EFFECTS OF MEDIAL SEPTAL LESION ON HIPPOCAMPAL EXTRACELLULAR GLUTAMATE AND GABA LEVELS DURING SPATIAL ALTERNATION TESTING.

The present study investigated spatial working memory assessed in spontaneous alternation (SA) task and hippocampal glutamate and GABA release prior to, during, and after SA test in sham-operated and electrolytic medial septal (MS) lesioned rats. Also, have been investigated the effects of MS lesion on KCl-stimulated release of glutamate and GABA in the hippocampus. Behavioral study showed that electrolytic lesion of MS significantly impaired SA performance. Although both groups of animals had an insignificant rise in their respective hippocampal glutamate efflux during the SA, the rise of MS lesioned animals was blunted when compared with control animals. Hippocampal GABA levels did not change during behavioral testing in both groups. Most of control animals showed increase in KCl-stimulated glutamate release. By contrast, only one MS lesioned rat showed increase in glutamate release in response to KCl stimulation. Most of control and MS lesioned rats were non-responders in GABA release in response to KCl stimulation. Decreased glutamate release (upon stimulation) in the MS lesioned rats may contribute to spatial working memory impairment in these animals. We propose that SA testing coupled with in vivo microdialysis sampling represents a suitable approach to revealing the neurochemical correlates of hippocampal-dependent memory function, and thus could be a useful tool for better understanding of the neurochemical basis of cognitive decline associated with various disorders and neurodegenerative diseases.

SPATIAL MEMORY IMPAIRMENT AND HIPPOCAMPAL CELL LOSS INDUCED BY OKADAIC ACID (EXPERIMENTAL STUDY).

In the present study, we evaluated and compared effect of intracerebroventricular (ICV) and intrahippocampal bilateral microinjection of okadaic acid (OA) on spatial memory function assessed in one day water maze paradigm and hippocampal structure in rats. Rats were divided in following groups: Control(icv) - rats injected with ICV and aCSF; Control(hipp) - rats injected intrahippocampally with aCSF; OAicv - rats injected with ICV and OA; OAhipp - rats injected intrahippocampally with OA. Nissl staining of hippocampal sections showed that the pyramidal cell loss in OAhipp group is significantly higher than that in the OAicv. The results of behavioral experiments showed that ICV or intrahippocampal bilateral microinjection of OA did not affect learning process and short-term spatial memory but induced impairment in spatial long-term memory assessed in probe test performance 24 h after training. OA-induced spatial memory impairment may be attributed to the hippocampal cell death. Based on these results OA induced memory deficit and hippocampal cell loss in rat may be considered as a potential animal model for preclinical evaluation of antidementic drug activity.

Effects of chronic memantine treatment on hippocampal extracellular glutamate and GABA levels during spatial alternation testing.

These experiments examined the release of glutamate (Glu) and GABA in the hippocampus of memantine (2,5mg/kg, i.p. for four weeks) or saline treated rats prior to, during, and after spontaneous alternation test. Glu and GABA release during the 10 min samples taken at the time of the behavioral testing of memantine or saline treated animals were not different from those seen immediately before and after testing. Similarly, the alternation scores were not significantly different between groups. We found increase in KCl-stimulated glutamate and GABA release in the hippocampus of memantine treated rat compared to the saline treated rat. This difference in KCl response between memantine treated and control rat was statistically significant (p<0,05). Our evaluation of memantine reveals that changes in KCl-stimulated Glu and GABA release after chronic memantine treatment did not affect working memory in adult rats assessed in spontaneous alternation task.

Effects of the uncompetitive nmda receptor antagonist memantine on recognition memory in rats.

Memantine is an NMDA receptor antagonist that has been recently approved in EU for the treatment of moderate to severe Alzheimer's disease. The previous studies have not allowed for the evaluation of the possible effects of this drug at therapeutic doses on different forms of memory. To address this question, we administered memantine to adult rats, using doses 2.5 or 5 mg/kg and evaluated the effects of these doses on open field activity and recognition memory. Memantine or saline was administered daily by intraperitoneal injection beginning on the day of behavioral testing and continuing 5 days. The main results of experiments are as follows: the memantine treatment produced a dose-related suppression of total ambulations. There was no significant impairment in detecting spatial and object novelty in the 2.5 mg/kg memantine treated rats. However, the 5 mg/kg intraperitoneal dose of memantine disrupted both recognition memory and locomotor behaviors. Our evaluation of memantine reveals that at doses lower than are required for neuroprotection disrupt memory. This raises the possibility that the beneficial effects seen in AD patients may be attributable to the interaction of memantine with other transmitter systems.

Spatial memory following selective cholinergic lesion of the nucleus basalis magnocellularis.

The aim of this study was to investigate the modulation of the cognitive function by the cholinergic cells of the nucleus basalis magnocellularis (NBM) and was designed to investigate the role of the NBM cholinergic cells in learning and memory using the immunotoxin 192 IgG-saporin to produce selective lesions of cholinergic NBM neurons. A total of 16 male outbred albino rats were used in the present study to investigate the ability of sham-operated and NBM immunotoxin lesioned rats to learn the location of a visible, as well as submerged platform in a water maze. Examination of the AChE stained sections showed that after injections of 192 IgG saporin into the NBM, animals exhibited significantly less AChE staining in PFC as compared to sections obtained from sham-operated animals. An overview of the data from both competition trials for each group show that the sham-operated rats in 13 trials out of 16 competition test trial used place strategy and NBM-lesioned ones used this strategy in 6 trials. Decreased place-bias in NBM-lesioned rats compared to the sham-operated rats was significant (t(d )= 2,42, P<0.02).The data obtained in the sham-operated and NBM-lesioned animals in the present study, demonstrate that the choice of strategy in the competition trial is related to performance during training: the rats exhibiting cue strategy (NBM-lesioned) on the competition trial had significantly worse performance during hidden platform training than those (sham-operated) exhibiting a place strategy. These findings suggest that the NBM is essential for accurate spatial learning and suggest its role in processing information about the spatial environment, but also we can propose, that the behavioral deficits described in the present study is nonmnemonic, possibly caused by deficit in attentional function.

[Regularities of the egocentric spatial memory development in children aged 24-60 months].

In order to assess development of the egocentric system of the spatial short-term memory in children (n=66) of different ages (24-60 months) the Inverted Delayed Reaction test has been used. It was found that in the children aged 24-36 months regularities of performance of the Inverted Delayed Reaction test significantly differ in conditions of different loads onto the mechanisms of dead reckoning; the children aged 36-60 months do not show sensitivity to different loads. In children aged 42+/-4 months functional elimination of any of the sensory system (visual, kinesthetic, vestibular) during rotation significantly deteriorated results of the Inverted Delayed Reaction test performance, while in children aged 60+/-4 months number of correct responses decreased if two or three sensory systems were eliminated simultaneously. The data obtained permit to conclude that the Inverted Delayed Reaction test is sufficiently sensitive for evaluation development of the egocentric spatial memory system in children and that formation of the dead reckoning mechanisms starts in an age of 24 months and in the period of 24-60 months its further upgrading does occur.

Effects of electrolytic lesion of medial septal nucleus on learning strategy selection in a visible platform version of the water maze.

This experiment investigated the ability of sham-operated and medial septal (MS) damaged rats to learn the location of a visible, as well as submerged platform in a water maze. The rats' responses on the competition test were classified as either cue or place, based on the swim path for those trials. Sham-operated rats acquired both the visible and hidden platform versions of the task, but when required to choose between the spatial location they had learned and the visible platform in a new location majority of them swam first to the old spatial location. The MS damaged rats acquired the visible platform version of the water maze task but failed to learn the platform's location in space. When the visible platform was moved to a new location they often swam directly to it. Sham-operated rats identified as place responders had significantly more accurate searches during hidden platform training, providing additional evidence of their effective use of a place learning strategy than MS is damaged. These findings suggest that in the absence of a septohippocampal functional system behaviour was not affected by spatial information and responding to local reinforced cues was enhanced. These data add to a growing literature demonstrating that the septo-hippocampal system is essential for accurate spatial learning and suggest its role in processing information about the spatial environment.

Exploratory behavior and recognition memory in medial septal electrolytic, neuro- and immunotoxic lesioned rats.

In the present study, the effect of the medial septal (MS) lesions on exploratory activity in the open field and the spatial and object recognition memory has been investigated. This experiment compares three types of MS lesions: electrolytic lesions that destroy cells and fibers of passage, neurotoxic - ibotenic acid lesions that spare fibers of passage but predominantly affect the septal noncholinergic neurons, and immunotoxin - 192 IgG-saporin infusions that only eliminate cholinergic neurons. The main results are: the MS electrolytic lesioned rats were impaired in habituating to the environment in the repeated spatial environment, but rats with immuno- or neurotoxic lesions of the MS did not differ from control ones; the MS electrolytic and ibotenic acid lesioned rats showed an increase in their exploratory activity to the objects and were impaired in habituating to the objects in the repeated spatial environment; rats with immunolesions of the MS did not differ from control rats; electrolytic lesions of the MS disrupt spatial recognition memory; rats with immuno- or neurotoxic lesions of the MS were normal in detecting spatial novelty; all of the MS-lesioned and control rats clearly reacted to the object novelty by exploring the new object more than familiar ones. Results observed across lesion techniques indicate that: (i) the deficits after nonselective damage of MS are limited to a subset of cognitive processes dependent on the hippocampus, (ii) MS is substantial for spatial, but not for object recognition memory - the object recognition memory can be supported outside the septohippocampal system; (iii) the selective loss of septohippocampal cholinergic or noncholinergic projections does not disrupt the function of the hippocampus to a sufficient extent to impair spatial recognition memory; (iv) there is dissociation between the two major components (cholinergic and noncholinergic) of the septohippocampal pathway in exploratory behavior assessed in the open field - the memory exhibited by decrements in exploration of repeated object presentations is affected by either electrolytic or ibotenic lesions, but not saporin.

Do amygdaloid nucleus centralis and nucleus lateralis serve similar functions in defensive responding in cats?

Bar pressing escape response has been trained, extinguished, retrained and then transformed into avoidance response in cats subjected to electrocoagulation of either the dorsolateral part of the central nucleus (Group CE) ox the lateral nucleus (Group L) of amygdala. In comparison with normal carts Group L was deficient in acquisition of the short latency escape responses and Group CE was handicapped in reacquisition of the escape response after the extinction procedure. Both lesioned groups were unable to acquire avoidance responding. Group CE was marked by gradual decrease of the sensitivity to shock in the course of learning, whereas Group L was less sensitive to changes in experimental procedures than the other two groups. However, most of the observed group differences were related to a decrease of sensitivity to shock and to a lowered general emotionality produced by lesions in both amygdaloid nuclei.

Characteristics of neuronal activity in prefrontal cortex during performance of spatial delayed reactions in monkeys.

Several types of neurons were differentiated on the basis of a study of neuronal activity in various parts of the cortex near the sulcus principalis during the execution of spatial delayed reactions by monkeys. It was established that the different types of neurons are represented in different numbers in different parts of the cortex near the sulcus principalis. The determination of several factors influencing the activity of these neurons and the comparison of data on their quantitative representation in the anterior, middle, and posterior parts of the cortex near the sulcus principalis with the existing behavioral data obtained after local ablations of identical regions of the brain made it possible to postulate that neurons belonging to the different types are involved in the analysis of different processes and represent different functional units.

Preferential ipsilateral influence of the posterior hypothalamus on the neocortex.

On the 10th--20th day after precollicular transection of the brain stem weak low-frequency electrical stimulation of the posterior hypothalamus preferentially activates the ipsilateral neocortex. After unilateral injury to the posterior hypothalamus, synchronous activity predominates in the ipsilateral neocortex. In premesencephalic animals weak single electrical stimulation of the posterior hypothalamus evokes the appearance of spindles in ipsilateral zones of the frontal cortex, whereas stronger single stimulation causes the diffuse generation of spindles in various parts of the neocortex. Besides this preferential unilateral effect, the influence of the posterior hypothalamus is found to be more strongly expressed in the frontal than in the occipital cortex. It is postulated that the posterior hypothalamus exerts its influence on the neocortex through the thalamic nuclei.

Significance of emotional excitation in the mechanisms of spatial short-term memory in lower apes.

Correlates of variation in the level of emotional tension are studied in long-term experiments on adult monkeys. The simultaneous appearance of the electrodermal response and of a change in the heart rate is shown to reflect more accurately a rise in the level of emotional tension. Continuous recording of autonomic indexes reveals an increase in tension level during the presentation of conditioned signals and the performance of the motor response in the spatial delayed response test program. The emotiogenic structures are thought to influence the specific mechanisms of short-term memory during the presentation of conditioned signals and the performance of food-procuring instrumental behavior.

[Concerning a conflict nature of the "spatial delayed response" test]. / O konfliktnoi prirode testa "prostranstvennaia otsrochennaia reaktsiia".

Neuropsychological analysis of rats' performance of the spatial delayed response (SDR) in different testing conditions revealed a conflict nature of the indirect variation of the SDR task. It was found that the execution of the response based on the image short-term memory interferes with the response differentiation acquired during learning the rule of indirect SDR performance, i.e., during acquisition of the spatial discrimination. It is evident that the maximization of conditions, which promote the acquisition of response differentiation (additional training of animals for spatial discrimination), makes it difficult to perform the indirect variation of the SDR task, while the minimization of these conditions facilitates the correct task performance.

[Formation of spatial short-term memory in 18-54-month old children]. / Formirovanie mekhanizmov prostranstvennoi kratkosrochnoi pamiati u detei v vozraste 18-54 mesiatsev.

The development of the spatial short-term memory (SSTM) in children aged 18-54-months was assessed by performance of the inverted delayed-response task (IDR). A child perceived the localization of a target object in one of the two containers (left or right) situated on a table in front of the child. The distance between the containers was 30 cm. Then the child was escorted to the opposite side of the table so that the target object that was earlier in the left container seemed to be in the right one. After the rotation, in 74% of cases children at the age of 18-24-months failed to localize the object correctly despite the presence of various reference objects in the room. Percent of correct responses increased with age. Children aged 24-54-months performed the IDR better in the presence of reference objects than in their absence. The preschool children at the age of 48-54-months correctly localized the object in 70% of cases even in the absence of the experimental reference objects. The results of this experiment demonstrate the stages of the SSTM development in children.

[Influence of the anterior and posterior hypothalamus on the conditioned reflex activity and delayed responses of lower simians]. / Urovni medlennoi bióelektricheskoi organizatsii golovnogo mozga cheloveka

In 4 adult monkeys, electrical stimulation of the anterior hypothalamus followed by subsidence in the animal and the ECoG synchronization evoked also an impairment of conditioned reflex activity and a decrease in the test performance during delayed responses. Strong stimulation of the posterior hypothalamus followed by emotional arousal and desynchronization in the ECoG, on the contrary, improved the conditioned reflex activity and increased the level of the test performance. The hypothalamus is then supposed to play a certain role in memory as an emotiogenic structure.

[The role of several brain stem structures in activation of the neocortex and motor reflexes in chronically premesencephalic cats]. / Rol' nekotorykh stvolovykh struktur v aktivatsii neokorteksa i dvigatel'nykh refleksov u khronicheski premezéntsefalicheskikh koshek

Chronic experiments were carried out in 18 cats. After premesencephalic section of the brain-stem, the neocortex can be activated both spontaneously and in response to the posterior hypothalamus or the forepaw skin stimulation. After bilateral lesions in the posterior hypothalamus, neither spontaneous nor the forepaw-skin stimulation-produced activation of the neocortex, was observed. Excitation of the mesencephalic RF is accompanied by activation of motor reflexes. A conclusion was made that the posterior hypothalamus, independently of the mesencephalic RF, is capable of activating the neocortex, while the mesencephalic RF, independently of the rostral structures, is responsible for the motor reflex activation.

[The role of several limbic structures in neocortical activation following brain stem section at the level of the corpora quadrigemina]. / Rol' nekotorykh limbicheskikh struktur v aktivatsii neokorteksa posle pererezki stvola mozga na urovne chetyrekholmiia

In chronic experiments on 25 adult cats, after transection of the brain-stem at the level of oral margins of the anterior colliculus, the effect of high-frequency electrical stimulation of the posterior hypothalamus and basal-lateral portion of the amygdala was studied. While stimulation of the posterior hypothalamus resulted in diffuse activation, that of basal-lateral portion of the amygdala rather rarely evoked a relatively weak long-latency activation of the neocortex. Frequently, stimulation of the basal-lateral amygdala induced epileptiform activity in the neocortex. Bilateral lesion of the amygdaloid complex did not affect the activating influence of the posterior hypothalamus on neocortex. It is suggested that the posterior hypothalamus, independently of the mesencephalic reticular formation and amygdaloid complex, exerts an activating influence on the neocortex.

[Characteristics of the activity of prefrontal cortex neurons during spatially delayed reactions in the monkey]. / Kharakteristika aktivnosti neironov prefrontal'noi kory vo vremia ispolneniia obez'ianami prostranstvennykh otsrochennykh reaktsii.

On the basis of unit activity in the cortex around sulcus principalis during the spatial delayed response, several types of neurons were distinguished in monkeys. The number of different neurons varied in different parts of the cortex. Determination of some factors affecting the activity of these neurons and comparison of data on their quantitative distribution in the anterior, medial and posterior parts of the cortex around sulcus principalis with the available behavioral data obtained with restricted removal of the same brain areas, lend support to the assumption that the neurons attributed to different types are responsible for a variety of processes and represent various functional units.

[Neocortical electrical activity of cats with premesencephalic brain stem section under chronic experimental conditions]. / Ob élektricheskoi aktivnosti novoi kory koshek s premezéntsefalicheskoi pererezkoi stvola mozga v usloviiakh khronicheskogo opyta

In 24 cats, premesencephalic section of the brain-stem affected the sleep-wakefulness cycle and caused desynchronization of the neocortical activity 3-4 days after total isolation of the mesencephalic RF. The data obtained corroborates the existence of a certain brain structure situated more rostrally than the mesencephalic RF which is able to cause by itself the neocortical activation.

[Role of emotional excitation in mechanisms of spatial short-term memory in lower monkeys]. / Znachenie émotsional'nogo vozbuzhdeniia v mekhanizmakh prostranstvennoi kratkosrochnoi pamiati u nizshikh obez'ian.

Correlates of the changes of emotional tension level were studied in adult macaca rhesus. Simultaneous appearance of skin-galvanic responses and changes of heart rate were shown to reflect the increase of emotional tension level. The latter was revealed with continuous recording of the above vegetative indices during presentation of conditioned signals and performance of spatial delayed response. Emotiogenic structures are supposed to have a promoting effect on functioning of the mechanisms of spatial short-term memory during the period of spatial discrimination of conditioned signals and food-procuring instrumental behaviour.