The characteristics of long-term potentiation (LTP) in field CA1 of living hippocampal slices from rats aged 17–33 days were studied after neonatal administration of bacterial lipopolysaccharide (LPS) to evaluate the long-term effects of neuroinflammation in early ontogeny on synaptic plasticity. A deficit of LTP was seen in field CA1 of the hippocampus of rats surviving neonatal proinflammatory stress (NPS), the most sensitive being the mechanism of induction. In rats of the NPS group, synaptic potentiation was absent or weak in 61% of experiments, though when normal induction occurred, LTP persisted throughout the observation period. Correlation analysis showed that impairments to the development of the mechanisms of long-term plasticity in response to NPS are probably associated with weakening of the afferent influx to hippocampal neurons. Initially low-amplitude responses in field CA1 to application of single stimuli to Schaffer collaterals dominated in the hippocampus of female rats of the NPS group but were significantly rarer in males. This is probably why the early phase of potentiation in living hippocampal slices from females was virtually absent, though slow potentiation gradually developed. The hippocampus of males of the NPS group showed a statistically significant link between the effects of suppression of LTP and synaptic depression of initial potentials; signs of convulsive activity appeared when potentiation was successful. In contrast to males and the results obtained from all control groups, the hippocampus of female rats showed facilitation of the development of post-tetanic potentiation. It is suggested that this effect may be relevant to protective functions, which are evidently less effectively utilized in the hippocampus of males.

The sequelae of craniocerebral trauma (CCT) were studied using a model based on severe (3–4 atm) lateral hydrodynamic percussion (liquid-percussive brain injury) in male Sprague–Dawley rats. With the aim of detecting the symptoms of anxiety states, the rats’ behavior was assessed in the dark-light box and the elevated plus maze test; sleep impairments were detected by recording the electrocorticogram (ECoG) before trauma and during the first week after trauma. The results provided evidence of the post-CCT development of signs of an anxiety state, accompanied by decreases in the proportion of REM sleep and decreases in the amplitude and frequency of the ECoG during this phase.

To assess early consequences of severe traumatic brain injury (TBI) we used lateral fluid percussion model (3-4 atm) in male Sprague-Dawley rats. To evaluate symptoms of anxiety light-dark box and elevated plus-maze tests were used; to estimate global brain function and sleep disturbances electrocorticogramms (ECoG) were recorded prior TBI and during acute posttraumatic period (first week after injury). Our results suggest that during acute posttraumatic period rats demonstrate symptoms of anxiety associated with reduced percentage of REM-sleep as well as its decreased frequency and amplitude.

Early postnatal proinflammatory stress may evoke behavioral impairments in adulthood; however, the underlying mechanisms are still elusive. The brain-derived neurotrophic factor (BDNF) plays a key role in neuroplastic changes in health, as well as in pathology. The BDNF gene is transcribed to exon-specific mRNAs and the pattern of their expression depends on stimulus. We suggested that disturbances of the exonspecific BDNF mRNA expression in the brain regions after stress induced by proinflammatory stimuli in the early postnatal period could be one of the underlying mechanisms of consequent behavioral impairments. Thus, the aim of the study was to examine the effects of proinflammatory stress in early postnatal ontogeny on the BDNF polypeptide content and the patterns of expression of the BDNF gene in the neocortex and hippocampus of prepubertal male rats. The proinflammatory stress was induced by the subcutaneous administration of bacterial lipopolysaccharide (LPS) to rat pups on postnatal days 3 and 5, while BDNF expression was studied in 36-day-old rats. The BDNF polypeptide content was estimated using an enzyme-linked immunosorbent assay, while a quantitative polymerase chain reaction followed by reverse transcription was used to detect the exon-specific BDNF mRNA expression. The levels of BDNF and its transcripts, containing the common exon IX were similar in the control and LPS-treated rats. In the rats treated with LPS, the level of BDNF mRNA containing exon IV was lower in the neocortex but not in the hippocampus. No changes in the expression of the transcripts containing exons I and VI were observed in any of the brain structures studied. We suggest that specific alterations in BDNF expression may be involved in susceptibility to the development of behavioral impairments of animals subjected to early proinflammatory stress.

Infectious diseases in early postnatal ontogenesis can induce neuroinflammation, disrupt normal central nervous system development, and contribute to pathogenesis of cerebral pathologies in adults. To study long-term consequences of such early stress, we induced neonatal proinflammatory stress (NPS) by injecting bacterial lipopolysaccharide into rat pups on postnatal days 3 and 5 and then assessed the levels of corticosterone, proinflammatory cytokines and their mRNAs, and neurotrophins and their mRNAs in the hippocampus and neocortex of the one-month-old animals. Long-term potentiation (LTP) was studied in hippocampal slices as an index of synaptic plasticity. NPS-induced impairments of LTP were accompanied by the accumulation of corticosterone and IL-6 in the hippocampus. In the neocortex, a decrease in exon IV BDNF mRNA was detected. We suggest that excessive corticosterone delivery to hippocampal receptors and proinflammatory changes persisting during brain maturation are among the principal molecular mechanisms responsible for NPS-induced neuroplasticity impairments.

The aim of our study was to investigate the effect of lentivirus-induced Wnt3a overexpression in the dentate gyrus of the hippocampus on the intensity of neurogenesis in this neurogenic zone of adult rats. Virus transduction resulting in local overproduction of Wnt3a was accompanied by a significant decrease in the density of doublecortin-positive cells in the transfected area. This may reflect the suppression of neuronal differentiation of cells generated in the hippocampus during adult neurogenesis. This effect was limited to the region of local overproduction of Wnt3a. A decreased level of doublecortin was not associated with any degenerative alterations in the dentate-gyrus tissue.

Intranasal administration of the polypeptide APHC3, an antagonist of the TRPV1 receptor, had acute anxiolytic and antidepressant effects, as well as an ability to modify the microglial response to proinflammatory stress and cytokine profile of the hippocampus. However, the acute antidepressant effect of the polypeptide was not related to the attenuation of neuroiflammation and probably had a different mechanism. The use of intranasal administration of the APHC3 peptide as a therapeutic approach aimed at decreasing depression symptoms needs additional studies in order to find the mechanism of action of this polypeptide in the central nervous system (CNS).

Adult neurogenesis is an intensively studied phenomenon that is presumably involved in brain functioning under normal and some pathological conditions. Neuroinflammation as a non-specific response of the nerve tissue to pathologic conditions may change the course of adult neurogenesis in the brain and thus enable long-term functional and structural alterations. In this short review, we discuss the interaction of adult neurogenesis and neuroinflammation with a special emphasis on the place that is occupied in both these processes by morphogenic proteins of the Wnt family, which play an important role in the development of the nervous system, as well as in the neuroplasticity of the adult brain.

Hippocampus is believed to be selectively vulnerable to stress. We hypothesized that this phenomenon may be mediated by relatively high vulnerability to neuroinflammation related to impairments of local glucocorticoid metabolism and signaling. We have evaluated inflammatory responses induced by acute or chronic combined stress in the cerebral cortex and hippocampus as well as circulating and brain corticosterone (CS) levels as well as expression of corticosterone target genes. The hippocampus showed higher stress-induced expression of the proinflammatory cytokine IL-1β as compared to the cerebral cortex. A month after the termination of the chronic stress, IL-1β mRNA in the cerebral cortex reached control level, while in the hippocampus it remained significantly increased. Under chronic stress, the maladaptive inflammatory response in hippocampus was accompanied by a significant increase in local CS levels, as compared to cerebral cortex. Under acute stress, the increased CS level induced changes in CS-regulated genes expression (CRF and IGF1), while this phenomenon was not observed after chronic stress. Thus, the hippocampus appears to be more vulnerable to stress-induced inflammation as compared to the neocortex and demonstrates persistent inflammatory response induced by chronic stress. Stress-induced maladaptive inflammatory response is associated with a selective increase in hippocampal CS accumulation and changes in CS signaling.

We studied the effect of chronic combined stress (model of experimental neurosis) on behavior of rats with different basal strategies of behavior in novelty conditions. Chronic stress resulted in decreases in the body weight and testosterone contents in the blood and neocortex in all animals. Animals with initially low orient- ing-exploratory response in the "open field" test did not exhibit substantial alterations of behavior during repeated testing in this test of the "dark-light chamber" test; however, the depression-like behavior was more expressed in the second forced swim test. Chronic combined stress did not significantly affect the behavior of this group of rats. Animals with initially high orienting-exploratory response in the "open field" test exhibited decreased locomotor and exploratory activity in the repeated "open field" tests. The decreases in the locomotor and exploratory activity were substantially less expressed in the repeated tests in these rats after chronic combined stress. The indices of depression-like behavior increased one month after the end of exposure to chronic combined stress. Our data demonstrate that different responses to novelty in the "open field" test do not allow predict with reasonable certainty the development of depression-like behavior after exposure to chronic combined stress.

Depression is the most common form of mental disability in the world. Depressive episodes may be precipitated by severe acute stressful events or by mild chronic stressors. Studies on the mechanisms of depression require both appropriate experimental models (most of them based on the exposure of animals to chronic stressors), and appropriate tests for assessment of depressive states. In this study male Wistar rats were exposed to two different chronic stress paradigms: an eight-week chronic unpredictable mild stress or a two-week combined chronic stress. The behavioral effects of stress were evaluated using sucrose preference, forced swim and open field tests. After the exposure to chronic unpredictable mild stress, anhedonia was developed, activity in the open field increased, while no changes in the duration of passive floating could be detected. After chronic combined stress, anhedonia was also evident, whereas behavior in the open field and forced swim test did not change. The levels of corticosterone in the blood and brain structures involved in stress-response did not differ from control in both experiments. The absence of significant changes in corticosterone levels and passive floating may be indicative of the adaptation of animals to chronic stress. Anhedonia appears to be a more sensitive indicator of depressive-like behavioral effects of chronic stress as compared to behavior in the forced swim or open field tests.

Dosed lateral fluid percussion was used to model craniocerebral trauma (CCT) of moderate to severe intensity in one- and two-year-old rats. Brain sections were stained with cresyl violet by the Nissl method and with an immunochemical reaction for glial fibrillary acidic protein (GFAP) – a marker for astrocytes. The results provide evidence that zones of direct and remote injury formed in the side ipsilateral to the blow. The direct injury zone corresponded to the area of direct contact of the column of liquid with the dura mater, while the remote injury zone was positioned lateral and caudal to the direct injury zone. Morphological detection of trauma depended on the strength of the blow and was seen in both age groups as astrocytic gliosis, with thinning of layer I of the cortex due to death of neurons. Signs of ischemic changes to neurons were probably associated with local impairment to blood supply. Brain damage in one-year-old rats was local in nature but was more diffuse in two-year-olds, while gliosis was characterized by inhomogeneity. The reproducibility and appropriateness of the model allow it to be used for investigation of the molecular genetic mechanisms of the sequelae of CCT in humans and for identifying common mechanisms in the sequelae of CCT and the pathogenesis of major diseases comorbid with CCT, particularly depression and epilepsy.

Effects of neonatal proinflammatory stress (NPS) on the development of anxiety and depressive-like behavior, stress responsiveness, hippocampal plasticity and conditioned fear response were studied in adolescent and adult male Wistar rats. On PND 3 and PND 5, the pups were subcutaneously injected with bacterial lipopolysaccharide (LPS, 50 μg/kg). In the open field test, signs of increased anxiety were demonstrated in adolescent (PND 32), but not in adult (PND 101) rats. In the elevated plus maze, no changes could be detected in adolescent rats, however, in the adults the number of entries into the open arms decreased suggesting increased anxiety after NPS. Signs of "behavioral despair" in the forced swim test, expressed in adolescent rats as a trend, became significant in the adults indicating depression-like behavior. In the majority of brain slices from PND 19-PND 33 rats subjected to NPS, deficit of LTP in the hippocampal CA1 field was detected, this deficit being associated with the impaired mechanisms of LTP induction. In the adult rats, NPS enhanced fear conditioning promoting improved formation of the novel context-foot shock association in the contextual fear conditioning paradigm without effect on cued fear conditioning. NPS significantly impaired functioning of the hypothalamic-pituitary-adrenal axis (HPAA), resulting in an elevated corticosterone level maintained in the adolescents but not in the adults and in modified corticosterone response to behavioral sub-chronic stress in both adolescent and adult rats. Thus, NPS induces "perinatal malprogramming" resulting in development of depression-like behaviors, associated with abnormalities in functioning of the HPAA, impaired hippocampal neuroplasticity (LTP) and changes in hippocampus-dependent memory formation.

We studied the changes in the expression of high-affinity TrkA and TrkB receptors of the nerve-growth factor and brain-derived neurotrophic factor in the rat hippocampus at different time points after the administration of Aβ(25–35) into the lateral cerebral ventricles. Studies on TrkA and TrkB expression were performed using immunohistochemistry and the method of the real-time polymerase chain reaction. We found that intracerebroventricular administration of Aβ(25–35) to rats resulted in long-term alterations in the system of neurotrophic signaling in the hippocampus. Expression of the TrkA receptor increased 28 days after treatment, whereas expression of the TrkB receptor increased 12 days and then decreased by 28 days after the treatment. Thus, alterations in neurotrophin signaling may be involved in the mechanisms that are responsible for Aβ(25–35)-induced impairment of hippocampal functions in rats.