In our previous studies, we have found a suppressive effect of a single administration of pentylenetetrazole (PTZ) at a subconvulsive dose on cellular proliferation in the dentate gyrus. In the present work, we show that this decrease in proliferation develops after acute anxiogenic effect of PTZ and is present only in the posterior part of the hippocampus, where a decrease in the number of neuronal NO synthase expressing cells has been also found. These changes were also accompanied by a decrease in the level of nNOS protein in the hippocampus. Taken together, these observations may indicate the possible involvement of nNOS in the suppression of cellular proliferation in the dentate gyrus of the posterior hippocampus during the development of the anxiogenic effect of PTZ.

Aging is a complex process associated with multimorbidity. Hypertension, one of widespread states, is among main causes of age-related alterations in behavior, emotionality and sociability. We studied the effects of long-term isolated housing on anxiety, depressive-like and social behavior as well as changes in the adrenocortical and sympathetic systems in the aging normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Ten-month-old male rats of both strains were subjected to 90-day isolated or group housing. Surprisingly, social isolation induced only mild effect on anxiety without influencing other affective-related behaviors. No effects of isolated housing on sociability or social novelty preferences were revealed. Despite the adrenal gland hypertrophy in the SHRs, corticosterone levels remained stable within the period of isolation but the expression of nuclear glucocorticoid receptor (Nr3c1) mRNA in the adrenals was lower in the SHR as compared to WKY rats. Pre-existing hypertension, associated with SHR genotype, did not significantly contribute to the effects of social isolation. The data suggest that the aged WKY and SHR rats are relatively resilient to chronic social stress associated with isolated housing.

Brain aging is associated with a progressive decrease in learning abilities, memory, attention, decision making, and sensory perception. Age-related cognitive disturbances may be related to a decrease in the functional capacities of the hippocampus. This brain region is essential for learning and memory, and the lifelong neurogenesis occurring in the subgranular zone of the dentate gyrus may be a key event mediating the mnemonic functions of the hippocampus. In the present study, we investigated whether age-related changes in hippocampal neurogenesis are associated with learning and memory disturbances. Four- and 24-month-old rats were trained to find a hidden platform in a water maze. Though the older group showed higher latency to search the platform as compared to the younger group, both groups learned the task. However, the density of proliferating (PCNA-positive), differentiating (Dcx-positive), and new neurons (pre-labeled BrdU-positive) was significantly lower in the hippocampus of aged rats as compared to young ones. This inhibition of neurogenesis could be related to increased local production of nitric oxide since the density of neurons expressing neuronal NO-synthase was higher in the aged hippocampus. Thus, we can suggest that an age-related decrease in neurogenesis is not directly associated with place learning in aged rats.

A delicate balance between quiescence and division of the radial glia-like stem cells (RGLs) ensures continuation of adult hippocampal neurogenesis (AHN) over the lifespan. Transient or persistent perturbations of this balance due to a brain pathology, drug administration, or therapy can lead to unfavorable long-term outcomes such as premature depletion of the RGLs, decreased AHN, and cognitive deficit. Memantine, a drug used for alleviating the symptoms of Alzheimer’s disease, and electroconvulsive seizure (ECS), a procedure used for treating drug-resistant major depression or bipolar disorder, are known strong AHN inducers; they were earlier demonstrated to increase numbers of dividing RGLs. Here, we demonstrated that 1-month stimulation of quiescent RGLs by either memantine or ECS leads to premature exhaustion of their pool and altered AHN at later stages of life and that aging of the brain modulates the ability of the quiescent RGLs to be recruited into the cell cycle by these AHN inducers. Our findings support the aging-related divergence of functional features of quiescent RGLs and have a number of implications for the practical assessment of drugs and treatments with respect to their action on quiescent RGLs at different stages of life in animal preclinical studies.

The dentate gyrus (DG), an important part of the hippocampus, plays a significant role in learning, memory, and emotional behavior. Factors potentially influencing normal development of neurons and glial cells in the DG during its maturation can exert long-lasting effects on brain functions. Early life stress may modify maturation of the DG and induce lifelong alterations in its structure and functioning, underlying brain pathologies in adults. In this paper, maturation of neurons and glial cells (microglia and astrocytes) and the effects of early life events on maturation processes in the DG have been comprehensively reviewed. Early postnatal interventions affecting the DG eventually result in an altered number of granule neurons in the DG, ectopic location of neurons and changes in adult neurogenesis. Adverse events in early life provoke proinflammatory changes in hippocampal glia at cellular and molecular levels immediately after stress exposure. Later, the cellular changes may disappear, though alterations in gene expression pattern persist. Additional stressful events later in life contribute to manifestation of glial changes and behavioral deficits. Alterations in the maturation of neuronal and glial cells induced by early life stress are interdependent and influence the development of neural nets, thus predisposing the brain to the development of cognitive and psychiatric disorders.

The relation of heavy cannabis use with decreased neuropsychological function has frequently been described but the underlying biological mechanisms are still largely unknown. This study investigates the relation of cannabis use with genome wide gene expression and subsequently examines the relations with neuropsychological function. Genome-wide gene expression in whole blood was compared between heavy cannabis users (N = 90) and cannabis naïve participants (N = 100) that were matched for psychotic like experiences. The results were validated using quantitative real-time PCR. Psychotic like experiences were assessed using the Comprehensive Assessment of Psychotic Experiences (CAPE). Neuropsychological function was estimated using four subtasks of the Wechsler Adult Intelligence Scale (WAIS). Subsequent in vitro studies in monocytes and a neuroblastoma cell line investigated expression changes in response to two major psychotropic components of cannabis; tetrahydrocannabinol (THC) and cannabidiol (CBD). mRNA expression of Protein Tyrosine Phosphatase Receptor Type F Polypeptide-Interacting-Protein Alpha-2 (PPFIA2) was significantly higher in cannabis users (LogFold Change 0.17) and confirmed by qPCR analysis. PPFIA2 expression level was negatively correlated with estimated intelligence (B=−22.9, p = 0.002) also in the 100 non-users (B=−28.5, p = 0.037). In vitro exposure of monocytes to CBD led to significant increase in PPFIA2 expression. However, exposure of monocytes to THC and neuroblastoma cells to THC or CBD did not change PPFIA2 expression. Change in PPFIA2 gene expression in response to cannabinoids is a putative mechanism by which cannabis could influence neuropsychological functions. The findings warrant further exploration of the role of PPFIA2 in cannabis induced changes of neuropsychological function, particularly in relation to CBD.

Lentiviral transduction is a powerful tool and widely used in neuroscience research to manipulate gene expression of cells. However, the injection of lentiviral vectors in the brain is not totally benign, it potentially induces focal neuroinflammation. Upon inflammation, microglial cells get activated and can induce major changes in tissue environment, which may interfere with experimental results. In the current study, two weeks after the injection of control viral construction in the dentate gyrus (DG) of rats, an activation of microglia was detected. To access the activation status, we used a fast and accurate method of phenotype detection - measurement of fractal dimension (FD). Microglial morphology is a key indicator of neuroinflammation, therefore FD of microglial cells may serve as a reliable index of inflammation status in the brain. Here we present a detailed description of image processing procedure of images of individual microglial cells. The method allows to preserve the complex structure of microglial cells and their thin processes on the output image, which is important for accurate FD assessment.

Selective vulnerability or resilience to mood disorders is related to individual differences or personality. In the present study forced swim test (FST) was used as a tool for division of male rats according to their immobility behavior. The animals were subjected to a chronic unpredictable mild stress (CUS). Depressive-like behavior and modifications in brain neurotrophin system of were examined after CUS exposure. The low immobile (LI) and high immobile (HI) rats demonstrated elusive differences in expression of BDNF ExVI mRNA and TrkA mRNA which was higher in the hippocampus and frontal cortex, respectively, of HI rats as compared to LI animals. Exposure to CUS resulted in development of depressive-like phenotype and increased anxiety in both subgroups; however, immobility in FST specifically decreased in the initially HI animals. In hippocampus of stressed LI rats, the contents of total BDNF mRNA decreased. In hippocampus of stressed HI rats, the content of TrkA mRNA increased whereas in frontal cortex, the content of BDNF exon I mRNA decreased in both LI and HI rats. The levels of BDNF ExIX and ExI as well TrkB mRNAs were higher in the hippocampus of HI rats as compared to LI rats. In general, the response of hippocampus to CUS was much more expressed as compared to frontal cortex. Thus, initially different stress coping strategies of rats in the FST (HI, LI) were associated with the development of similar behavioral phenotypes after chronic unpredictable stress; however, these phenotypes were associated with different alterations in neurotrophin systems of the brain.

Pharmacoresistance in epilepsy is an important problem from both clinical and fundamental perspectives. The existent hypotheses of pharmacoresistance are based on long term plastic rebuilding of the epileptic brain. One of potential mechanisms mediating such protracted changes are alterations of gene expression induced by epigenetic modifications of chromatin in brain cells of epileptic patients. Recently, changes in DNA methylation and histone post-translational modifications were reported in brain tissues of patients with pharmacoresistant epilepsy. Unfortunately, these data remain fragmentary and contradictory, therefore the results of animal models can partially fill this gap. The authors present a short review of the data concerning a potential role of epigenetic modifications in epilepsy.

Background: Aging is associated with some cognitive decline and enhanced risk of development of neurodegenerative diseases. It is assumed that altered metabolism and functions of neurotrophin systems may underlie these age-related functional and structural modifications. Cerebrolysin(TM) (CBL) is a neuropeptide mixture with neurotrophic effects, which is widely used for the treatment of stroke and traumatic brain injury patients. It is also evident that CBL has an overall beneficial effect and a favorable benefit-risk ratio in patients with dementia. However, the effects of CBL on cognition and brain neurotrophin system in normal aging remain obscure. Objective: The aim of the present study was to examine the age-related modifications of endogenous neurotrophin systems in the brain of male Wistar rats and the effects of CBL on learning and memory as well as the levels neurotrophins and their receptors. Methods: Old (23-24 months) and young (2-3 months) male Wistar rats were used for the study. A half of animals were subjected to CBL course (2.5 ml/kg, 20 i.p. injections). Behavior of rats was studied using the open field test and simple water maze training. The contents of NGF and BDNF were studied using enzyme-linked immunosorbent assay; the expression of neurotrophin receptors was estimated by Western-blot analysis. Results: CBL treatment did not affect general status, age-related weight changes, general locomotor activity as well as general brain histology. In a water maze task, a minor effect of CBL was observed in old rats at the start of training and no effect on memory retention was found. Aging induced a decrease in neurotrophin receptors TrkA, TrkB, and p75NTR in the neocortex. CBL counteracted effects of aging on neocortical TrkA and p75NTR receptors and decreased expression of proNGF without influencing overall NGF levels. BDNF system was not significantly affected by CBL. Conclusion: The pro-neuroplastic "antiaging" effects of CBL in the neocortex of old animals were generally related to the NGF rather than the BDNF system.

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.

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.

Nowadays, there is no definite answer to the question whether a single seizure episode can influence cognitive functions. However, elucidating this issue has a great clinical significance, since adequate therapeutic interventions may be needed soon after the seizure occurrence if long-lasting cognitive impairments can be launched shortly after a seizure. The existing clinical observations in patients with new-onset epilepsy often imply the pre-existing brain pathology which may lead to both epileptogenesis and deterioration of mental functions. On the other hand, in some cases a positive correlation between seizure severity (frequency) and the degree of cognitive deterioration can be demonstrated suggesting that an effect of a single seizure episode may be negligible. In any case, objective difficulties of clinical investigations of seizure-induced cognitive impairments make the experimental studies on this issue highly actual, and some recent advance in this area suggests the existence of long-lasting cognitive effects of even a single seizure episode. Possible mechanisms and potential clinical significance of this phenomenon are discussed.

We have performed a quantitative analysis of temporal pattern of immunohistochemical staining to PCNA and Dcx in brain tissue under the influence of 10% neutral buffered formalin (fixation for 3.5 h–7 weeks). After 7 days of fixation we found a decrease in Dcx and, to a lesser extent, PCNA immunoreactivity. Later, no further decline in immunoreactivity occurred. Our data may be useful for optimization of neurogenesis assessment protocols in mammalian and human brains.