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

ПЕЧЕНЬ И ЕЕ ЛИМФАТИЧЕСКИЙ РЕГИОН ПРИ ВОЗДЕЙСТВИЯХ БЕНЗ[A]ПИРЕНА В ЭКСПЕРИМЕНТЕ

Background: Benzo[a]pyrene (BaP) is the widespread environmental toxicant with carcinogenic activity. BaP undergoes metabolic activation in the liver microsomal monooxygenase system, and its regional lymph nodes act as peripheral filters, purifying lymph formed in the liver. It remains an open question about the significance of the integral liver and lymphatic system work in supporting processes of adaptation and resistance to the BaP effects. Objective: The purpose of our investigation was to study structural and metabolic changes in the liver and its lymph region in males Wistar rats weighing 180–220 g. Methods: Animals of the experimental group (n =20) daily for 3 days was performed BaP injections: intraperitoneally with 2 mg per 100 g of body weight in 0.2–0.3 ml of olive oil. Rats in the control group (n =20) received in the same mode of injection of olive oil. The light and electron microscopy morphometric study of the liver and its regional lymph nodes morphometric analysis were performed. The intensity of lipid peroxidation in the liver was measured by the number of diene conjugates (DC), ketotriene conjugates (KC) and malondialdehyde (MDA). Results: Simultaneous increase of the hepatic sinusoids relative area and the specific area of the regional lymph nodes sinus system was discovered under the BaP effect. At ultrastructural level dilatation of the Disse spaces, filling of cell detritus and collagen fibers bundles of these spaces were noted. Damage of nuclear apparatus, balloonie expansion of granular endoplasmic reticulum profiles were found in hepatocytes, condensation of the mitochondrial matrix was observed. The relative squares of B-dependent zones increased and T-dependent paracortical zone reduced in the regional lymph nodes. The increase in the content of KC and MDA in liver was dentified. Conclusion: benzo[a]pyrene causes interrelated cascade of reactions in the liver and in its lymphatic region: a disturbance of the blood-lymph barrier morphological organization, the difficulty of lymph drainage from the organ. These promotes development of tissue hypoxia and apoptosis, protein synthesizing and energy cell apparatus disruptions, formation of lymphoid tissue temporary groups in the liver. Бенз[a]пирен (БаП) — широко распространенный в окружающей среде токсикант, обладающий канцерогенной активностью. БаП подвергается метаболической активации в системе микросомных монооксигеназ печени, а ее регионарные лимфатические узлы выступают в роли периферических фильтров, очищающих образующуюся в печени лимфу. Остается открытым вопрос о значимости интегральной работы печени и лимфатической системы в обеспечении процессов адаптации и резистентности к воздействиям БаП. Цель исследования: изучить структурно-метаболические изменения в печени и ее лимфатическом регионе у самцов крыс линии Wistar массой 180–220 г. Методы: животным опытной группы (n =20) ежедневно в течение 3 сут проводили инъекции БаП внутрибрюшинно, по 2 мг на 100 г веса тела в 0,2–0,3 мл оливкового масла. Крысы контрольной группы (n =20) получали в таком же режиме инъекции оливкового масла. Выполняли морфометрическое исследование светооптических препаратов и электроннограмм печени, морфометрический анализ ее регионарных лимфатических узлов. Об интенсивности перекисного окисления липидов в печени судили по числу диеновых конъюгатов (ДК), кетотриеновых конъюгатов (КТ) и малонового диальдегида (МДА). Результаты: при воздействии БаП происходит синхронное  увеличение относительной площади печеночных синусоидов и удельной площади синусной системы регионарных лимфатических узлов. На ультраструктурном уровне отмечена дилатация пространств Диссе, заполнение их клеточным детритом пучками коллагеновых волокон. В гепатоцитах обнаружены повреждения ядерного аппарата, баллонообразные расширения профилей гранулярного эндоплазматического ретикулума, наблюдалось конденсирование митохондриального матрикса. В регионарных лимфатических узлах возросли относительные размеры В-зависимых зон и уменьшилась удельная площадь Т-зависимой паракортикальной зоны. Выявлено повышение содержания КТ и МДА в печени. Заключение: воздействие бенз[a]пирена приводит к развитию взаимосвязанного каскада реакций в печени и ее лимфатическом регионе: нарушению организации гемато-лимфатического барьера, изменению корней лимфатической системы в печени, затруднению оттока лимфы от органа. Это способствует развитию тканевой гипоксии и апоптоза, нарушению белковосинтетического и энергетического аппаратов клеток, образованию временных скоплений лимфоидной ткани в печени.

Competitiveness estimation of fishery complex enterprises of Astrakhan region

In terms of global economic challenges the increase of Russian fishery complex competitiveness is possible on the basis of competitive position strengthening of both Russian and regional enterprises. In this case, when selecting competitive enterprises proactive development of the largest fisheries enterprises in a region must be considered first of all. The factors that determine the competitiveness of a fishery complex are their production capacities and high rate of water bio-resources catch. The purpose of the study is to apply strategic analysis tools for competitive advantage estimation of fisheries and fish-processing enterprises of Astrakhan region. We also determine the trends of competitive advantage increase of these companies. The use of the strategic analysis tool – Boston Consulting Group matrix – made it possible to determine the competitive advantages of enterprises on the regional market among the important fishing enterprises, to assess their competitive ability from the view point of both the product and a producer. Using a Shewhart control chart we have determined the limits of correspondence of real fish catch rate to the level of an enterprise sustainable development. We have also identified enterprises that decrease the fishing amount. Using the ABC – analysis the business – segment called “frozen fish” has been revealed. It is characterized with the highest level of competitiveness that confirms the opportunity to make a raw material base for its subsequent processing and selling in the market. The results of the suggested approach to the estimation of the enterprise competitiveness have revealed the companies that are strategically important for the fishery complex development in Astrakhan region. Furthermore, they may be used for planning of possible trends of fishery activity development in Astrakhan region to increase competitive potential of fisheries and fishery processing enterprises in the region

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

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

Experimental hyperthermia: expression of proteins involved in the regulation of ovarian corpus luteum apoptosis in the acute and recovery periods

Background.Heat shock effects can initiate apoptosis of oocytes and corpus luteum cells in mammalian ovaries. During folliculogenesis, follicular apoptosis is regulated by Bcl-2 and BAX proteins which are key effectors of granular cell death. Mechanisms of disruption of the ovarian corpus luteum development under heat stress remain largely unclear.Aim of the research: to identify the expression features of anti-apoptotic Bad and proapoptotic Bcl-2 proteins in the rat ovarian luteocytes in the acute (by day 3) and recovery (by days 7 and 14) periods after a single exposure of experimental hyperthermia (EH) (rectal temperature 43.5 °C).Materials and methods. The expression of Bad and Bcl-2 was determined immunohistochemically using an indirect two-stage streptavidin-biotin method.Results. On day 3 after EH, the expression areas of both Bad and Bcl-2 increased 2-fold, but the ratio of Bcl-2/Bad areas did not change, indicating that the intensity of apoptosis along the mitochondrial pathway in luteocytes in the acute period was  maintained within physiological values. On day  7, the Bad and Bcl-2 expression areas remained at the level of day 3, but the Bcl-2/Bad index decreased, indicating the activation of the apoptosis internal pathway in the ovarian corpus luteum cells. By day 14, the protein expression areas decreased (Bad – by 1.7 times, Bcl-2 – by 3.2 times) compared to the acute period, and the Bcl-2/Bad index decreased by 2 times compared to the control and the acute period group.Conclusion. The observed predominance of proapoptotic Bad protein over antiapoptotic Bcl-2 in luteocytes on day 14 after EH indicates the anti-apoptotic protection violation, which leads to the apoptosis mitochondrial pathway activation of  the latter. A decrease in Bcl-2 expression can be regarded as a manifestation of the defective luteocytes removal mechanism and the body’s desire to normalize the ovarian-uterine cycle disrupted by high temperature exposure