Long-term crowding in rats can lead to anxiety-depressive disorders. Antidepressants, including imipramine, are used in clinical and experimental settings to correct such states. The aim of this study was to test whether Imipramine has an antidepressant and/or anxiolytic effect on the behavior of rats kept in overcrowded conditions. The effect of daily (4 days before and 10 days during crowding) intraperitoneal injections of imipramine (10 mg/kg) on the behavior of male Wistar rats housed in overcrowded (16 rats per cage) and standard (4–5 rats per cage) conditions was studied in the open field, light–dark and elevated plus maze tests for anxiety, as well as in the forced swim test, after imipramine withdrawal (days 12 and 15 of overcrowding). In addition, body weight gain on days 8 and 12 of overcrowding and plasma corticosterone levels on day 16 of overcrowding were assessed in the same groups of rats. In standard housing conditions, imipramine did not alter rat behavior in all tests. Overcrowding led to the activation of behavioral responses in the light–dark and elevated plus maze tests, which was not reduced by imipramine (except for three indices), indicative of no significant corrective effect of this drug in these tests on the behavior of rats kept in overcrowded conditions. In the forced swim test, overcrowding led to increased immobility, while imipramine corrected this disorder. Body weight gain decreased after imipramine treatment in both standard and overcrowded (to a greater extent) conditions, suggesting a negative side effect of this antidepressant. Plasma corticosterone levels did not differ in rats kept in either overcrowded or standard conditions and were not altered by imipramine. Thus, imipramine had a therapeutic effect on increased immobility in overcrowded rats in the forced swim test, suggesting that the behavioral changes observed in this test in rats under overcrowded conditions are depressive-like behavioral disorders, i.e., imipramine exerted a pronounced antidepressant effect on rats in the forced swim test.

Housing animals in an enriched environment (EE) is known to prevent the development of anxious-depressive disorders and cognitive impairments caused by various stresses. A very limited number of studies on learning and memory have used the Morris water maze and exposure of animals to proinflammatory stress (PIS) before the influence of EE. We report here the first investigations of the reverse sequence of interaction between EE and stress: animals were first kept in an EE and then exposed to PIS. For this purpose, 40 rats aged 25–45 days were placed in an EE and another 40 rats were kept in standard conditions. PIS in rats of both groups was induced by giving either singe doses of bacterial lipopolysaccharide (LPS) (350 μg/kg) (acute stress) or repeated doses of 200 μg/kg (chronic stress) 1 h before the start of behavioral tests and during these tests. Control animals were given the same volume of saline. The data obtained here indicate that rats kept in the EE found the hidden underwater platform faster and swam a shorter distance to it than rats kept in standard conditions. In animals subjected to acute and chronic LPS stress, prior housing in EE conditions led to the normalization of behavioral indicators to those seen in the control rats. In these rats, EE produced improvements in behavioral indicators on assessment of working memory. These results shows that EE has an important role in beneficial influences on the behavior of rats when seeking the safe platform.

Goal of the current work was to conduct comparative analysis of the effects of acute and chronic lipopolysaccharide-induced stress on the behavior of rats in the Morris water maze test and on expression of mRNA of proinflammatory cytokines and BDNF in different brain structures. Relevance of this study is related to poor understanding of the effects of acute and chronic stress on manifestation of cognitive brain functions, as well as ambiguity of the literature data on the effects of both stresses on hypothalamic pituitary axis and expression of the proinflammatory cytokine genes. In the experiments with rats, acute lipopolysaccharide (LPS)-induced stress improved learning in the Morris water maze. For the period of learning, the rats under acute stress swam on average less distance to reach a hidden platform, spent less time in the peripheral zone of the pool (thigmotaxis), and had low speed compared to the control animals and to the group of rats under chronic LPS-induced stress. In the test without a platform in the pool there were no significant differences between the groups on the time spent in the platform quadrant and distance swum. Acute stress caused substantial increase of the TNF-α and IL-1β mRNA concentrations in the hippocampus and amygdala, but not in the frontal lobe in comparison with the control animals. Although chronic stress increased the levels of the TNF-α and IL-1β mRNA in the amygdala and hippocampus compared to the control groups, significance between the groups was only marginal and BDNF concentration did not differ from the control animals in any of the brain structures mentioned. Expression of the IL-6 mRNA only marginally increased in the amygdala of the animals under the acute LPS-induced stress and marginally decreased in the animals under chronic LPS stress in the hippocampus relative to the control groups. In total, the most pronounced molecular-biochemical changes occurred in the amygdala and hippocampus, where increase of the expression of the TNF-α and IL-1β interleukins mRNAs were observed in the animals under acute and chronic LPS-induced stress and no changes in the BDNF mRNA concentration were observed in the frontal lobe.

The effects of early proinflammatory stress induced by administration of bacterial lipopolysaccharide (LPS) on the days 3 and 5 of life on learning and long-term and working memory in adult rats were studied in the Morris water maze. In the control group, females were less successful than males at learning; at the end of training, the distance traveled to the platform, latency, and time at the periphery were greater in females and the proportion of trials in which they found the platform was lower. Learning difficulties in females were linked with deficits in long-term memory. Early proinflammatory stress impaired learning only in males, decreasing swimming speed and the proportion of trials with successful platform finding and increasing the latency of reaching the platform and swimming distance. Long-term memory was impaired in males of the LPS group. Testing of working memory with a daily change of platform position did not identify any cognitive differences between males and females in the control group, though sex differences were present in the level of motor activity and platform search tactics at the beginning of the experiments. Early proinflammatory stress did not affect working memory, but did affect locomotor activity in males, decreasing swimming speed and increasing platform-reaching latency. Thus, sex differences were found in the effects of early proinflammatory stress on learning and memory in rats in the Morris water maze; males showed the greatest behavioral impairments.

Recent studies have significantly expanded our understanding of the functions of GABAergic interneurons in cortical neural networks. Interneurons of specific classes are involved in generating interictal activity in the cortex not only in certain types of pathology, but also in conditions in which inhibition is mediated mainly via GABAB receptors. Interictal activity consists of high-amplitude spikes, where a short excitatory phase is followed by a long inhibitory phase occurring almost simultaneously in different parts of the cortex. Highamplitude spikes reflect the synchronous action of excitatory neurons in a local area, while synchronous activity in remote areas is determined by feedback between pyramidal cells and interneurons, when the activity of a large mass of neurons occurs simultaneously within a narrow time interval. Synchronization of interictal spikes involves Martinotti cells, as well as parvalbumin, neurogliaform, and vasoactive intestinal peptide-expressing interneurons, which, as experimental data show, also inhibit via GABAB receptors. Several mechanisms are now known which synchronize neuron activity in cortical neural networks: via electrical connections, volume conduction, and synaptic feedback – both between pyramidal neurons and interneurons and between interneurons. We propose that the mechanism of synchronization of interictal spikes in cortical neural networks operates as follows. This mechanism appears to operate in the same way both in local neural networks and over distances. When excitation occurs, it is followed by inhibition mediated by feedback; this limits the excitation period and thus creates a time window for integration, and this also occurs in neighboring cortical neural networks. At the initial stage, the amplitudes of interictal spikes are small and nonsimultaneous in different parts of the cortex. As time progresses, ever more pyramidal neurons become active during the time window, thus increasing the amplitude of the interictal spike, in turn increasing inhibition. Increased inhibition due to feedback ultimately begins to affect neighboring neural networks, with the result that interictal spikes appear almost simultaneously in different parts of the cortex. This produces a significant lengthening of postspike inhibition, as inhibition within a neural network is supplemented by inhibition from neighbors via inhibitory feedback.

Current experimental evidence shows that interictal discharges consist of a short spike and a slow wave, which is regarded as long-lasting hyperpolarization. Feedback inhibitory connections were studied by modeling the synchronization of interictal discharges. Studies in rats in a state of light narcotic sleep with application of GABAA receptor blockers to the cortex showed that interictal discharges arose in neighboring areas of the cortex, first independently of each other and then synchronized. The durations of slow waves (inhibitory phase) were identical in experiments in which interictal discharges arose simultaneously. Recording in these and other experiments showed increases in the time delay between the moments at which interictal discharges were generated. The durations of the slow waves (inhibitory phase) of interictal discharges increased in conditions of increased synchronization. Interictal discharges occurring initially had longer durations of inhibition than those at a neighboring point, as inhibition from neighboring networks via feedback inhibitory connections is added to the intrinsic inhibition in the neural network. When excitation occurred, it was followed by onset of feedback inhibition, which restricted the duration of excitation, thus creating a time window for integration; this also occurred in neighboring neural networks in the cortex.

Modern experimental data show that interictal discharges consist of a short spike and a slow wave, which is regarded as a prolonged hyperpolarization. On the model of interictal discharges synchronization, a study of reciprocal inhibitory connections was carried out. In rats in light narcotic sleep, after application of GABA A-receptor blockers to the cortex, interictal discharges occurred in neighboring cortical areas independently of each other, and then synchronization occurred. In the experiments in which the interictal discharges occurred simultaneously, the durations of the slow wave (inhibitory phase) were the same. During the registration in these and other experiments, there was an increase in the time delay between the moments of interictal discharges generation. Under conditions of increased synchronization, the duration of the slow wave (inhibitory phase) of interictal discharges increased. Interictal discharges, which occurred first, had a longer duration of inhibition compared to the duration in the neighboring point, because the inhibition from the neighboring networks via feedback inhibitory connections is added to its own inhibition in the neuronal network. When excitation occurred, it was followed by inhibition via feedback, which limited the period of excitation, and thus created a temporary integration window, and this also happened in the neighboring neural networks of the cortex.

It is well known that neonatal pro-inflammatory challenge (NPC) acquire a predisposition to the development of a number of neuropsychiatric diseases: depression, anxiety disorders, autism, attention deficit hyperactivity disorder. Symptoms of these diseases can manifest themselves in adulthood and adolescent after repeated exposure to negative influences. Preventing the development of the negative consequences of NPC is one of the main tasks for researchers. The exposure to an enriched environment (EE) was shown to have anxiolytic, anti-depressive, and pro-cognitive effects. The present work was aimed to investigate the effects of the long-term EE on anxious-depressive and conditioned fear behavior in normal male and female rats and subjected to NPC. The NPC was induced by subcutaneous administration of lipopolysaccharide (LPS, 50 μg/kg) on 3d and 5th PNDs. The control animals received saline (SAL). The rats were placed in the EE from 25 to 120 PND. Animals housed in the standard conditions (STAND) served as controls. In adult female and male rats of the STAND groups, LPS did not affect the anxiety, depressive-like behavior and conditioned fear. The EE increased motor and search activity in males and females. In the open field, the EE reduced anxiety in males of the SAL and LPS groups and in females of SAL groups compared to the STAND housed animals. In the elevated plus maze, the EE decreased anxiety only in males of the SAL group. In the sucrose preference test, the EE did not change sucrose consumption in males and females of SAL and LPS groups, while, in the forced swimming test, the EE reduced depressive-like behavior in females of both SAL and LPS groups. The enrichment decreased the contextual conditioned fear in male and female of SAL groups, but not of the LPS group, and did not affect the cue conditioned fear. The corticosterone reactivity to the forced swimming stress increased in males of the EE groups. The basal level of IL-1beta in blood serum decreased in males of the SAL-EE group. Thus, the EE reduced anxiety in males, depressive-like behavior in females, and contextual conditioned fear in males and females compared to the STAND housed animals. Although the NPC did not affect these behaviors in the STAND groups, LPS prevented the beneficial EE effects on anxiety and conditioned fear. The opposing effects of LPS were dependent on sex and type of testing.

We report here studies on the effects of ovariectomy (OE) in females performed at age 35 days on the development and extinction of a conditioned fear reaction and on learning in the Morris water maze in adult rats. The behavior of OE females was compared with the behavior of males and sham-operated females. We compared the effects of OE in animals after early proinflammatory stress (administration of bacterial lipopolysaccharide on postnatal days 3 and 5, LPS group) and in a control group (administration of physiological saline, PS group). OE hindered the development of a conditioned fear response to sound in the LPS group and also slowed the extinction of fear in both the PS and LPS groups as compared with sham-operated females. On training in the Morris water maze, OE in the PS group improved learning in females as compared with sham-operated females, making them as successful in solving the spatial task as males. Early proinflammatory stress had similar effects on males and OE females, degrading many measures of learning in the Morris maze. OE did not affect working memory in the daily platform change test. OE eliminated sex differences in the behavior of females as compared with males in many respects and made them more prone to proinflammatory stress.

Abstract—We studied the effect of activation of the immune system in early ontogeny (administration of lipopolysaccharide, LPS, on day 3 and 5 after birth at a dose of 50 µg/kg) on various aspects of the social behavior of adult male and female rats: social interaction and dominance. The behavior of rats was compared with the level of corticosterone and interleukin 1-beta in the blood serum taken before the start of testing. The males of the LPS group had an increased interaction time in the social interaction test compared to the control, as well as an increased number of wins in the tube dominance test. The winners in the tube test were characterized by a higher basal level of interleukin 1-beta in the blood serum. In females, there were no changes in social behavior after the LPS administration in early ontogeny. These results indicate the influence of early proinflammatory stress on the social behavior of adult male rats (but not females) and the association of behavior changes with the basal level of interleukin 1-beta.

The role of female sex hormones produced by the ovaries in the occurrence of sex-related features in the anxious-depressive behavior of rats was studied. Proinflammatory stress was created in half the cohort of rat pups by administration of bacterial lipopolysaccharide at a dose of 50 μg/kg (LPS group) at ages 3 and 5 days; the other half received saline (PS group, controls). Half of the females underwent bilateral ovariectomy (OE) at age 35 days and the other half underwent sham ovariectomy (SOE) without removing the ovaries. The behavior of two groups of females was compared with the behavior of males at age 75–100 days. OE increased female weight but did not induce any behavioral changes in anxiety tests as compared with SOE females. Ovariectomy produced some smoothing out of differences in anxiety levels compared with males. OE led to depression-like behavior, which was apparent only in animals of the LPS group. OE reduced differences in corticosterone levels between males and females in animals of the LPS group. OE had the greatest impact on animals after early proinflammatory stress.

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.

Degeneration of septal cholinergic neurons caused by the immunotoxin 192IgG-saporin (SAP) is a model of the pathological state that occurs in Alzheimer's disease. We studied whether overexpression of nerve growth factor (NGF) in the hippo campus, where septal neurons send their projections, may reduce the consequences of this damage. A lentiviral suspension carrying a cassette with CMV-NGF-IRES-GFP or CMV-IRES-GFP (control, pCSC) was injected into both hippocampi. Control rats received an equivalent amount of PBS instead of SAP and the control virus construction PBS-pCSC. Analysis of choline acetyltransferase (ChAT) immunostaining showed that NGF overexpression in the hippocampus did not prevent the strong loss of ChAT-positive neurons in the septal area caused by the immunotoxin. In Open Field test, both SAP-NGF and SAP-pCSC-injected rats exhibited hyperactivity; in contrast, in the Y-maze SAP-induced hyperactivity was prevented by NGF overexpression. In the beam walking test, the NGF-expressing group of rats showed significant improvement of motor performance. Analysis of the acetylcholine esterase activity in the hippocampi, which we used as a marker of cholinergic function, revealed that the level of AChE was increased in the SAP-NGF group compared to SAP-pCSC. In conclusion, our data suggest that NGF overexpression in the hippocampus of rats may partly compensate some 192IgG-saporin-induced impairments related to cholinergic deficit.

Experiments on Wistar rats addressed the manifestations of impulsive behavior in relation to age and sex in three groups of animals. One group received s.c. proinflammatory bacterial lipopolysaccharide (LPS) 50 μg/kg at ages three and five days; the other two groups were controls. One of these received the same volume of physiological saline on the same days and the other, the intact group, received no treatment. Impulsive behavior was assessed by the delay discounting method. Administration of LPS had no significant effect on the manifestation of impulsive behavior in males or females at young age (2.5 months). However, females generally (the overall group) were less impulsive at young age than males. Assessment of impulsivity at mature age (six months) in new groups of animals showed that there were no between-sex differences. Impulsivity at this age was most marked in the LPS group. Control adult animals were less impulsive than young controls. No such age-related differences were seen in rats of the LPS group, particularly males.

В опытах на крысах линии Вистар исследовали проявления импульсивного поведения в зависимости от возраста и пола у трех групп животных. Одной группе в возрасте трех и пяти дней вводили подкожно провоспалительный бактериальный липополисахарид, ЛПС, в дозе 50 мкг/кг; две другие группы были контрольными. Одной из них в те же дни и в том же объеме вводили физиологический раствор, а другой, интактной группе, ничего не вводили. Импульсивное поведение оценивали с помощью методики delay discounting. Введение ЛПС не оказывало существенного влияния на проявление импульсивного поведения у самцов и самок в молодом возрасте (2.5 мес). Однако самки в целом (с учетом данных по всем группам) в молодом возрасте были более импульсивными, чем самцы. Исследование импульсивности в зрелом возрасте (6 мес) на новых группах животных показало отсутствие у них различий по полу. Наиболее выраженной в этом возрасте импульсивность была у ЛПС-группы. Контрольные взрослые животные были менее импульсивными, чем молодые. У крыс ЛПС-группы, особенно у самцов, таких различий по возрасту не наблюдалось.

Early proinflammatory stress created by administration of lipopolysaccharide (LPS) (50 μg/kg s.c.) on days 3 and 5 of postnatal life led to decreases in movement activity, reductions in exploratory behavior, and increases in anxiety in rats at adolescent age (1–1.5 months) in the open field and elevated plus maze tests. Greater changes in anxiety behavior were seen in males than females. Administration of LPS in early ontogeny induced signs of depression-like behavior at adolescent age in both males and females, this being detected in the anhedonia test as a reduction in the preference for 1% sucrose solution, unlike the situation in the control groups. The forced swimming test showed signs of depression-like behavior in males but not in females, but only on first testing. In adult rats (3–3.5 months), after increased handling and acquisition of food-procuring reflexes, these changes in anxiety and depression-like behavior largely disappeared. Administration of LPS at early age led to increased serum IL-1β levels in adult males after repeated stress exposure, while females showed increased corticosterone levels as compared with control animals. These results provide evidence of increased signs of anxious-depressive behavior in rats after early exposure to proinflammatory stress, along with sex-related differences and the possibility of correcting the negative consequences of stress in later life.