EFFECTS OF SELECTIVE CHOLINERGIC AND GABAERGIC LESIONS OF THE NUCLEUS BASALIS MAGNOCELLULARIS ON PLACE OR RESPONCE LEARNING IN PLUS-SHAPED MAZE.

In the present study we evaluated effects of selective cholinergic or GABAergic lesions of the nucleus basalis magnocellularis (NBM) using immunotxins 192 IgG-saporin and GAT1-SAP on place and response learning in plus-shaped maze. In current behavioral paradigm rats learned food-rewarded mazes that were efficiently learned using either place or turning strategies. A histological evaluation indicated that 192 IgG-saporin lesions specifically depleted cholinergic neurons but did not result in noticeable damage to the GABAergic cells within NBM. GAT1-SAP lesions resulted extensive damage of GABAergic and a mild reduction of cholinergic NBM neurons. The results of present behavioral experiments showed, that selective lesions of cholinergic or GABAergic neurons in the NBM impair, but do not abolish, the animal's ability to learn location of rewarded arm of maze (place learning) or a skilled motor behavior (response learning). Our findings suggest the role of NBM cholinergic and GABAergic cortical projection neurons in processing of cognitive information. We suggested that lesions of NBM projections to the cortex modulate learning-mediated plasticity and impair both place and response learning.

MEMANTINE ATTENUATES THE OKADAIC ACID INDUCED SHORT-TERM SPATIAL MEMORY IMPAIRMENT AND HIPPOCAMPAL CELL LOSS IN RATS.

In the present study, the possible beneficial effect of memantine on the Okadaic Acid (OA) induced spatial short-term memory impairment was examined in spatial alternation task, and the neuroprotective potential of memantine on OA-induced structural changes in the hippocampus was evaluated by Nissl staining. OA was dissolved in artificial cerebrospinal fluid (aCSF) and injected intracerebroventriculary (ICV) 200 ng in a volume of 10 µl bilaterally. Vehicle control received aCSF ICV bilaterally. Control and OA injected rats were divided into 2 subgroups injected i.p. with saline or memantine (5 mg/kg). Memantine or saline were given daily for 13 days starting from the day of OA injection. Behavioral study showed that bilateral ICV microinjection of OA induced impairment in spatial short-term memory. Nissl staining in the present study showed that the ICV microinjection of OA significantly decreased the number of surviving pyramidal neurons in the CA1 region of the hippocampus. Chronic administration of memantine effectively attenuated OA induced spatial short-term memory impairment and the OA-induced neuropathological changes in the hippocampus. Therefore, ICV injection of OA can be used as an experimental model to study mechanisms of neurodegeneration and define novel therapeutics targets for AD pathology.

Selective lesion of GABA-ergic neurons in the medial septum by GAT1-saporin impairs spatial learning in a water-maze.

The aim of this study was to investigate the role of the medial septal (MS) GABAergic cells in hippocampal dependent spatial learning using the immunotoxin GAT1-SAP to produce selective lesions of GABAergic MS neurons. In current study rats were trained in a visible platform version of the Morris water maze in which either a place or cue strategy could be used to escape successfully. Immunohistochemical studies showed that intraseptal injection of GAT1-SAP extensively damaged GABAergic MS neurons and spared most cholinergic neurons. The rats' responses on the competition test were classified as either cue or place, based on the swim path for those trials. An overview of the data from both competition trials for each group show that the control rats in 14 trials out of 16 competition test trial used place strategy, while MS-lesioned ones used this strategy in 2 trials only. Decreased place-bias in MS-lesioned rats compared to the control rats was significant (P<0.01). The data obtained in the control and GAT1-SAP lesioned animals in the present study, demonstrate that lesioned rats were impaired in hidden platform trials during training, and displayed a pronounced cue-bias in competition tests. Therefore, above data suggest involvement of the MS GABAergic neurons in organization of the spatial map-driven behavior and this structure, along with the hippocampus, should be viewed as a constituent of the functional system responsible for the cognitive types of spatial memory.

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.

Effects of the uncompetitive NMDA receptor antagonist memantine on spatial memory in medial septal lesioned rats.

These experiments examined the effects of acute administration of memantine (2.5 or 5 mg/kg) or saline on spatial memory and learning process within single sessions, on place versions of food-rewarded maze in MS electrolytic lesioned and sham-lesioned rats. Sham-lesioned rats trained in the place task learned more rapidly than did MS electrolytic lesioned rats. This fact certifies for obvious deficit of the place learning performance strategy in the MS-lesioned rats. The results indicate that the drug-treated (5 mg/kg memantine) sham-lesioned rats exhibited significantly impaired performance relative to the saline controls in terms of trials-to-criterion (P<0.05). 2.5 mg/kg memantine administered 30 min before behavioral testing, did not affect performance in place learning task. 2.5 mg/kg and 5 mg/kg memantine administered before behavioral testing, did not improve performance in place learning task in MS electrolytic lesioned rats. Our experimental data support the interpretation that memantine does not produce intolerable side effects in human AD patients because it is being used at doses that are below the threshold for interacting with NMDA receptors.

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.

Effects of excitotoxic lesions of the CA1 region of the hippocampus on acquisition of a place and cue water maze task.

The aim of the present study was to investigate the effects of excitotoxic lesions of the dorsal CA1 region of the hippocampus on acquisition of a place and cue water maze task. The ibotenic acid injections into CA1 produced removal of the pyramidal cells in CA1, while saving most of the pyramidal cells in CA3 and granule cells in DG intact. In conditions of visible platform training trials, differences in the platform reaching latency between the animals of different groups, were not found. When testing was performed in conditions of submerged platform, the latency of the platform finding was significantly increased (P<0.05). This fact certifies for deficit of the place learning strategy in the CA1-lesioned rats. Decreased place-bias in CA1-lesioned rats in hidden platform training trials compared to the sham-operated rats was significant, but in testing trials 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. Decreased place-bias in CA1-lesioned rats compared to the sham-operated rats was not significant. We suggest that spatial learning deficits observed after dorsal hippocampal lesions cannot be accounted solely to the loss of dorsal hippocampal CA1 region cells.

Object exploration and reactions to spatial and nonspatial changes in dentate gyrus lesioned rats.

In order to investigate the possible involvement the DG in spatial and object recognition memory, we have opted for a non-associative task where no explicit reward was present. Colchicine was used for bilateral DG lesions for its well-known specificity for DG lesion. Colchicine-induced lesions produce severe damage in the granule cells of DG, while minimally affecting pyramidal cells in CA1 and CA3. The main results are as follows: The overall habituation to the familiar environment in DG lesioned rats was decreased than in sham operated rats. There was no significant impairment in detecting spatial novelty. Lesions of the DG did not affect the detection of a novel object placed in a familiar location. Considering both the impaired habituation and the generally intact detection of spatial changes, we suggest that exploratory activity in relation to the entire environment and to the particular objects is thought to be subserved by diverse nervous substrate, and testing in the given conditions allows for their differential estimation.

Synthesis and modeling of polysiloxane-based salt-in-polymer electrolytes with various additives.

The effect of both nanoparticles and low molecular weight borate esters on the ionic conductivity of cross-linked polysiloxanes was systematically investigated by means of measuring conductivity spectra in the impedance regime at temperatures between -30 and 90 degrees C. Salt-in-polymer electrolytes were prepared by dissolving lithium triflate (LiSO(3)CF(3)) in comblike polysiloxanes bearing one methyl and one oligoether side group per silicon. An amount of 10 mol % of the oligoether side groups exhibited a terminal allytrimethoxysilane serving as a cross-linker moiety (T(0.1)OPS). Thus prepared polymer electrolyte membranes were completely amorphous and mechanically stable with an optimum conductivity value of 5.7 x 10(-5) S x cm(-1) at 15 wt % of lithium triflate (LiSO(3)CF(3)) at room temperature (T(0.1)OPS + 15 wt % LiSO(3)CF(3)). Further investigations concerned the influence of additives, i.e., nanosized ceramic fillers (alpha-Al(2)O(3) and SiO(2), up to 10 wt %) as well as two low molecular weight borate esters (tris(2-(2-methoxyethoxy)ethyl) borate (B2) and tris(2-(2-(2-methoxyethoxy)ethoxy)ethyl) borate (B3)) with maximum concentrations of 40 wt % as referred to polysiloxane T(0.1)OPS. The addition of borate esters resulted in a considerable increase of the conductivity, while still maintaining the mechanical stability. Optimum conductivities of 3.7 x 10(-5) and 1.6 x 10(-4) S x cm(-1) were measured for B2 and B3, respectively, at room temperature. A fit of the temperature-dependent DC conductivity by the empirical Vogel-Tammann-Fulcher (VTF) equation showed that there was an increased number density of mobile charge carriers in the case of borate esters as additives. However, the shape of the conductivity spectra in the dispersive regime changed considerably in going from nanoparticles as additives to borate esters. A careful and consistent modeling of the conductivity spectra and of the temperature dependence of the DC conductivity was done within the framework of the MIGRATION concept. The result was that the addition of borate esters to the polymer host most probably increased both number density of mobile charge carriers as well as their mobility.

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.

In situ detection of APRIL-rich niches for plasma-cell survival and their contribution to B-cell lymphoma development.

A proliferation inducing ligand (APRIL) is one of the most recently cloned members of the tumor necrosis factor (TNF) family. Early experiments implicated a pathophysiological role for APRIL in the promotion of solid tumors. Later, identification of APRIL receptors on B lymphocytes indicated a physiological role for APRIL in humoral responses. We have been able to generate antibodies that detect APRIL protein in human tissues. The study of in situ APRIL expression showed that APRIL mainly regulates late stages of B-cell humoral responses. It also provided evidence that APRIL may modulate tumor development in patients, but only for specific B-cell malignancies. Here, we will review to what extent fine characterization of in situ expression adds valuable information on APRIL (patho) physiological functions.

Tumors that look for their springtime in APRIL.

Inflammatory cells produce a proliferation inducing ligand (APRIL), one of the most recently cloned members of the tumor necrosis factor (TNF) family. Early experiments implicated APRIL as a promoting factor in the natural course of various cancers, reinforcing the concept that host inflammatory reactions are part of a tumor development. Recent studies have further analyzed the tumor-promoting role of APRIL in patients with solid tumors or with hematological malignancies. Here, we will review the recent literature, and provide evidence that APRIL may be a useful prognostic tool and a potential target in the treatment of some cancers.

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.