Glucocorticoide und Psychiatrische Erkrankungen: Mechanismen Stress-induzierter Kognitiver Defizite
Biologische Psychiatrie
Zusammenfassung der Projektergebnisse
Chronic stress can negatively impact individuals’ daily life and is a major risk factor for psychiatric disorders. One of the deleterious effects of stress is impaired cognitive function, which is likely mediated by impaired functioning of the prefrontal cortex (PFC). Yet exactly how stress disrupts the function of the PFC is incompletely understood. Stress causes the release of glucocorticoids (GCs) and their binding to GC receptors (GRs) mediates the effects of stress on neural circuits. This project therefore aimed to examine how activation of GRs in the PFC could mediate the deleterious effects of stress on PFC function and thus cognition. To this end, we aimed to expose mice to chronic stress and examine how manipulations of GRs in specific subpopulations of PFC neurons would affect the effects of stress on cognition and its neuronal mechanisms. To examine cognition in mice we tested them on spatial working memory (SWM) and also examined hippocampal-prefrontal synchrony, which is an important neural circuit mechanism underlying SWM. Unexpected obstacles were encountered early in the project, when our proposed chronic stress paradigm, chronic social defeat (CSD) failed to disrupt SWM, although it had other expected behavioral effects. This led us to explore the effects of other chronic stress paradigms on SWM and we found that both chronic corticosterone treatment as well as early maternal separation (EMS) stress caused SWM impairments. Electrophysiological recordings during these two paradigms, however, revealed that they have divergent effects on hippocampal-prefrontal synchrony: whereas CORT treatment enhanced synchrony, EMS impaired it. This suggests that different stress paradigms can impair cognition through different neuronal mechanisms. We also began to characterize the influence of the hippocampus on the prefrontal cortex, which might help interpret the functional consequences of the hippocampal-prefrontal synchrony alterations we observed. To this end, we collected a dataset of PFC neurons recorded during SWM while the dorsal hippocampus was optogenetically silenced. Our preliminary results indicate, interestingly, that hippocampal silencing has a largely excitatory effect on PFC neurons. Ongoing analysis of this dataset is focused on examining how silencing affects task-related activity patterns during SWM but already we have indication that the effects differ from those reported following silencing of ventral hippocampal inputs to PFC. Finally, we addressed the important question of how the PFC responds to aversive events. Using a classical fear conditioning paradigm, we investigated how neurons in the two main subregions of the PFC, the prelimbic (PL) and infralimbic (IL) cortices, react to conditioned stimuli (CS) predicting aversive outcomes. Consistent with the classical view of the PL and IL promoting and inhibiting fear responses, respectively, we found that neural responses to threat-predicting cues were more frequently observed in PL. However, when examining responses around the termination of defensive responses (i.e. transitions from fear to safety), we found that these were equally prominent in the IL and PL subregions, thus challenging the accepted view of how these two subregions encode threats. In summary, this project could reveal both how the PFC responds to aversive stressful events and how stress affects the function of the PFC and cognitive function.
Projektbezogene Publikationen (Auswahl)
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Investigating neuronal activity in medial prefrontal cortex during transitions between fear and safety. Dissertation for obtaining a doctorate degree in natural sciences presented to the Faculty of Biosciences of Goethe University in Frankfurt am Main. December 2018.
Sebastian Betz
