I. V. Chueva

Neurophysiological correlates of delayed visual differentiation tasks in monkeys: the effects of the site of intracortical blockade of NMDA receptors.

A delayed visual differentiation task using stimuli of different colors was used in rhesus macaques to study the characteristics of visual recognition, short-term memory, and the responses of neurons recorded simultaneously in the visual and prefrontal areas of the cortex, along with their relationships with the site of intracortical (fields 17 or 46) perfusion of the glutamate receptor antagonist 2-amino-5-phosphonovaleric acid (APV). The behavioral characteristics and spike activity of individual cells in cortical fields 17 and 46 were recorded before and after perfusion with APV and after washing away of traces of APV. Multifactor dispersion analysis showed that the effect of APV in monkeys consisted of decreases in the probability of correct responses, leading to a decrease (two-fold) in the duration of short-term storage of information and a significant increase in the motor reaction time. The probability of correct solutions depended on the site of APV perfusion in the cortex, while the motor response time was independent of the perfusion site. Perfusion of field 46 with APV, unlike perfusion of field 17, altered the spike activity only of neurons in the prefrontal cortex, while no significant changes were seen in the neuron activity of the visual cortex. The actions of APV were accompanied by significant desynchronization of neuron activity in these two areas as compared with the level of synchronization in normal conditions; after traces of APV were washed away, the extent of desynchronization decreased. The neurophysiological correlates of cognitive dysfunctions associated with degradation of visual recognition and short-term memory due to modification of glutamatergic structures by blockade of NMDA receptors are discussed.

Effect of NMDA on the activity of cortical glutaminergic structures in delayed visual differentiation in monkeys.

The effect of intracortical perfusion with the glutamate agonist NMDA on visual recognition and short-term memory, as well as on the responses of visual cortex neurons, were studied in rhesus macaques. A microdialysis technique was used in combination with multichannel microelectrode recording of single cortical cells in the immediate vicinity of the dialysis tube in a behavioral experiment in which the monkey had to solve a task involving delayed visual differentiation of stimuli of different colors. NMDA altered the characteristics of recognition in monkeys. The duration of information storage in short-term memory was increased significantly (2–4-fold), and there was a significant reduction in the motor response time for all delay periods. These changes were accompanied by a significant rearrangement of neuron activity in the visual cortex at all stages of the behavioral task. At different stages of the task, 70–85% of the neurons showed 2–5-fold increases in activity, while 6–20% showed reductions in activity. These results demonstrate an involvement of visual cortex glutaminergic structures in the processes of visual recognition and short-term memory, as well as a nootropic effect obtained by intracortical administration of NMDA.

Neurophysiological correlates of improvements in cognitive characteristics in monkeys during modification of NMDA-ergic structures of the prefrontal cortex

The effects of modification of NMDA-ergic structures by microdialysis perfusion in the prefrontal cortex (field 8) with NMDA glutamate (2 mM) on visual recognition and short-term memory (STM) were studied in rhesus macaques, using methods based on the deferred differentiation of stimuli of different colors. Impulse activity of neurons in the prefrontal and visual cortex was measured during these experiments, both before and after administration of NMDA. NMDA increased (2-fold) the duration of short-term retention of information and significantly reduced the latent period of the motor response at all delay periods, and also produced significant changes in neuron activity in the prefrontal cortex: depending on the stage of behavior, activity decreased in 60–75% of neurons and increased in 8–26%. NMDA produced significant increases in the cross-correlation coefficients between the responses of neurons in the visual and prefrontal cortex. The results showed that glutaminergic structures in the prefrontal cortex are involved in processes of visual recognition and STM in monkeys. The effect of NMDA, which synchronized cortical neuronal processes, improved the short-term understanding of visual information.

Impairments in working memory and decision-taking processes in monkeys in a model of Alzheimer's disease.

Studies were performed on two groups of animals (three monkeys in each). Monkeys of group I received unilateral intracerebroventricular injections of the neurotoxin p75-saporin (the ribosomal toxin saporin bound to monoclonal antibody to the p75NTR receptor), which elicits irreversible degradation of cholinergic neurons in the basal nuclei of Meynert, along with the enzyme dopamine-β-hydroxylase (DBH-saporin), which impairs the functioning of noradrenergic neurons in the locus ceruleus. Monkeys of group II received injections of sterile physiological saline (0.9% NaCl). Monkeys were trained to discriminate stimuli containing different types of information (spatial frequency grids, geometric figures with different colors, different spatial relationships between objects) and perform spatial selection. The characteristics of working memory were identified in delayed differentiation tasks in monkeys of both groups before and after injections. These studies provided the first evidence that the development of Alzheimer’s disease in rhesus macaques is characterized by a deficiency of working memory, this being based on impairment of two components of these processes. Impairment of the first in monkeys of group I was manifest in delayed visual differentiation as a significant decrease in correct responses. The extent of decreases depended on the duration of the delay and the type of visual information. Impairment of the second component, associated with decision-taking processes, was characterized by an increase in refusals to take decisions and was independent of the duration of delays and the type of visual information. Monkeys given injections of physiological saline showed no significant differences in these characteristics. The features of impairments in these memory components resulting from the development of Alzheimer’s disease demonstrate that the structural-functional organization of cholinergic and noradrenergic mechanisms responsible for sensory processing differ from those involved in decision-taking.

Disorders of Learning and Memory Processes in a Monkey Model of Alzheimer's Disease: The Role of the Associative Area of the Cerebral Cortex

The processes of learning and storage of the results of learning were studied in a model of Alzheimer’s disease in two groups of rhesus macaques (three individuals in each group). Studies were performed after injection of neurotoxins (group I) and physiological saline (group II, controls). Two months after injections (stage C1), learning parameters were studied in monkeys of both groups using a new stimulus discrimination test (filled geometrical figures versus outline figures). There were significant differences between the animals of the two groups. Learning was hindered in monkeys of group I, with significant increases in the learning time (the time to achieve a stable probability of correct responding of 0.85) and in the probability of refusals. Monkeys of group II showed no learning impairment. Animals were trained to discriminate new stimuli (images of two monkeys) six months after injections (stage C3). Learning was impaired in animals of group I, such that learning measures had the same levels as previously; monkeys of group II showed no learning impairment. Analysis of the characteristics of working memory, which is involved in storing the results of new learning, was performed at stage C1; monkeys of group I showed significant degradation of these measures, with a significant decrease in the probability of correct solutions at stage C1 (to a level of 0.5), with some increase at stages C2 (at four months) and C3, along with a significant increase in the probability of refusals, values being similar at all time points. For monkeys of group II, these characteristics showed no degradation. Motor response times at stages C1, C2, and C3 were not different for the two groups of monkeys. The structural-functional organization of interactions between sensory and cognitive processes during learning and the storage of information in working memory are discussed, as is the role of the associative areas of the cortex in these interactions.

Organization of Working Memory Processes in Monkeys: The Effects of a Dopamine Receptor Agonist

The effects of the dopamine receptor agonist agroclavin on cognitive processes associated with mechanisms of visual recognition and long-term and working (short-term) memory were studied in delayed visual differentiation and delayed spatial selection tasks in monkeys (rhesus macaques). Measurements made before and after p.o. pharmacological treatment with this agent were used to identify the p.o. dose (5 mg/kg) inducing a significant effect. The psychotropic effect of agroclavin, which induced cognitive dysfunction, was present in all the monkeys studied to one extent or another. Behavioral criteria were: the probability of correct solutions of the visual differentiation task, the probability of refusals to resolve the task, and the time taken for correct motor responses. Despite individual differences in these behavioral characteristics in monkeys, significant changes due to agroclavin were consistently evident in all animals. There was a reduction in the probability of correct solutions, due to worsening of the characteristics of short-term memory; most monkeys showed increases in the numbers of refusals to solve tasks and increases in the time for correct motor responses during these solutions. In fact, all monkeys showed no increases in the number of erroneous solutions in visual differentiation and spatial selection tasks without delays, though in most cases there were increases in the time taken for correct motor reactions and the number of refusals to solve tasks. Data were obtained indicating that the effect of agroclavin was not uniform with respect to different types of visual information. The possible structural-functional organization of processes underlying working memory is discussed on the basis of the conclusion that the behavioral characteristics studied here reflect different components of cognitive processes realized by structures with different functional properties and different locations.

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 Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s 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.

Specific characteristics of cholinergic mechanisms of short-term memory in monkeys for different types of visual information: the effects of amizil.

Experiments on rhesus macaques were used to study the relationship between the characteristics of delayed visual differentiation and stimulus properties in conditions of pharmacological treatment with the m-cholinoreceptor blocker amizil, with the aim of identifying how modification of cholinergic structures affects different types of information. Disturbances to short-term memory for all stimuli consisted of reductions in the duration of retention and increases in motor reaction times, but occurred at different doses of the blocker: amizil at a dose of 0.3 mg/kg significantly decreased the retention duration for information relating to spatial relationships. Delayed discrimination of shape, contrast, and size worsened after treatment with amizil at a dose of 0.45–0.50 mg/kg, while decreases in the duration of short-term storage of information relating to color started after amizil doses of 0.6–0.8 mg/kg. It is suggested that the short-term memory system includes a set of neurophysiological mechanisms in which the cholinergic structures are organized differently and whose specific properties result in differences in the characteristics of short-term storage of different types of visual information.

Neurophysiologic correlates of the decision-making processes in the cerebral cortex of monkeys during visual recognition

The impulse activity of groups of neurons of the visual, prefrontal, and inferotemporal cortex was recorded simultaneously in behavioral experiments on monkeys solving a problem of delayed visual differentiation of variously colored stimuli. The neurophysiological correlates of the decision-making processes were studied. Erroneous motoric reactions were accompanied in all monkeys by significant reorganizations of the patterns of impulse activity of the neurons. In the case of correct solutions of the monkeys, synchronization in time and cross-correlation which was significant in magnitude between the activity of the groups of neurons were observed. Incorrect solutions were accompanied by desynchronization and by a decrease in cross-correlation between the activity of these groups of neurons. Possible decision-making mechanisms and the causes of the desynchronization of the informational processes during erroneous reactions are discussed.

An antioxidant-induced improvement in the cognitive characteristics of monkeys: Neurophysiological correlates in the visual cortex

After the injection of the antioxidant, oxymethacil (4–5 μg/kg), in an investigation in monkeys of the processes of delayed visual recognition, their cognitive characteristics were significantly improved.: the duration of the short-term storage of information increased (by a factor of 2–3) and the time of the motor reaction decreased. The improvement of the cognitive characteristics was accompanied by changes in the neuronal activity in the visual cortex at all stages of recognition. The activity of the majority of the neurons increased in the case of discrimination without delay; it decreased significantly in the case of delayed discrimination. The administration of oxymethacil induced an increase in the auto-and cross-correlation coefficients in the respondent reactions of the recorded groups of neurons. The results obtained suggest that oxymethacil possesses nootropic properties, and the participation of the visual cortex of monkeys in the realization of these properties for the improvement of cognitive characteristics.