Effects of Social Isolation on the Development of Anxiety and Depression-Like Behavior in Model Experiments in Animals.

This review describes the role of social isolation in the development of anxiety and depression-like behavior in rodents. The duration of social isolation, age from onset of social isolation, sex, species, and strain of animals, the nature of the model used, and other factors have been shown to have influences. The molecular-cellular mechanisms of development of anxiety and depression-like behavior under the influence of social isolation and the roles of the HHAS, oxidative and nitrosative stress, neuroinflammation, BDNF, neurogenesis, synaptic plasticity, as well as monoamines in these mechanisms are discussed. This review presents data on sex differences in the effects of social isolation, along with the effects of interactions with other types of stress, and the roles of an enriched environment and other factors in ameliorating the negative sequelae of social isolation.

[Propranolol Impairs Memory Reconsolidation at Single and Multiple Paired with Tone Painful Electrocutaneous Stimulations].

In the current paper there were used two methods for assessment of the propranolol effect on reactivated memory at reconsolidation phase--a classical pavlovian conditioning and the two-ways escape reflex. The difference between these two models was that in the first case a tone was paired with electrocutaneous painful stimulation only once, while in the second case it was applied multiply. Reminding was produced in the first case by placing the animals into the same context, whereas in the second case by application of the same amount of pairings of conditional and unconditional stimuli as it was used at the first day of learning. Propranolol reduced intensity of freezing reaction on 25% from the baseline at the classical conditioning approach and practically led to disappearance of memory and complete regress of the two-ways escape reflex. There was suggested on existence of the possible different mechanisms of noradrenergic blockade on memory loss at the stage of its reconsolidation in the used models of learning.

[Does Impulsivity Affect a Long-term and Working Memory in rats?].

In the present paper usingthe method of delay discounting three groups of animals were discovered: a) those that at choice between immediate weak and delayed strong rewards have chosen an immediate reinforcement (high impulsive rats); b) those that were able to inhibit its own behavior and get the delayed reinforcement (low impulsive rats); and c) the rats with both types of reactions. In the water maze the different groups of rats did find a hidden platform for different time, swum various distance and with different speed. The differences however were significant only at overall comparison (for all days and trials) of the above mentioned parameters of the water maze learning. ANOVAs Group x Days, Group x Trials, and Groups x Days x Trials interactions were insignificant. The data obtained indicate that the difference between groups was appeared evidently due to the difference in general motor activity, rather than difference in their cognitive abilities assessed by reference and working memory tasks.

[Impulsive Choice Improves the Cue Memory at an 8-arms Radial Maze Learning in Rats].

At the process of learning in an 8-arm radial maze the impulsive animals found the reinforced arms and ate the pellets faster, than self-control and ambivalent rats. They committed less working memory errors at the cue memory task, though there was no difference in the rate of learning and a number of errors of reference memory in animals of different groups. During reversion learning at the change of reinforced arms on unre- inforced, and vice versa, the impulsive animals spent less time to enter into the reinforced arms compared to other groups. They had fewer errors of cue working and reference memory, but the rate of learning was the same as in other groups. The date obtained indicate that in the impulsive rats in comparison with the other groups of animals are stronger the general motor activity and better the working memory.

[Stress reactivity and stress-resilience in the pathogenesis of depressive disorders: involvement of epigenetic mechanisms].

The data of epigenetic studies of stress reactivity and resilience in the pathogenesis of depression in experimental animals and humans subjected to stress at different periods of life are analyzed. Specific chromatin modifications, first of all histone acetylation and methylation, are controlling expression of definite genes in distinct brain structures. Epigenetic modulation of particular genes related to development of pro-depressive or antidepressive stress response are discussed (5HT transporter and receptors, corticotropin releasing hormone, glucocorticoid and their receptors, BDNF and other neurotrophic factors).

[Animal Models of Depression: Behavior as the Basis for Methodology, Assessment Criteria and Classifications].

Analysis of the current state modeling of depression in animals is presented. Criteria and classification systems of the existing models are considered as well as approaches to the assessment of model validity. Though numerous approaches to modeling of depressive states based on disturbances of both motivational and emotional brain mechanisms have been elaborated, no satisfactory model of stable depression state has been developed yet. However, the diversity of existing models is quite positive since it allows performing targeted studies of selected neurobiological mechanisms and laws of depressive state development, as well as to investigate mechanisms of action and predict pharmacological profiles of potential antidepressants.

[Role of glycogen synthase kinase-3 in mechanisms of learning and memory].

In the current paper a review of the role of GSK-3b in mechanisms of learning and memory is presented. A regulation of GSK-3 by phosphorylation of serine and tyrosine sites and through Wnt signaling pathway by disruption of axin-ß-catenin complex is described. The data on participation of GSK-3b in regulation of NMDA-dependent long-term depression and potentiation, and the possible mechanisms of enzyme's influence through NMDA receptors and AMPA endocytosis are shown. A role of GSK-3b in development of Alzheimer's disease through inhibition of Wnt signaling parthway by beta-amyloid resulting in a strengthening of GSK-3b activity with further hyperphosphorylation of tay and formation of the neurofibrillary complexes are also considered. Behaviour of animals with knockout and overexpression of GSK-3b gene and effects of GSK-3 inhibitors in different behavioural models are also described.

Theta driving both inhibits and potentiates the effects of nicotine on dentate gyrus responses.

The medial septal area of conscious rats was stimulated through previously implanted electrodes at a frequency of 7.7 Hz for 20 min each day for 7 days to evoke rhythmic slow activity in CA1 at a similar frequency to spontaneous theta. Two weeks later in the anaesthetized rats the effects of a single subcutaneous injection of nicotine (0.4 mg/kg) on fEPSPs, evoked in the dentate gyrus by separate stimulation of the MPP and LPP, were studied and compared with those obtained in controls. Nicotine increased the firing of locus coeruleus neurons and the slope of the fEPSPs evoked by LPP stimulation, but not by MPP stimulation. Prior theta driving considerably increased the effect of nicotine on the responses evoked by stimulation of the MPP and abolished the nicotine-induced potentiation of the responses evoked by stimulation of the LPP. The results are attributed to theta driving increasing the amount of noradrenaline released by nicotine and to noradrenaline producing a beta-adrenoceptor long-lasting potentiation at the medial perforant path synapse and a long-lasting depression at the lateral perforant path synapse.

Theta driving both inhibits and potentiates the effects of nicotine on dentate gyrus responses.

The medial septal area of conscious rats was stimulated through previously implanted electrodes at a frequency of 7.7 Hz for 20 min each day for 7 days to evoke rhythmic slow activity in CA1 at a similar frequency to spontaneous theta. Two weeks later in the anaesthetized rats the effects of a single subcutaneous injection of nicotine (0.4 mg x kg(-1)) on fEPSPs, evoked in the dentate gyrus by separate stimulation of the MPP and LPP, were studied and compared with those obtained in controls. Nicotine increased the firing of locus coeruleus neurones and the slope of the fEPSPs evoked by LPP stimulation, but not by MPP stimulation. Prior theta driving considerably increased the effect of nicotine on the responses evoked by stimulation of the MPP and abolished the nicotine-induced potentiation of the responses evoked by stimulation of the LPP. The results are attributed to theta driving increasing the amount of noradrenaline released by nicotine and to noradrenaline producing a beta-adrenoceptor long-lasting potentiation at the medial perforant path synapse and a long-lasting depression at the lateral perforant path synapse.

Biphasic effects of atropine on sensory-evoked hippocampal rhythmical slow activity in urethane-anaesthetized rats.

This study investigated the response of hippocampal RSA, recorded from electrodes in CA1 and the contralateral dentate gyrus of urethane-anaesthetized rats, to atropine sulphate administered at 15 min intervals in a cumulative dose-response schedule (1, 3, 10, 50 and 50 mg x kg(-1) i.p.). The power of CA1 and dentate gyrus RSA in the 3-7 Hz band was increased after administering the first 3 doses of atropine (1, 3 and 10 mg x kg(-1) cumulatively) in rats held in the stereotaxic frame or removed from the frame and given electrical sensory stimulation to the base of the tail. This increase in RSA was dependent on sensory input, since it was not seen in animals outside the frame unless sensory stimulation was given, and it was abolished by increasing the dose of atropine (an additional 50 and 50 mg x kg(-1) cumulatively). Methylatropine (6 mg x kg(-1) i.p.) did not increase RSA power. The biphasic effect of atropine on sensory-evoked hippocampal RSA activity may be explained by differential effects at pre- and post-synaptic sites e.g. in the septo-hippocampal system or on pathways processing sensory information.

Modulation of latent inhibition in the rat by altered dopamine transmission in the nucleus accumbens at the time of conditioning.

Latent inhibition describes a process by which pre-exposure of a stimulus without consequence retards the learning of subsequent conditioned associations with that stimulus. It is well established that latent inhibition in rats is impaired by increased dopamine function and potentiated by reduced dopamine function. Previous evidence has suggested that these effects are modulated via the meso-accumbens dopamine projections. We have now undertaken three experiments to examine this issue directly, especially in the light of one study in which latent inhibition was reported to be unaffected by direct injection of amphetamine into the accumbens. Latent inhibition was studied using the effect of pre-exposure of a tone stimulus on the subsequent formation of a conditioned emotional response to the tone. 6-Hydroxydopamine-induced lesions of dopamine terminals in the nucleus accumbens resulted in potentiation of latent inhibition. Bilateral local injections of the dopamine antagonist haloperidol into the nucleus accumbens (0.5 microg/side) before conditioning also potentiated latent inhibition. Moreover, such injections were able to reverse the disruptive effect of systemic amphetamine (1mg/kg, i.p.) on latent inhibition. Bilateral local injection of amphetamine (5 microg/side) into the nucleus accumbens before conditioning was able to disrupt latent inhibition, provided that it was preceded by a systemic injection of amphetamine (1mg/kg) 24h earlier.We conclude that the attenuation of latent inhibition by increased dopamine function in the nucleus accumbens is brought about by impulse-dependent release of the neurotransmitter occurring at the time of conditioning. The previously reported failure to disrupt latent inhibition with intra-accumbens amphetamine is probably due to impulse-independent release of dopamine. The implications of these conclusions for theories linking disrupted latent inhibition to the attentional deficits in schizophrenia, and to the dopamine theory of this disorder, are discussed.

Conditionally immortal neuroepithelial stem cell grafts restore spatial learning in rats with lesions at the source of cholinergic forebrain projections cholinergic forebrain projections Conditionally immortal neuroepithelial stem cell grafts restore spatial leaming in rats with lesions at the source of cholinergic forebrain projections.

Purpose: Loss of cholinergic projections from the basal forebrain (BF) to the cortex and from the medial septal area (MSA) to tbe hippocampus is a reliable correlate of cognitive deficits in aging and Alzheimer's disease (AD). We assessed the capacity of grafts of the conditionally immortal MHP36 clonal stem cell line to improve spatial learning in rats showing profound deficits after lesions to these projections. Methods: Rats were lesioned by infusions of S-AMPA unilaterally into BF or bilaterally into both BF and MSA. MHP36 cells were implanted ipsilaterally in cortex or basal forebrain two weeks after unilateral BF lesions, and in cortex and hippocampus bilaterally six months after bilateral BF-MSA lesions. Intact and lesion-only controls received vehicle. Six weeks later rats were assessed in spatial learning and memory tasks in the water maze, and then perfused for identification of grafted cells by beta-galactosidase immunohistocheniistry. Results: Lesioned rats with MHP36 grafts, whether implanted two weeks or six months after lesioning, learned to find a submerged platform in the water maze as rapidly as intact controls, and showed a strong preference for the platform quadrant on probe trials, whereas lesioned controls were impaired in all measures. Grafted cells of both neuronal and glial morphologies, migrated away from cortical implantation sites in BF Lesioned rats to the striatum, thalamus and basal forebrain lesion area. Cells implanted in basal forebrain showed a similar distribution. In rats with bilateral BF-MSA lesions, grafts implanted in the hippocampus migrated widely through all layers but cortical grafts largely escaped up the needle tract into the meninges. Conclusions: Although MHP36 grafts were functionally effective in both lesion models, the site and age of lesions and site of implantation influenced the pattern of engraftment. This flexibility encourages the development of conditionally immortal human stem cell lines with similar capacities for functional repair of variable neuronal degeneration in AD or aging.

The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: implications for schizophrenia.

Latent inhibition (LI) consists in a retardation of conditioning seen when the to-be-conditioned stimulus is first presented a number of times without other consequence. Disruption of LI has been proposed as a possible model of the cognitive abnormality that underlies the positive psychotic symptoms of acute schizophrenia. We review here evidence in support of the model, including experiments tending to show that: (1) disruption of LI is characteristic of acute, positively-symptomatic schizophrenia; (2) LI depends upon dopaminergic activity; (3) LI depends specifically upon dopamine release in n. accumbens; (4) LI depends upon the integrity of the hippocampal formation and the retrohippocampal region reciprocally connected to the hippocampal formation; (5) the roles of n. accumbens and the hippocampal system in LI are interconnected.

Are the cognitive-enhancing effects of nicotine in the rat with lesions to the forebrain cholinergic projection system mediated by an interaction with the noradrenergic system?

Experiments were conducted to test the hypothesis that the enhancing effect of nicotine on water maze performance in rats with lesions of the forebrain cholinergic projection systems (FCPS) is mediated by an interaction with the noradrenergic system, in particular the ascending dorsal noradrenergic bundle (DNAB) and its projection areas. Three groups of rats received lesions of either: i) the nucleus basalis (NBM) and medial septal area/diagonal band (MSA/DB) by infusion of alpha-amino-3-hydroxy-4-izoxazole propionic acid (AMPA) (FCPS group), ii) DNAB, by infusion of 6-hydroxydopamine (6-OHDA) (NOR group), or iii) both FCPS plus DNAB (COMB group). Control animals received vehicle. Choline acetyltransferase activity was reduced in the cortex and hippocampus of the FCPS and COMB groups and in the hippocampus of the NOR group. NA level was reduced in the cortex and hippocampus of the FCPS and COMB groups, but not the FCPS group. In a reference memory task, the performance of both the NOR and COMB groups, but not the NOR group, was significantly worse than that of controls; there was no effect of nicotine administration (0.1 mg/kg) on escape latency or other measures in this task. In a working memory task, FCPS and COMB rats took longer to find the submerged platform on the second and following trials, and there was a significant enhancement of performance by nicotine in both groups, but not in controls. These results indicate that the enhancing effects of nicotine in rats with FCPS lesions are not mediated by an interaction with the DNAB.

Interactions between the effects of propranolol and nicotine on radial maze performance of rats with lesions of the forebrain cholinergic projection system.

This experiment investigated the hypothesis that nicotine-induced regional release of noradrenaline contributes to the improvements in radial maze performance following nicotine treatment in rats with lesions to the forebrain cholinergic projection system (FCPS), by examining whether pretreatment with the noradrenergic beta-receptor antagonist propranolol abolished the facilitative effects of nicotine. After S-AMPA (8.0mM) lesions to the nuclei of origin of the FCPS in the nucleus basalis and medial septal areas, rats displayed long-lasting impairment in long-term reference and short-term working memory in both spatial (place) and associative (cue) radial maze tasks. Performance of control and lesioned rats was assessed after administration of nicotine (0.1mg/kg), propranolol (either 0.5 or 5.0mg/kg) and both treatments. Nicotine reduced working memory error rates in lesioned animals, but did not affect the performance of controls. Propranolol dose-relatedly increased error rates in both control and lesioned animals. Adverse effects were more marked in controls, all four types of error being increased under the high dose of propranolol, whereas in lesioned rats significant increases in error rates above baseline were confined to working memory. The low dose of propranolol, in conjunction with nicotine, abolished the improvement in working memory seen with nicotine alone in lesioned rats. However, under joint treatment with the high dose, the substantial increases in working memory error rates seen in lesioned rats after propranolol alone were reduced to baseline level. In controls, reduction in errors to baseline was seen only in the cue task; place task errors remained significantly elevated. These results suggest that both cholinergic depletion and noradrenergic blockade exert disruptive effects on cognition, but that these effects are largely independent, since an additive or interactive mechanism would be predicted to produce greater disruption, following noradrenergic blockade, in lesioned rather than in control animals. Although facilitative effects of nicotine were abolished with the low dose of propranolol, the results further suggest that these effects are independent of release of noradrenaline, since nicotine continued to reduce errors in control and lesioned animals following blockade of beta receptors with the high dose of propranolol.

Generalization of the conditioned reflexes established by direct electrical stimulation of the hippocampus.

In four dogs instrumental defensive conditioned reflexes to direct electrical stimulation of the hippocampus were elaborated. After reaching 60 percent CR performance, unreinforced stimulations of several limbic structures were given to test generalization. Positive generalization was more frequent than negative one. The generalization effect changed considerably in the course of further conditioning, during which two main types of changes were observed. After repeated stimulations of additional points in the hippocampus, the septum and the limbic cortex, a strengthening of the generalization effect was observed, while test stimulations of the amygdala and the hypothalamus resulted in a gradual decrease of the generalization effect, including its complete disappearance.