A stressz-függő viselkedés (szorongás) vazopresszinerg és oxytocinerg kontrollja: vizsgálatok Brattleboro patkányok felhasználásával = Neuropeptidergic control of stress-related behavior including anxiety-related behavior by arginine vasopressin and oxytocin: studies employing the model organism Brattleboro rat

A modern társadalmakat gazdaságilag leginkább sújtó betegségek közül a stresszel kapcsolatba hozható szorongás és a depresszió előfordulása kiemelkedő. A stressz-tengely szabályozásában betöltött fontos szerepéből kiindulva a vazopresszin (AVP) fontos az érzelmi zavarok kialakulásában is. Kísérleteiben a nucleus paraventricularis hypothalami (PVN) sejtjeiből ürülő AVP neuromodulátor szerepét vizsgáltuk stresszben és ezzel kapcsolatos érzelmi zavarokban. Modellállatként természetes mutációval AVP hiányossá vált Brattleboro patkányokat használtunk. A kutatásainkat az alapkérdést befolyásoló egyéb tényezők vizsgálatára is kiterjesztettük. Kimutattuk, hogy az AVP felnőtt állatban stressz-függő módon járul hozzá a adrenokortikotropin (hipofízeális stressz-komponens) elválasztáshoz, míg a perinatális korban szabályozó szerepe elsődleges. Ugyanakkor, a stressz-tengely hipofízeális és mellékvese komponenseinek szintje disszociál, azaz a glukokortikoid elválasztást ismeretlen faktorok is szabályozzák. A stressz-során a PVN-ben parakrin módon ürülő AVP elősegíti a stressz-tengely kiindulási állapotba való visszatérését. A Brattleboro patkányok csökkent stressz-reaktivitásukkal összhangban kevésbé depressziós fenotípust mutatnak centrális támadásponttal. Vizsgálataink a szervezetben zajló stressz-folyamatok szabályozásának jobb megértéséhez vittek közelebb. Eredményeinket számos nemzetközi konferencián, 20 nemzetközi folyóirat cikkben és 4 könyvfejezetben ismertettük. | In modern societies the prevalence of stress-induced anxiety and depression is increasing. Based upon the important regulatory role of vasopressin (AVP) in stress-axis, its prominent role in the development of emotional disorders could be also supposed. Our goal was to examine the neuromodulatory role of AVP, released from the paraventricular nucleus of the hypothalamus (PVN), in stress and related psychopathologies. As a model animal we used naturally AVP mutant Brattleboro rats. The research was extended to the examination of other related processes. We showed that in adult animals AVP had stress-dependent contribution to the adrenocorticotropin (hypophyseal stress component) release, while it was the primary regulator during the perinatal period. However, the hypophyseal and adrenal level of the stress-axis were dissociated, thus glucocorticoid secretion could be regulated by unknown factors as well. The AVP, released in a paracrine manner from the PVN, promoted the return of the stress hormone levels to the initial state. In accordance with reduced stress reactivity Brattleboro rats showed less depressive-like phenotype based on a central effect. Our studies added details to the regulation of stress processes and related psychopathologies. We presented the results on many international conferences, in 20 peer-reviewed international journals and 4 book-chapters

Restoration of peripheral V2 receptor vasopressin signaling fails to correct behavioral changes in Brattleboro rats.

Beside its hormonal function in salt and water homeostasis, vasopressin released into distinct brain areas plays a crucial role in stress-related behavior resulting in the enhancement of an anxious/depressive-like state. We aimed to investigate whether correction of the peripheral symptoms of congenital absence of AVP also corrects the behavioral alterations in AVP-deficient Brattleboro rats. Wild type (WT) and vasopressin-deficient (KO) male Brattleboro rats were tested. Half of the KO animals were treated by desmopressin (V2-receptor agonist) via osmotic minipump (subcutaneous) to eliminate the peripheral symptoms of vasopressin-deficiency. Anxiety was studied by elevated plus maze (EPM), defensive withdrawal (DW) and marble burying (MB) tests, while depressive-like changes were monitored in forced swimming (FS) and anhedonia by sucrose preference test. Cell activity was examined in septum and amygdala by c-Fos immunohistochemistry after 10min FS. KO rats spent more time in the open arm of the EPM, spent less time at the periphery of DW and showed less burying behavior in MB suggesting a reduced anxiety state. KO animals showed less floating behavior during FS revealing a less depressive phenotype. Desmopressin treatment compensated the peripheral effects of vasopressin-deficiency without a significant influence on the behavior. The FS-induced c-Fos immunoreactivity in the medial amygdala was different in WT and KO rats, with almost identical levels in KO and desmopressin treated animals. There were no differences in central and basolateral amygdala as well as in lateral septum. Our data confirmed the role of vasopressin in the development of affective disorders through central mechanisms. The involvement of the medial amygdala in the behavioral alterations of vasopressin deficient animals deserves further attention

Az UV-B sugárzás hatása a kukorica fejlődésére = Effect of UV-B radiation on maize development

Az ózonréteg évtizedek óta tartó vékonyodása az UV-B sugárzás globális szinten történő megemelkedéséhez vezetett. Nemesítési programunkban ezért célul tűztük ki olyan beltenyésztett vonalak és hibridek nemesítését, melyek e negatív környezeti hatást jobban tolerálni tudják. Ugyanazon 10 eltérő tenyészidejű és különböző genetikai háttérbázissal rendelkező beltenyésztett vonalakat vizsgálva megállapítottuk, hogy a magasabb sugárzási szint a a kukorica leveleiben szignifikánsan magasabb össz-antocián termelést eredményezett. Mérési eredményeink igazolták, hogy vannak olyan anyagok, melyek antociántartalma eleve magas, így ezért a nagyobb UV-B sugárzásra kevésbé reagálnak, míg más típusok szignifikánsan magasabb össz-antocián termelésel reagálnak. A martonvásári levélmintáknál kipróbálásra került egy új, fluoreszcencia leképezési technikán alapuló módszer. Ennek segitségével a különböző stresszorok által okozott funkciócsökkenés képszerűen is megjelenithető. A speciális fitotron kamrában mértük a magasabb UV-B sugárzás fotoszintézisre gyakorolt hatását. Az itt kapott eredmények is igazolták egyes korai genotípusok érzékenységét, ami a netto fotoszintetikus aktivitásuk csökkenésében jelentkezett. Az antioxidáns enzimek aktivitásával kapcsolatos eredményeink is azt a megfigyelést támasztják alá, hogy ezek a korai, az UV-B sugárzásra érzékeny beltenyésztett vonalaknak a reaktív oxigénformákat elimináló képessége gyengébb, mint a későieké. | The ozone layer has become thinner in recent decades, leading to an increase in UV-B radiation on a global scale. One aim of our breeding programme is thus to develop inbred lines and hybrids capable of tolerating this negative environmental effect. Tests on ten inbred lines with diverse vegetation periods and genetic backgrounds revealed that a higher radiation level led to the production of a significantly higher quantity of total anthocyanin in maize leaves. The measurements proved that the initial anthocyanin content was higher in some genotypes, which thus had a milder response to higher UV-B radiation levels, while other types responded with a significant increase in total anthocyanin production. A new method based on the fluorescence imaging technique was tested on leaf samples taken in Martonvásár. This method allows the reduction in functioning ability caused by various stressors to be recorded before the damage is measurable by other means. The special phytotron chamber was used to determine the effect of higher UV-B radiation levels on photosynthesis. These measurements confirmed the sensitivity of certain early genotypes, revealed by a reduction in net photosynthetic activity. Measurements on the activity of antioxidant enzymes confirmed that early inbred lines sensitive to UV-B radiation were less able to eliminate reactive oxygen species than later genotypes

Cyclophilin D regulates lifespan and protein expression of aging markers in the brain of mice

Abstract Cyclophilin D (cypD) modulates the properties of the permeability transition pore, a phenomenon implicated in the manifestation of many diseases including aging. Here, we examined the effects of partial or complete deletion of cypD on i) lifespan, ii) forebrain protein expression of 18 aging markers as well as regional expression of GFAP, mGluR1, and alpha-synuclein, and iii) behaviour of aged (> 24 month) male and female mice. Both male and female cypD heterozygous but not KO mice exhibited increased lifespans compared to WT littermates, associated with alterations in the protein expression of some markers, albeit without exhibiting changes in behaviour

Blunted HPA axis response in lactating, vasopressin-deficient Brattleboro rats

Adaptation to stress is a basic phenomenon in mammalian life that is mandatorily associated with the activity of the hypothalamic–pituitary–adrenal (HPA) axis. An increased resting activity of the HPA axis can be measured during pregnancy and lactation, suggesting that these reproductive states lead to chronic load in females. In this study, we examined the consequences of the congenital lack of vasopressin on the activity of the HPA axis during lactation using vasopressin-deficient Brattleboro rats. Virgin and lactating, homozygous vasopressin-deficient rats were compared with control, heterozygous rats. In control dams compared with virgins, physiological changes similar to those observed in a chronic stress state (thymus involution, adrenal gland hyperplasia, elevation of proopiomelanocortin mRNA levels in the adenohypophysis, and resting plasma corticosterone levels) were observed. In vasopressin-deficient dams, adrenal gland hyperplasia and resting corticosterone level elevations were not observed. Corticotropin-releasing hormone (Crh) mRNA levels in the hypothalamic paraventricular nucleus were elevated in only the control dams, while oxytocin (OT) mRNA levels were higher in vasopressin-deficient virgins and lactation induced a further increase in both the genotypes. Suckling-induced ACTH and corticosterone level elevations were blunted in vasopressin-deficient dams. Anaphylactoid reaction (i.v. egg white) and insulin-induced hypoglycemia stimulated the HPA axis, which were blunted in lactating rats compared with the virgins and in vasopressin-deficient rats compared with the controls without interaction of the two factors. Vasopressin seems to contribute to the physiological changes observed during lactation mimicking a chronic stress state, but its role in acute HPA axis regulation during lactation seems to be similar to that observed in virgins. If vasopressin is congenitally absent, OT, but not the CRH, compensates for the missing vasopressin; however, the functional restitution remains incomplete

Depressive- and anxiety-like behaviors and stress-related neuronal activation in vasopressin-deficient female Brattleboro rats.

Vasopressin can contribute to the development of stress-related psychiatric disorders, anxiety and depression. Although these disturbances are more common in females, most of the preclinical studies have been done in males. We compared female vasopressin-deficient and +/+ Brattleboro rats. To test anxiety we used open-field, elevated plus maze (EPM), marble burying, novelty-induced hypophagia, and social avoidance tests. Object and social recognition were used to assess short term memory. To test depression-like behavior consumption of sweet solutions (sucrose and saccharin) and forced swim test (FST) were studied. The stress-hormone levels were followed by radioimmunoassay and underlying brain areas were studied by c-Fos immunohistochemistry. In the EPM the vasopressin-deficient females showed more entries towards the open arms and less stretch attend posture, drank more sweet fluids and struggled more (in FST) than the +/+ rats. The EPM-induced stress-hormone elevations were smaller in vasopressin-deficient females without basal as well as open-field and FST-induced genotype-differences. On most studied brain areas the resting c-Fos levels were higher in vasopressin-deficient rats, but the FST-induced elevations were smaller than in the +/+ ones. Similarly to males, female vasopressin-deficient animals presented diminished depression- and partly anxiety-like behavior with significant contribution of stress-hormones. In contrast to males, vasopressin deficiency in females had no effect on object and social memory, and stressor-induced c-Fos elevations were diminished only in females. Thus, vasopressin has similar effect on anxiety- and depression-like behavior in males and females, while only in females behavioral alterations are associated with reduced neuronal reactivity in several brain areas

Cannabinoid modulation of midbrain urocortin 1 neurones during acute and chronic stress

Neurons in the centrally projecting Edinger-Westphal nucleus (EWcp) are the main site of urocortin 1 (Ucn1) synthesis in the mammalian brain, and are assumed to play a role in the animal's stress response. Because endocannabinoid signalling has also been strongly implicated in stress, we hypothesised that endocannabinoids may modulate the functioning of the urocortinergic EWcp. First, using in situ hybridisation, we demonstrated cannabinoid receptor 1 (CB1R) mRNA expression in mouse EWcp-neurones that were Ucn1-negative. Dual- and triple-label immunocytochemistry revealed the presence of CB1R in several GABA-immunopositive fibres juxtaposed to EWcp-Ucn1 neurones. To test functional aspects of such an anatomical constellation, we compared acute (1 hour restraint) and chronic (14 days chronic mild stress) stress-induced changes in wild type (WT) and CB1R knockout (CB1R-KO) mice. Acute and, especially, chronic stress resulted in an increase in Ucn1 content of the EWcp, which was attenuated in CB1R-KO mice. CB1R-KO mice had higher basal and chronic stress-induced adrenocorticotrophin and corticosterone levels and were more anxious on the elevated plus-maze vs. WT. Collectively, our results show for the first time EWcp-Ucn1 neurones are putatively innervated by endocannabinoid sensitive, inhibitory, GABAergic afferents. In addition, we provide novel evidence the absence of the CB1 receptor alters the Ucn1 mRNA and peptide levels in EWcp neurones, concomitant with an augmented stress response and increased anxiety-like behaviour. (c) 2012 The Authors. Journal of Neuroendocrinology (c) 2012 Blackwell Publishing Ltd

Maternal neglect with reduced depressive-like behavior and blunted c-fos activation in Brattleboro mothers, the role of central vasopressin.

Early mother-infant relationships exert important long-term effects in offspring and are disturbed by factors such as postpartum depression. We aimed to clarify if lack of vasopressin influences maternal behavior paralleled by the development of a depressive-like phenotype. We compared vasopressin-deficient Brattleboro mothers with heterozygous and homozygous normal ones. The following parameters were measured: maternal behavior (undisturbed and separation-induced); anxiety by the elevated plus maze; sucrose and saccharin preference and forced swim behavior. Underlying brain areas were examined by c- fos immunocytochemistry among rest and after swim-stress. In another group of rats, vasopressin 2 receptor agonist was used peripherally to exclude secondary changes due to diabetes insipidus. Results showed that vasopressin-deficient rats spend less time licking-grooming their pups through a centrally driven mechanism. There was no difference between genotypes during the pup retrieval test. Vasopressin-deficient mothers tended to explore more the open arms of the plus maze, showed more preference for sucrose and saccharin and struggled more in the forced swim test, suggesting that they act as less depressive. Under basal conditions, vasopressin-deficient mothers had more c-fos expression in the medial preoptic area, shell of nucleus accumbens, paraventricular nucleus of the hypothalamus and amygdala, but not in other structures. In these areas the swim- stress-induced activation was smaller. In conclusion, vasopressin-deficiency resulted in maternal neglect due to a central effect and was protective against depressive-like behavior probably as a consequence of reduced activation of some stress-related brain structures. The conflicting behavioral data underscores the need for more sex specific studies