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The role of GABA in stress resilience

Funder: Netherlands Organisation for Scientific Research (NWO)Project code: 451-13-001
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The role of GABA in stress resilience

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Traumatic stress, especially early in life, exerts substantial and long-lasting influences on the brain and is a major risk factor for psychiatric disorders. However, most people do not develop psychopathology following adversity. Focusing on resilience to trauma rather than vulnerability can enhance our understanding of key processes underlying psychopathology. Moreover, important methodological advantages are present due to the absence of psychopathology and medication in resilient individuals. Resilience to trauma depends on multiple neurobiological factors. I propose that the functionality of the γ-aminobutyric acid (GABA) system in the brain is a key moderator of resilience to trauma. Prior research has shown that the GABA system and stress are closely intertwined: traumatic stress has long-lasting influences on the GABA system, and stress reactivity (including HPA axis functionality) is mediated by GABAergic circuitry. To test this hypothesis, I apply a fundamental and integrative approach in human subjects. First, I examine the effects of early life trauma on adult GABA levels in plasma and cerebrospinal fluid in an existing unique cohort study. Second, I investigate whether early life trauma affects in vivo GABA levels in the prefrontal cortex under basal and acute stress conditions using state-of-the-art 7Tesla magnetic resonance spectroscopy (7T-MRS) in a selected subgroup of this cohort. Third, I examine the interaction between combat-related trauma, plasma GABA levels, and resilience to psychopathology in an existing prospective military cohort. In all studies, I study (epi)genetic variation related to the GABA system to probe potential underlying resilience mechanisms. This proposal investigates the GABA system as a pro-resilience factor in humans and combines imaging, genetic, epigenetic, and neuroendocrine approaches within several unique cohort studies. It will yield novel neurobiological insights into GABA resilience circuitry and may identify innate resilience mechanisms which can be used for early intervention strategies.

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