Interaktion von Negative Valence System und Cognitive System

Sex-dependent effects and gene-environment interactions will be investigated by applying escalating aggression paradigms. Specifically, the project will investigate the effects of early life stress on aggression in response to threat and hyperactivity as well as social decision-making in 32 BXD mouse strains, the progenitor strains (C057Bl/6J and DBA/2J), and the F1 BXD cross. The project aims to identify the quantitative trait loci (QTL) and putative candidate genes contained within the QTL and associate them with specific behavioral responses of stressed and unstressed cohorts of mice. The publicly available database GeneNetwork (www.genenetwork.org) will be used to validate the findings which include measurements of mRNA and protein expression, and methylation patterns in mouse brains

Develop virtual scenarios to assess decision strategies in cartoon-like and naturalistic contexts. The core question is how healthy individuals and patients make (mal-)adaptive aggressive decisions in social conflicts given their threat sensitivity, cognitive functions, and learning experience. We plan to present mathematically well-defined aggressive decision scenarios to healthy participants as well as patients across diagnostic categories with high scores of aggressive behavior, threat sensitivity, and inference of hostile intent in others. Computational models that accurately explain behavioral choices and neural responses (tested using fMRI and pupillometry) will be developed to identify the aggressive decision strategies humans employ in approach-avoidance conflicts of increasing complexity and ecological realism. The purpose will be to determine if patients use overly aggressive strategies that are not warranted by the necessary defense of self-threats and underlying neural circuits.

Investigate context-dependent aggression triggered by frustrative non-reward or acute social threats. Using newly developed approaches, multiple behavioral domains will be assessed in a semi-naturalistic, autonomous mouse habitat. Specifically, the habitat assesses the inter-individual dynamics of social interactions, aggressions, and hierarchy and the individual reward learning and impulsivity through different integrated modules. Intermittent challenges comprise intruder aggression and frustrative non-rewards. Within this LCD, circuit mechanisms are dissected through chemogenetic interventions, in vivo recordings, and functional MRI in awake mice during task performance. This approach in the first funding period will enable us to disentangle the specific functions of candidate entry points in prefrontal to ventral striatum pathways with respect to their modulation of aggression and dominance for potential interventions.

Address sex-specific NVS (reactive aggression) and CS (different dimensions of psychopathy, proactive aggression) associated risk factors, and risk factor-based biosignatures in young people. Considering the interacting genetic, environmental, and hormonal factors related to these specific aggressive behavior dimensions, C04 will identify specific and shared factors and mechanisms related to NVS and CS in female and male youth with and without pathological aggression. Implementing deep-learning algorithms, sex-specific, data-driven subgroups in relation to dimensions of aggressive behavior will be described and probed against the NVS and CS. Group-level risk factors of aggressive behavior dimensions, and individual risk factor-based subgrouping will be the basis of developing a biologically informed stratification strategy for tailored treatment. Models and classifiers will be established cross-sectionally in available data and replicated in the prospectively collected cross-sectional data (Q01). In addition, C04 will test the models and classifiers for predictive validity in the longitudinal data of the TRR Q01 cohort.

Link questionnaire measures of aggression to specific neural substrates using structural MRI. The resulting patterns of aggression-related neuroanatomical variability will be co- registered with the Allen Human Brain Atlas providing gene-expression data, to highlight genes with a spatial pattern of expression that matches the neuroimaging findings. Utilizing the neurotypical control data, a normative model of neuroanatomical diversity within the NVS and CS will be established to quantify neuroanatomical abnormalities within these systems in individual cases

Identify specific neuronal mechanisms related to the NVS and CS in female and male clinical samples with a history of early-life maltreatment (ELM) who exhibit externalizing, aggressive psychopathologies as opposed to internalizing, non-aggressive psychopathologies. We will therefore explore the interaction of the NVS and CS as well as the modulating effects of theory-of-mind (ToM) on the NVS and CS using a series of fMRI and behavioral tasks. Furthermore, we will investigate the role of hormonal stress responses and will use EMA to assess anger and aggression in everyday life. Thus, we will be able to combine behavioral phenotyping in natural conditions of everyday life and neurobiological correlates of psychopathology in order to detect clinically relevant biosignatures for AMD.

Test the interaction of the CS and frustrative non-reward as part of the NVS. It will investigate the electrophysiological correlates of frustrative feedback in aggression-prone patients. In the aftermath of induced stress, an EEG task-battery including frustrative feedback will be applied for extraction of error-related negativity (ERN) and contingent negative variation to monitor electro-physiologic signaling of the relevant learning and frustration processes. In half of the participants, tDCS over the prefrontal cortex will be applied to enhance cognitive control, with participants being put into a stress context inducing frustration.