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

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

Somatostatin neurons of the bed nucleus of stria terminalis enhance associative fear memory consolidation in mice

Excessive fear learning and generalized, extinction-resistant fear memories are core symptoms of anxiety and trauma-related disorders. Despite significant evidence from clinical studies reporting hyperactivity of the bed nucleus of stria terminalis (BNST) under these conditions, the role of BNST in fear learning and expression is still not clarified. Here, we tested how BNST modulates fear learning in male mice using a chemogenetic approach. Activation of GABAergic neurons of BNST during fear conditioning or memory consolidation resulted in enhanced cue-related fear recall. Importantly, BNST activation had no acute impact on fear expression during conditioning or recalls, but it enhanced cue-related fear recall subsequently, potentially via altered activity of downstream regions. Enhanced fear memory consolidation could be replicated by selectively activating somatostatin (SOM), but not corticotropin- releasing factor (CRF) neurons of the BNST, which was accompanied by increased fear generalization. Our findings suggest the significant modulation of fear memory strength by specific circuits of the BNST.SIGNIFICANCE STATEMENT:The bed nucleus of stria terminalis mediates different defensive behaviors and its connections implicate its integrative modulatory role in fear memory formation, however, the involvement of BNST in fear learning has yet to be elucidated in detail. Our data highlight that BNST stimulation enhances fear memory formation without direct effects on fear expression. Our study identified somatostatin cells within the extended amygdala as specific neurons promoting fear memory formation. These data underline the importance of anxiety circuits in maladaptive fear memory formation, indicating elevated BNST activity as a potential vulnerability factor to anxiety and trauma-related disorders

Changes in neuroplasticity following early-life social adversities

Social adversities experienced in childhood can have a profound impact on the developing brain, leading to the emergence of psychopathologies in adulthood. Despite the burden this places on both the individual and society, the neurobiological aspects mediating this transition remain unclear. Recent advances in preclinical and clinical research have begun examining neuroplasticity-the nervous system's ability to form adaptive changes in response to new experience-in the context of early-life vulnerability to social adversities and plasticity-related alterations following such traumatic events. A key mediator of plasticity-related molecular processes is the brain-derived neurotrophic factor (BDNF), which has also been implicated in various psychiatric disorders related to childhood social adversities. Preclinical and clinical data suggest early-life social adversities (ELSA) might be associated with accelerated maturation of social network circuitry, a possible ontogenic adaptation to the adverse environment. Neural plasticity decreases by adulthood, lessening the efficacy of treatment in ELSA-related psychiatric disorders. However, literature data suggest that by increasing BDNF/TrkB signalling through antidepressant treatment a juvenile-like plasticity state can be induced, which allows for reorganization of the social circuitry when guided by psychotherapy and surrounded by a safe and positive environment