Eine Untersuchung zur Rolle des Mineralocorticoidrezeptors, des Alters und der Valenz sowie der neuronalen Aktivierung

Es ist weithin bekannt, dass Cortisol zu einer Verschlechterung des deklarativen Gedächtnisabrufs führt. Cortisol bindet im Gehirn an zwei Rezeptortypen, den Mineralocorticoidrezeptor (MR) und den Glucocorticoidrezeptor (GR). Bisher wurden Cortisoleffekte vor allem auf den GR attribuiert. Mittlerweile konnte aber gezeigt werden, dass auch der MR eine wichtige Rolle im deklarativen Gedächtnis spielt. Zudem scheint Cortisol während des deklarativen Gedächtnisabrufs zu einer Deaktivierung in dafür wichtigen Hirnarealen, wie beispielsweise dem Hippocampus, zu führen, was eine Ursache für den verschlechterten Abruf zu sein scheint. Wie sich Cortisol im autobiographischen Gedächtnis auswirkt, ist wenig untersucht worden. Bisher weiß man, dass Cortisol auch den autobiographischen Abruf verschlechtert, indem Erinnerungen weniger spezifisch abgerufen werden. Dies scheint jedoch vor allem bei neutralen Erinnerungen und in Abhängigkeit des Cortisolanstiegs zu geschehen. Diese Dissertation hatte daher das Ziel, den Einfluss von Cortisol auf das autobiographische Gedächtnis in Abhängigkeit des Mineralocorticoidrezeptors, des Alters und der Valenz der Erinnerung und der zugrundliegenden neuronalen Korrelate genauer zu untersuchen. Dazu wurden drei unabhängige Studien durchgeführt. In der ersten Studie wurde bei Gesunden, Patienten mit Depression und Patienten mit Borderline-Persönlichkeitsstörung untersucht, wie sich die Stimulation des MR auf den autobiographischen Gedächtnisabruf auswirkt. In der zweiten Studie wurde in einer gesunden Stichprobe überprüft, ob der Einfluss von Cortisol vom Alter und der Valenz der abgerufenen Erinnerung abhängig ist. Die dritte Studie widmete sich der Frage, welche Auswirkung Cortisol auf die neuronale Aktivierung während des autobiographischen Gedächtnisabrufs hat. Die Hauptergebnisse dieser Dissertation sind folgende: 1) Weder bei Gesunden noch bei Depression oder Borderline-Persönlichkeitsstörung führt die Stimulation des MR zu einer Verbesserung der autobiographischen Gedächtnisleistung. Der MR scheint daher eher eine untergeordnete Rolle im autobiographischen Gedächtnis zu spielen. 2) Im autobiographischen Gedächtnis gibt es einen Neuheits- und Valenzeffekt. Neuere und neutrale Erinnerungen werden mit höherer Spezifität abgerufen. Cortisol beeinflusst das autobiographische Gedächtnis in Abhängigkeit von Valenz und Alter der Erinnerung. 3) Cortisol führt während des autobiographischen Gedächtnisabrufs zu einer Deaktivierung im amPFC. Diese Deaktivierung könnte das Bindeglied zwischen erhöhten Cortisolwerten und einer verringerten Spezifität autobiographischer Erinnerungen darstellen. Die Ergebnisse werfen neues Licht darauf, wie sich Cortisol auf den autobiographischen Gedächtnisabruf auswirkt. Während die Ergebnisse zeigen, dass der MR eine untergeordnete Rolle im autobiographischen Gedächtnis zu spielen scheint, betonen sie die Wichtigkeit verschiedener Charakteristika der abgerufenen Erinnerungen. Zudem bietet sich mit der Deaktivierung im amPFC ein erster Hinweis darauf, wie unter erhöhten Cortisolwerten eine Verschlechterung des autobiographischen Gedächtnisses zustande kommt

Diabetes insipidus and Guillain-Barré-like syndrome following CAR-T cell therapy: a case report

Background: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common adverse event of CD19-directed chimeric antigen receptor (CAR) T cell therapy. Other neurological adverse events, however, have not methodically been described and studied. Furthermore, safety data on CAR-T cell therapy in patients with central nervous system (CNS) lymphoma remain limited. Main body: We here report occurrence of a Guillain-Barré-like syndrome (GBS) and central diabetes insipidus (cDI) following tisagenlecleucel therapy for relapsed high-grade lymphoma with CNS involvement. Both complications were refractory to standard treatment of ICANS. Weakness of respiratory muscles required mechanical ventilation and tracheostomy while cDI was treated with desmopressin substitution for several weeks. Muscle-nerve biopsy and nerve conduction studies confirmed an axonal pattern of nerve damage. T cell-rich infiltrates and detection of the CAR transgene in muscle-nerve sections imply a direct or indirect role of CAR-T cell-mediated inflammation. In line with current treatment guidelines for GBS, intravenous immunoglobulin was administered and gradual but incomplete recovery was observed over the course of several months. Conclusions: This case report highlights the risk of rare but severe neurological adverse events, such as acute GBS or cDI, in patients treated with CAR-T cells. It further underlines the importance of appropriate patient surveillance and systematic reporting of rare complications to eventually improve treatment

Changes in leaf functional traits with leaf age: when do leaves decrease their photosynthetic capacity in Amazonian trees?

Most leaf functional trait studies in the Amazon basin do not consider ontogenetic variations (leaf age), which may influence ecosystem productivity throughout the year. When leaf age is taken into account, it is generally considered discontinuous, and leaves are classified into age categories based on qualitative observations. Here, we quantified age-dependent changes in leaf functional traits such as the maximum carboxylation rate of ribulose-1,5-biphosphate carboxylase/oxygenase (Rubisco) (Vcmax), stomatal control (Cgs%), leaf dry mass per area and leaf macronutrient concentrations for nine naturally growing Amazon tropical trees with variable phenological strategies. Leaf ages were assessed by monthly censuses of branch-level leaf demography; we also performed leaf trait measurements accounting for leaf chronological age based on days elapsed since the first inclusion in the leaf demography, not predetermined age classes. At the tree community scale, a nonlinear relationship between Vcmax and leaf age existed: young, developing leaves showed the lowest mean photosynthetic capacity, increasing to a maximum at 45 days and then decreasing gradually with age in both continuous and categorical age group analyses. Maturation times among species and phenological habits differed substantially, from 8 ± 30 to 238 ± 30 days, and the rate of decline of Vcmax varied from −0.003 to −0.065 μmol CO2 m−2 s−1 day−1. Stomatal control increased significantly in young leaves but remained constant after peaking. Mass-based phosphorus and potassium concentrations displayed negative relationships with leaf age, whereas nitrogen did not vary temporally. Differences in life strategies, leaf nutrient concentrations and phenological types, not the leaf age effect alone, may thus be important factors for understanding observed photosynthesis seasonality in Amazonian forests. Furthermore, assigning leaf age categories in diverse tree communities may not be the recommended method for studying carbon uptake seasonality in the Amazon, since the relationship between Vcmax and leaf age could not be confirmed for all trees

In situ short-term responses of Amazonian understory plants to elevated CO₂

The response of plants to increasing atmospheric CO2 depends on the ecological context where the plants are found. Several experiments with elevated CO2 (eCO2) have been done worldwide, but the Amazonian forest understory has been neglected. As the central Amazon is limited by light and phosphorus, understanding how understory responds to eCO2 is important for foreseeing how the forest will function in the future. In the understory of a natural forest in the Central Amazon, we installed four open-top chambers as control replicates and another four under eCO2 (+250 ppm above ambient levels). Under eCO2, we observed increases in carbon assimilation rate (67%), maximum electron transport rate (19%), quantum yield (56%), and water use efficiency (78%). We also detected an increase in leaf area (51%) and stem diameter increment (65%). Central Amazon understory responded positively to eCO2 by increasing their ability to capture and use light and the extra primary productivity was allocated to supporting more leaf and conducting tissues. The increment in leaf area while maintaining transpiration rates suggests that the understory will increase its contribution to evapotranspiration. Therefore, this forest might be less resistant in the future to extreme drought, as no reduction in transpiration rates were detected.</p

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals

Differential Modulation of Beta-Adrenergic Receptor Signaling by Trace Amine-Associated Receptor 1 Agonists

Trace amine-associated receptors (TAAR) are rhodopsin-like G-protein-coupled receptors (GPCR). TAAR are involved in modulation of neuronal, cardiac and vascular functions and they are potentially linked with neurological disorders like schizophrenia and Parkinson's disease. Subtype TAAR1, the best characterized TAAR so far, is promiscuous for a wide set of ligands and is activated by trace amines tyramine (TYR), phenylethylamine (PEA), octopamine (OA), but also by thyronamines, dopamine, and psycho-active drugs. Unfortunately, effects of trace amines on signaling of the two homologous β-adrenergic receptors 1 (ADRB1) and 2 (ADRB2) have not been clarified yet in detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular reasons for TAAR1 ligand promiscuity and for observed differences in signaling effects on particular aminergic receptors we compared TAAR, tyramine (TAR) octopamine (OAR), ADRB1/2 and dopamine receptors at the structural level. We found especially for TAAR1 that the remarkable ligand promiscuity is likely based on high amino acid similarity in the ligand-binding region compared with further aminergic receptors. On the other hand few TAAR specific properties in the ligand-binding site might determine differences in ligand-induced effects compared to ADRB1/2. Taken together, this study points to molecular details of TAAR1-ligand promiscuity and identified specific trace amines as allosteric or orthosteric ligands of particular β-adrenergic receptor subtypes

Psychophysiological stress response and memory in borderline personality disorder

Background: Previously, we found that patients with borderline personality disorder (BPD) but not healthy controls (HC) showed improved memory retrieval after hydrocortisone administration. Objective: In this study, we examined whether increases in endogenous cortisol after psychosocial stress are associated with memory function in patients with BPD and in healthy individuals. Methods: We recruited 49 female patients with BPD and 49 female HC. All participants were exposed to a psychosocial stressor, the Trier Social Stress Test (TSST) and a control condition (Placebo (P-)TSST) in randomized order. Salivary cortisol, alpha amylase (sAA) and blood pressure were measured in response to stress. Subsequently, we examined free recall of a previously learned word list, autobiographical memory, and working memory. Results: We found a stress*time*group interaction effect for the cortisol response and for sAA to stress, which is mainly triggered by a slightly different increase in cortisol between groups from pre to post TSST. Furthermore, BPD patients showed a less pronounced increase in diastolic blood pressure compared to HC after stress. There was no effect of stress on memory performance in any tests, either in healthy controls or in patients with BPD. Conclusion: Our results suggest a slightly blunted response of the HPA axis and the sympathetic nervous system to stress in BPD compared to healthy women. In contrast to hydrocortisone administration, psychosocial stress did not improve memory retrieval in BPD patients. This might be explained by lower cortisol concentrations and parallel increases in norepinephrine and negative affect after stress

Neural correlates of glucocorticoids effects on autobiographical memory retrieval in healthy women

It is well known that elevated cortisol after stress or after exogenous administration impairs episodic memory retrieval including autobiographical memory (AM) retrieval. This impairment might be mediated by deactivation of a neural network associated with memory retrieval including the prefrontal cortex (PFC) and limbic structures. However, the neural underpinnings of these cortisol effects on AM retrieval have not been investigated yet. In this study, thirty-three healthy women received either placebo or 10 mg hydrocortisone in a double blind cross-over design before completing an AM test during fMRI. In this test, participants are asked to recall specific events from their own past in response to a cue word. In a first step, we analyzed the neural underpinnings of AM retrieval in the placebo condition. We found an activation pattern consistent with core regions involved in autobiographical memory recall, including the ventromedial PFC, anterior medial (am)PFC, inferior frontal gyrus, the posterior cingulate cortex, the tempoparietal junction, the middle temporal gyrus and the hippocampus. Further, we analyzed brain activation during AM retrieval after hydrocortisone compared to placebo. Region of interest (ROI) analyses revealed a hydrocortisone-induced deactivation during AM retrieval in the right amPFC. Results of the ROI analyses were non-significant in the left and right hippocampus, the left and right vmPFC and the left amPFC In sum, during AM retrieval hydrocortisone had the most pronounced effects on the amPFC. This might be explained by the strong involvement of this brain region in self-referential behavior, which is essential for recalling autobiographic information

Resting-state functional connectivity after hydrocortisone administration in patients with post-traumatic stress disorder and borderline personality disorder

In a previous study, we found that - in contrast to healthy individuals - patients with borderline personality disorder (BPD) and post-traumatic stress disorder (PTSD) showed better memory retrieval performance after hydrocortisone administration compared to placebo. As these results suggest an altered function of corticosteroid receptors in the brain in PTSD and BPD, we examined the effect of hydrocortisone on brain activation in both disorders. We recruited 40 female healthy controls, 20 female unmedicated patients with PTSD and 18 female unmedicated patients with BPD. We conducted a placebo-controlled cross-over study, in which all participants underwent two resting state MRI measurements after they received either a placebo or 10 mg hydrocortisone orally and in randomized order. There was a time interval of one week between the measurements. We analysed resting state functional connectivity (RSFC) with the hippocampus and the amygdala as seed regions. Compared to healthy controls, both patient groups showed reduced hippocampus RSFC to dorsomedial prefrontal cortex (dmPFC). Positive hippocampus dmPFC RSFC correlated negatively with childhood trauma (r = -0.47) and with severity of clinical symptoms, measured with the Borderline Symptom List (r = -0.44) and the Posttraumatic Stress Diagnostic Scale (r = -0.45). We found neither differences in amygdala RSFC nor an effect of hydrocortisone administration. Childhood trauma might lead to decreased positive hippocampus dmPFC RSFC. This might explain symptoms of PTSD and BPD that are characterized by dysfunctional fear regulation