Nitric oxide mediates local activity-dependent excitatory synapse development

Learning related paradigms play an important role in shaping the development and specificity of synaptic networks, notably by regulating mechanisms of spine growth and pruning. The molecular events underlying these synaptic rearrangements remain poorly understood. Here we identify NO signaling as a key mediator of activity-dependent excitatory synapse development. We find that chronic blockade of NO production in vitro and in vivo interferes with the development of hippocampal and cortical excitatory spine synapses. The effect results from a selective loss of activity-mediated spine growth mechanisms and is associated with morphological and functional alterations of remaining synapses. These effects of NO are mediated by a cGMP cascade and can be reproduced or prevented by postsynaptic expression of vasodilator-stimulated phosphoprotein phospho-mimetic or phospho-resistant mutants. In vivo analyses show that absence of NO prevents the increase in excitatory synapse density induced by environmental enrichment and interferes with the formation of local clusters of excitatory synapses. We conclude that NO plays an important role in regulating the development of excitatory synapses by promoting local activity-dependent spine-growth mechanisms

Expression of Guanylyl Cyclase (GC)-A and GC-B during Brain Development: Evidence for a Role of GC-B in Perinatal Neurogenesis

Atrial (ANP) and C-type (CNP) natriuretic peptide generate physiological effects via selective activation of two closely related membrane receptors with guanylyl cyclase (GC) activity, known as GC-A and GC-B. As yet, however, the discrete roles for ANP/GC-A vs. CNP/GC-B signaling in many mammalian tissues are still poorly understood. We here used receptor affinity labeling and GC assays to characterize comparatively GC-A/GC-B expression and functional activity during rat brain development. The study revealed that GC-B predominates in the developing and GC-A in the adult brain, with regional differences each between cerebral cortex, cerebellum, and brain stem. Whereas GC-A levels nearly continuously increase between embryonal d 18 and adult, GC-B expression in brain is highest and widely distributed around postnatal d 1. The striking perinatal GC-B peak coincides with elevated expression of nestin, a marker protein for neural stem/progenitor cells. Immunohistochemical investigations revealed a cell body-restricted subcellular localization of GC-B and perinatal abundance of GC-B-expressing cells in regions high in nestin-expressing cells. However, and supported by examination of nestin-GFP transgenic mice, GC-B and nestin are not coexpressed in the same cells. Rather, GC-B(+) cells are distinguished by expression of NeuN, an early marker of differentiating neurons. These findings suggest that GC-B(+) cells represent neuronal fate-specific progeny of nestin(+) progenitors and raise the attention to specific and pronounced activities of CNP/GC-B signaling during perinatal brain maturation. The absence of this activity may cause the neurological disorders observed in GC-B-deficient mice

Extended effect of chronic social defeat stress in childhood on behaviors in adulthood

Individuals exposed to social stress in childhood are more predisposed to developing psychoemotional disorders in adulthood. Here we use an animal model to determine the influence of hostile social environment in adolescence on behavior during adult life. One-month-old adolescent male mice were placed for 2 weeks in a common cage with an adult aggressive male. Animals were separated by a transparent perforated partition, but the adolescent male was exposed daily to short attacks from the adult male. After exposure to social stress, some of the adolescent mice were placed for 3 weeks in comfortable conditions. Following this rest period, stressed young males and adult males were studied in a range of behavioral tests to evaluate the levels of anxiety, depressiveness, and communicativeness with an unfamiliar partner. In addition, adult mice exposed to social stress in adolescence were engaged in agonistic interactions. We found that 2 weeks of social stress result in a decrease of communicativeness in the home cage and diminished social interactions on the novel territory. Stressed adolescents demonstrated a high level of anxiety in the elevated plus-maze test and helplessness in the Porsolt test. Furthermore, the number of dividing (BrdU-positive) cells in the subgranular zone of the dentate gyrus was significantly lower in stressed adolescents. After 3 weeks of rest, most behavioral characteristics in different tests, as well as the number of BrdU-positive cells in the hippocampus, did not differ from those of the respective control mice. However, the level of anxiety remained high in adult males exposed to chronic social stress in childhood. Furthermore, these males were more aggressive in the agonistic interactions. Thus, hostile social environment in adolescence disturbs psychoemotional state and social behaviors of animals in adult life

Effect of a sorbent composition based on aluminum oxide and polydimethylsiloxane on the reproductive system of <i>db/db</i> female mice with genetically determined obesity and type 2 diabetes mellitus

Metabolic syndrome, obesity, type 2 diabetes mellitus are characterized by the accumulation of toxic metabolic products in the internal environment of the organism. The development of innovative medicines based on a sorbent matrix modified with  biologically active molecules remains relevant. The sorbent composition from aluminum oxide and polydimethylsiloxane is considered promising. The aim of the study. To investigate the effect of the sorbent composition from aluminum oxide and polydimethylsiloxane on the uterus and ovaries of db/db  mice with obesity and type 2 diabetes mellitus. Materials and methods. The sorbent composition (0.665 g/kg in 200 μl of distilled water) was administered to 14-week-old animals through an intragastric tube once a day for 7 days. The comparison groups were female rats injected with placebo (daily intragastrical administration of 200 µl of water for 7 days) and intact animals. Digital images of light-optical preparations stained with hematoxylin and eosin were processed using Image-Pro Plus 4.1 software. In the ovaries, the numerical density of primordial, primary, secondary follicles and corpus luteum was determined. The width of the uterus layers, the diameters of the blood and lymphatic vessels, the width of the interstitial fissures in both organs were measured. The statistical significance of differences was determined using the Mann – Whitney test. Results. In the myometrium and endometrium of the uterus of db/db mice, dilatation of arteries, veins, lymphatic vessels and edema were noted due to the accumulation of tissue fluid in the interstitium layers. There were no tertiary follicles in the ovaries. The introduction of the sorbent composition contributed to a decrease in the diameters of arteries, veins, lymphatic vessels of the uterus, a decrease in edema in both organs due to the narrowing of the prelymphatic slits, and stimulated an increase in the numerical density of secondary follicles. Conclusion. A corrective effect of the sorbent composition of aluminum oxide and  polydimethylsiloxane on prelymphatic slits, blood and lymphatic vessels in the uterus and ovaries in db/db mice with obesity and type 2 diabetes mellitus was revealed

noxin, a novel stress-induced gene involved in cell cycle and apoptosis

We describe a novel stress-induced gene, noxin, and a knockout mouse line with an inactivated noxin gene. The noxin gene does not have sequelogs in the genome and encodes a highly serine-rich protein with predicted phosphorylation sites for ATM, Akt, and DNA-dependent protein kinase kinases; nuclear localization signals; and a Zn finger domain. noxin mRNA and protein levels are under tight control by the cell cycle. noxin, identified as a nitric oxide-inducible gene, is strongly induced by a wide range of stress signals: gamma- and UV irradiation, hydrogen peroxide, adriamycin, and cytokines. This induction is dependent on p53. Noxin accumulates in the nucleus in response to stress and, when ectopically expressed, Noxin arrests the cell cycle at G1; although it also induces p53, the cell cycle arrest function of Noxin is independent of p53 activity. noxin knockout mice are viable and fertile; however, they have an enlarged heart, several altered hematopoietic parameters, and a decreased number of spermatids. Importantly, loss or downregulation of Noxin leads to increased cell death. Our results suggest that Noxin may be a component of the cell defense system: it is activated by various stress stimuli, helps cells to withdraw from cycling, and opposes apoptosis

Altered Hippocampal Neurogenesis and Amygdalar Neuronal Activity in Adult Mice with Repeated Experience of Aggression

Repeated experience of winning in a social conflict setting elevates levels of aggression and may lead to violent behavioral patterns. Here, we use a paradigm of repeated aggression and fighting deprivation to examine changes in behavior, neurogenesis, and neuronal activity in mice with positive fighting experience. We show that for males, repeated positive fighting experience induces persistent demonstration of aggression and stereotypic behaviors in daily agonistic interactions, enhances aggressive motivation, and elevates levels of anxiety. When winning males are deprived of opportunities to engage in further fights, they demonstrate increased levels of aggressiveness. Positive fighting experience results in increased levels of progenitor cell proliferation and production of young neurons in the hippocampus. This increase is not diminished after a fighting deprivation period. Furthermore, repeated winning experience decreases the number of activated (c-fos-positive) cells in the basolateral amygdala and increases the number of activated cells in the hippocampus; a subsequent no-fight period restores the number of c-fos-positive cells. Our results indicate that extended positive fighting experience in a social conflict heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and decreases neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights

Neuronal nitric oxide synthase contributes to the regulation of hematopoiesis

Nitric oxide (NO) signaling is important for the regulation of hematopoiesis. However, the role of individual NO synthase (NOS) isoforms is unclear. Our results indicate that the neuronal NOS isoform (nNOS) regulates hematopolesis in vitro and in vivo. nNOS is expressed in adult bone marrow and fetal liver and is enriched in stromal cells. There is a strong correlation between expression of nNOS in a panel of stromal cell lines established from bone marrow and fetal liver and the ability of these cell lines to support hematopoietic stem cells; furthermore, NO donor can further increase this ability. The number of colonies generated in vitro from the bone marrow and spleen of nNOS-null mutants is increased relative to wild-type or inducible- or endothelial NOS knockout mice. These results describe a new role for nNOS beyond its action in the brain and muscle and suggest a model where nNOS, expressed in stromal cells, produces NO which acts as a paracrine regulator of hematopoietic stem cells

Assessment of regularities of ground-level air radionuclide contamination at the Russian coast of the Baltic Sea in the course of the long-term Leningrad Nuclear Power Plant (1983-1999) operation

Long-term results of ground-level air radionuclide contamination at the Russian coast of the Baltic Sea (nuclear facilities in the vicinity of the town of Sosnovy Bor) are under consideration. As compared with 1992-1997 [1], the Leningrad Nuclear Power Plant (NPP) equipment hermetic sealing (in 1998-1999) caused both the reduction of detection frequency of 131I aerosol and the maximum concentrations of 137Cs in the ground-level air at the NPP site. Long-term weekly nuclides' concentration time series were examined by the correlation analysis. Results of the analysis are presented. The seasonal fluctuations of 7Be concentrations in the ground-level air were examined by the harmonic (Fourier) analysis. The seasonal fluctuations of its concentrations with the maximum in spring-summer period are shown