The contribution of within-amygdala meta-plasticity to stress-related psychopathologies

• Applicant: Professor Dr. Hansjürgen Volkmer
• Subject Area: Biological Psychiatry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457171758

The amygdala modulates emotional memory formation in brain areas, such as hippocampus and medial prefrontal cortex. Under extreme conditions, amygdala modulation may lead to the formation of abnormal plasticity in these areas and to the development of trauma related psychopathologies, such as depression and post-traumatic stress disorder. However, emotional experiences induce long-term plasticity in the amygdala by itself. Such alterations within the amygdala, which affect also the ability of other brain regions, such as the hippocampus and mPFC to respond to challenges later on, represent a form of meta-plasticity. In recent years we have examined the impact of within-amygdala metaplasticity on emotional behaviors and coping with stress. Specifically, gene expression was locally regulated by lentiviral vectors in way that experience-induced metaplasticity within the BLA was recapitulated. This approach was found to be very effective and it enables us now to systematically address the implications of lasting alterations of BLA functioning to vulnerability to stress-related psychopathologies and to stress resilience. Here we will focus on manipulating synaptic plasticity within the BLA as a way to affect within-amygdala meta-plasticity in the context of stress and trauma. In an extension of our approach, the BDNF-trkB pathway will be modulated by lentiviral intervention in order to study the impact of altered amygdala plasticity (inducing meta-plasticity) on plasticity of associated brain regions, the mPFC and hippocampus, known to contribute to the stress response and trauma. Subsequently, animals are exposed to various anxiety and trauma-related conditions. Specifically, we will examine: (1) anxietyrelated behaviors under basal conditions in the absence of actual threat; (2) anxiety-related behaviors following acute stress exposure; (3) learning under stressful conditions as a measure of stress coping; and (4) vulnerability to develop psychopathology symptoms after a traumatic event. Behavioral testing will be followed by electrophysiological and morphological analyses, aiming to elucidate the involvement of these BLA meta-plasticity factors in modulating the activity in other stress-related brain regions such as the mPFC and hippocampus and in regulating co-activity patterns in the limbic network. Conducting this type of multifaceted assessment would allow attributing aspects of anxiety-related behaviors (state anxiety, pathological anxiety or stress coping) to alterations in plasticity and meta-plasticity within the BLA. Previous studies revealed sizable individual differences in responding to stress. We will employ our recently developed profiling approach, which allows differentiating between exposed-affected and exposed-unaffected individuals. This individual differentiation will enable more accurately to associate electrophysiological, biochemical and morphological alterations with the behavioral findings.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professor Dr. Gal Richter-Levin, Ph.D.