We study endogenous stress-response systems and associated neural circuitry. We focus on methods to observe and interfere with the action of the Autonomic Nervous System (ANS) and Hypothalamic-Pituitary-Adrenal Axis (HPA-axis). Building on existing work on ANS (e.g., Koenig 2020, Sigrist et al. 2021) and HPA-Axis (e.g., Schär et al. 2022) functioning in children and adolescents with psychiatric disorders and childhood trauma, we recently shifted
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Background: The endocannabinoid system is a neuromodulatory system and well known to interact with the Hypothalamic-Pituitary-Adrenal Axis (HPA-axis). Key molecular target of the endocannabinoid receptor is the CB1-receptor, that is targeted by two main endogenous ligands, the endocannabinoids N-arachidonyl ethanolamine (anandamide, AEA) and 2-archidonyl glycerol (2-AG). AEA and 2-AG are synthesized on demand in post-synaptic neurons and subsequently released in the synaptic cleft where they target the CB1-receptor. Activation of CB1-receptors result in a robust suppression of neurotransmitter release, resulting in both excitatory and inhibitory transmission as CB1 receptors are expressed on a variety of synapses like glutamatergic, GAGAergic, serotonergic, noradrenergic and dopaminergic terminals. Endocannabinoid signaling has a “gatekeeping” function on the HPA-axis. During acute stress - due to increased FAAH activity - AEA rapidly decreases to enable enhanced HPA-axis signaling, likely mediated by corticotropin-releasing hormone (CRH) dependent mechanisms. This model is supported by findings on higher corticosterone levels after AEA depletion, an increases in anxiety-like behaviour as well as a deficit in extinction of aversive memory. Following chronic corticosterone exposure FAAH activity increases resulting in reduction of AEA levels. The vast majority of findings stem from animal research. Two hydrolytic enzymes, fatty acid amide hydrolase (FAAH) for AEA and monoacylglycerol lipase (MAGL) for 2-AG, have been identified to degrade the corresponding lipid endocannabinoids. We translate existing murine models studying the endocannabinoid system to children and adolescents with psychiatric disorers, in the hope to identify novel therapeutic targets for pharmacological intervention.
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last update 2024 09 23
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