In the standard condition an object (A) was presented in the sample phase and then presented again in the test phase alongside a new object (B). Both fornix-transected (Fx) and control (Co) rats spent more time exploring the new object than the familiar object after retention delays of 1 min and 15 min. In two configural conditions designed to test sensitivity to reconfigured stimuli, the original sample (A) was now either re-presented alongside its rearranged version (), or the re-arranged version itself () was presented with a new object (B). In the first configural condition, both the Co and Fx rats spent more time exploring the reconfigured sample () than the original version of the sample (A) following a delay of 1 min, but not 15 min. In the second configural condition, both Co and Fx rats spent more time exploring the new object (B) than the reconfigured version of the sample () following a delay of 15 min but not 1 min. These present results do not support Sutherland and Rudy's hypothesis on hippocampal function; however, they demonstrate that memory of objects as well as memory of reconfigured objects could easily be examined in a test based on spontaneous exploratory behaviour.     

Visual discrimination learning in dwarf goats and associated changes in heart rate and heart rate variability

We studied visual discrimination learning in a group of Nigerian dwarf goats using a computer-based learning device which was integrated in the animals' home pen. We conducted three consecutive learning tasks (T1, T2 and T3), each of which lasted for 13 days. In each task, a different set of four visual stimuli was presented on a computer screen in a four-choice design. Predefined sequences of stimulus combinations were presented in a pseudorandom order. Animals were rewarded with drinking water when they chose the positive stimulus by pressing a button next to it. Noninvasive measurements of goats' heartbeat intervals were carried out on the first and the last 2 days of each learning task. We analysed heart rate (HR) and heart rate variability (HRV) of resting animals to study sustained physiological effects related to general learning challenge rather than acute excitement during an actual learning session. The number of trials to reach the learning criterion was 1000 in T1, when visual stimuli were presented to the goats for the first time, but decreased to 210 in T2 and 240 in T3, respectively. A stable plateau of correct choices between 70% and 80% was reached on Day 10 in T1, on Day 8 in T2 and on Day 6 in T3. We found a significant influence of the task and of the interaction between task and day on learning success. Whereas HR increased throughout T1, this relationship was inverted in T2 and T3, indicating different effects on the HR depending on how familiar goats were with the learning task. We found a significant influence of the task and the interaction between task and time within the task on HRV parameters, indicating changes of vagal activity at the heart. The results suggest that changes in HR related to learning were predominantly caused by a withdrawal of vagal activity at the heart. With regard to nonlinear processes in heartbeat regulation, increased deterministic shares of HRV indicated that the animals did not really relax until the end of T3. Comparing changes of HR and HRV in T3 and in a subsequent postexperiment (PE), we assume a positive effect of such cognitive challenges once the task had been learned by the animals.     

Electrical activity in the prefrontal cortex specific to no-go reaction of conditioned hand movement with colour discrimination in the monkey

Summary Monkeys were trained to perform hand movements in a reaction time task with discrimination between positive (go) and negative (no-go) light signals, and field potentials in various cortical areas were recorded and analysed with chronically implanted cortical electrodes. As previously reported, areas such as the prefrontal, premotor and motor cortices were active in association with simple visually-initiated, reaction-time hand movements. The caudal part of the dorsal bank of the principal sulcus was found to be activated specifically on no-go trials during discrimination, and revealed a relatively sharp surface-negative, depth-positive potential. The potential appeared at a latency of 110–150 ms, which was 150–210 ms earlier than the movement onset on go trials. With reversal of the go and no-go signals, this potential was found to be recorded only on no-go trials, irrespective of the colour used for the stimulus. It is suggested that the activity in the dorsal bank of the principal sulcus is related to the judgement not to execute the movement and/or the suppression of motor execution.     

A biological context for the self-nonself discrimination and the regulation of effector class by the immune system

An effective immune response to an antigen requires two sets of decisions: Decision 1, the sorting of the repertoire, and Decision 2, the regulation of effector class. The repertoire, because it is somatically generated, large, and random, must be sorted by a somatic mechanism that subtracts those specificities (anti-self) that, if expressed, would debilitate the host, leaving a residue (anti-nonself) that, if not expressed, would result in the death of the host by infection. The self-nonself discrimination is the metaphor used to describe Decision 1, the sorting of the repertoire. In order to be functional, the sorted repertoire must be coupled to a set of biodestructive and ridding effector functions, such that the response to each antigen is treated in a coherent and independent manner. Although a reasonably complete framework for Decision 1 exists, Decision 2 lacks conceptualization. The questions that must be considered to arrive at a proper framework are posed. It should be emphasized that manipulation at the level of Decision 2 is where clinical applications are likely to be found.     

Operant conditioning studies of taste discrimination in the pigeon (Columba livia)

In the conditioning procedure employed in this study, pigeons were trained to dip their bills into a container and then to peck either at a left or at a right key, depending on whether the container was full of distilled water or of a solution of the substance being tested. The discrimination thresholds found (from one bird each) were 2 g/l (0.034 M) for NaCl, 2 g/l (0.024 M) for NaHCO₃, 1 g/l (0.013 M) for KCl, 0.5 g/l (0.005 M) for KHCO₃. Following the same procedure, two birds were then faced with the choice between the solution of the known substance and of a novel one. A higher degree of discrimination was found between NaHCO₃ and KHCO₃ than between NaHCO₃ and NaCl; in the latter case, choices appeared to be mostly based on the concentration of the two substances.