Glukokortikoidok és magatartási rendellenességek: agresszió, szorongás, és depresszió integrált vizsgálata = Glucocorticoids and behavioural disorders: a study integrating effects on aggression, anxiety and depression

Összehasonlító módon leírtuk az abnormális és normális agresszivitás idegrendszeri hátterét. Kidolgoztuk a stressz által indukált szorongásnak egy új modelljét, és leírtuk ennek idegrendszeri hátterét. Vizsgáltuk a depresszió stresszfüggését, és ennek idegrendszeri hátterét. Mindhárom viselkedési modell esetében (glukokotikoid-függő abnormális agresszió modell, stressz által kiváltott szociális elkerülés modell, szociális alárendeltség által kiváltott depresszió modell) tisztáztuk a glukokortikoidok szerepét. Farmakológiai kísérleteinkben új, potenciális gyógyszercélpontokat azonosítottunk (az NK1 receptort az abnoprmális agresszió esetében, illetve a CB1 receptort a stressz által kiváltott szorongás esetében). Megfigyeléseket tettünk a három magatartási zavar integrált szabályozására vonatkozólag. A projekt keretében végzett vizsgálatokból eddig 22 publikáció született, amelyek összesített impakt faktora megközelíti a 80-at. Az eredményekből még további 4-5 publikáció írását tervezzük. Az eltelt rövid idő alatt (a publikációk jelentős része 2007-ben illetve 2008-ban született) a projekt keretében írt publikációkra több mint 100-szor hivatkoztak. | We compared the neural background of normal and abnormal aggression in a model recently developed by us. We developed a new model of stress-induced anxiety, and characterized its neural background. The stress- dependence of depression symptoms was studied in a model involving chronic social submission. The role of glucocorticoids was clarified in all three models (i.e. the glucocorticoid-dependent abnormal aggression model, the stress-induced social avoidance model, and the submission-induced depression model). New pharmacological targets were identified for abnormal aggression and stress-induced anxiety (the NK1 receptor and the cannabinoid CB1 receptor, respectively). We also studied the integrated control of aggression, anxiety and depression. The project lead to 22 publications so far, the cumulative impact factor of which is close to 80. We plan to write 4-5 publications in addition. In the short time elapsed, the above mentioned 22 publications were cited more than 100 times. We mention that many of the publications were written in 2007 and 2008

Cannabinoidok szerepe a traumák által előidézett viselkedési zavarok kialakulásában = The role of cannabinoids in the development of trauma-induced behavioral deficits

A projekt fontos felismerése, hogy a traumák által előidézett poszt-traumás stressz zavar-szerű viselkedési zavarok neuronális háttere erősen függ a traumatikus élmény jellegétől, és attól a kihívástól, amelyet a kísérleti szituáció jelent. Sőt, a trauma által előidézett idegrendszeri változásoknak van egy olyan időbeli fejlődése, amely a viselkedés szintjén nem ismerhető fel. Ez a komplexitás tükörképe a humán zavar komplexitásának, és magyarázatul szolgálhat a zavar kezelésének nehézségeire. Eredményeink arra is rámutatnak, hogy a zavar laboratóriumi tanulmányozása komplex megközelítést igényel; a szokványosan alkalmazott kétnapos kondicionált félelem teszt nem alkalmas a traumák által előidézett viselkedési zavarok mechanizmusainak megértésére. Eredményeink szerint a cannabinoidok szerepét a viselkedés szabályozásában a ""coping"" stratégiákkal összefüggésben érthetjük meg. A fokozott anandamid és esetleg 2-AG jelátvitel az aktív coping stratégiákat erősíti. Azok az alapvető viselkedési stratégiák, amelyek alapján az egyed megválaszolja a környezeti kihívásokat (vagyis a coping), fontos szerepet játszanak a pszichiátriai zavarok kialakulásában, és az aktív coping stratégiák erősítését konkrét terápiás célként jelölték meg több pszichiátriai zavar esetében. Így az endocannabinoid jelátvitel fokozása terápiás opcióként jelenik meg olyan pszichiátriai zavaroknál, amelyeknél a coping stratégiák fontos szerepet játszanak, többek között a poszt-traumás stressz zavar esetében is. | Our studies revealed that neural changes underlying trauma-induced post-traumatic stress disorder-like behavioral deficits depend on the nature of the traumatic experience and the challenge subjects are exposed to during behavioral testing. Moreover, neural changes have a temporal evolution that is not reflected at behavioral level. This complexity mirrors the complexity of the human disorder and may explain why the treatment of this disorder is so difficult. Our findings also show that this field needs a complex, multidimensional approach; the frequently used 2-day long conditioned fear test is insufficient to understand the mechanisms of trauma-induced behavioral deficits. As it regards the role of cannabinoid signaling in trauma-induced behavioral deficits, we suggest that this role can be best described in terms of coping styles. Enhanced anandamide (and possibly 2-AG) signaling increases the predilection of animals to adopt an active coping style. Basic alternative strategies by which individuals respond to environmental challenges (i.e. coping styles) have wide-ranging health implications from immunity to psychopathology, and active coping has been indicated as a therapeutic goal for psychological interventions in various disorders. As such, the enhancement of endocannabinoid signaling may become a therapeutic option in emotional disorders that are characterized changes in coping strategies e.g. in post-traumatic stress disorder

Monoacylglycerol lipase inhibition-induced changes in plasma corticosterone levels, anxiety and locomotor activity in male CD1 mice

The hypothalamus-pituitary-adrenal-axis is strongly controlled by the endocannabinoid system. The specific impact of enhanced 2-arachidonoylglycerol signaling on corticosterone plasma levels, however, was not investigated so far. Here we studied the effects of the recently developed monoacylglycerol lipase inhibitor JZL184 on basal and stress-induced corticosterone levels in male CD1 mice, and found that this compound dramatically increased basal levels without affecting stress responses. Since acute changes in corticosterone levels can affect behavior, JZL184 was administered concurrently with the corticosterone synthesis inhibitor metyrapone, to investigate whether the previously shown behavioral effects of JZL184 are dependent on corticosterone. We found that in the elevated plus-maze, the effects of JZL184 on "classical" anxiety-related measures were abolished by corticosterone synthesis blockade. By contrast, effects on the "ethological" measures of anxiety (i.e. risk assessment) were not affected by metyrapone. In the open-field, the locomotion-enhancing effects of the compound were not changed either. These findings show that monoacylglycerol lipase inhibition dramatically increases basal levels of corticosterone. This endocrine effect partly affects the anxiolytic, but not the locomotion-enhancing effects of monoacylglycerol lipase blockade

Neurochemically distinct populations of the bed nucleus of stria terminalis modulate innate fear response to weak threat evoked by predator odor stimuli

Anxiety and trauma-related disorders are characterized by significant alterations in threat detection, resulting in inadequate fear responses evoked by weak threats or safety stimuli. Recent research pointed out the important role of the bed nucleus of stria terminalis (BNST) in threat anticipation and fear modulation under ambiguous threats, hence, exaggerated fear may be traced back to altered BNST function. To test this hypothesis, we chemogenetically inhibited specific BNST neuronal populations (corticotropin-releasing hormone - BNSTCRH and somatostatin - BNSTSST expressing neurons) in a predator odor-evoked innate fear paradigm. The rationale for this paradigm was threefold: (1) predatory cues are particularly strong danger signals for all vertebrate species evoking defensive responses on the flight-avoidance-freezing dimension (conservative mechanisms), (2) predator odor can be presented in a scalable manner (from weak to strong), and (3) higher-order processing of olfactory information including predatory odor stimuli is integrated by the BNST. Accordingly, we exposed adult male mice to low and high predatory threats presented by means of cat urine, or low- and high-dose of 2-methyl-2-thiazoline (2MT), a synthetic derivate of a fox anogenital product, which evoked low and high fear response, respectively. Then, we tested the impact of chemogenetic inhibition of BNSTCRH and BNSTSST neurons on innate fear responses using crh- and sst-ires-cre mouse lines. We observed that BNSTSST inhibition was effective only under low threat conditions, resulting in reduced avoidance and increased exploration of the odor source. In contrast, BNSTCRH inhibition had no impact on 2MT-evoked responses, but enhanced fear responses to cat odor, representing an even weaker threat stimulus. These findings support the notion that BNST is recruited by uncertain or remote, potential threats, and CRH and SST neurons orchestrate innate fear responses in complementary ways

Effects of resocialization on post-weaning social isolation-induced abnormal aggression and social deficits in rats

As previously shown, rats isolated from weaning develop abnormal social and aggressive behavior characterized by biting attacks targeting vulnera- ble body parts of opponents, reduced attack signaling, and increased defensive behavior despite increased attack counts. Here we studied whether this form of violent aggression could be reversed by resocialization in adulthood. During the first weak of resocialization, isolation-reared rats showed multiple social deficits including increased defensiveness and decreased huddling during sleep. Deficits were markedly attenuated in the second and third weeks. Despite improved social functioning in groups, isolated rats readily showed abnormal features of aggres- sion in a resident-intruder test performed after the 3-week-long resocialization. Thus, post-weaning social isolation-induced deficits in prosocial behavior were eliminated by resocialization during adulthood, but abnormal aggression was resilient to this treatment. Findings are compared to those obtained in humans who suffered early social maltreatment, and who also show social deficits and dysfunctional aggression in adulthood

Effects of adverse early-life events on aggression and anti-social behaviours in animals and humans

We review the impact of early adversities on the development of violence and antisocial behaviour in humans, and present three aetiological animal models of escalated rodent aggression, each disentangling the consequences of one particular adverse early-life factor. A review of the human data, as well as those obtained with the animal models of repeated maternal separation, post-weaning social isolation and peripubertal stress, clearly shows that adverse developmental conditions strongly affect aggressive behaviour displayed in adulthood, the emotional responses to social challenges and the neuronal mechanisms activated by conflict. Although similarities between models are evident, important differences were also noted, demonstrating that the behavioural, emotional and neuronal consequences of early adversities are to a large extent dependent on aetiological factors. These findings support recent theories on human aggression, which suggest that particular developmental trajectories lead to specific forms of aggressive behaviour and brain dysfunctions. However, dissecting the roles of particular aetiological factors in humans is difficult because these occur in various combinations; in addition, the neuroscientific tools employed in humans still lack the depth of analysis of those used in animal research. We suggest that the analytical approach of the rodent models presented here may be successfully used to complement human findings and to develop integrative models of the complex relationship between early adversity, brain development and aggressive behaviour. © 2014 British Society for Neuroendocrinology

The Origin of Glucocorticoid Hormone Oscillations

Characterization of a peripheral hormonal system identifies the origin and mechanisms of regulation of glucocorticoid hormone oscillations in rats