Genetische und pharmakologische Analyse der Motivationskontrolle - manisch-depressives Verhalten bei Drosophila
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zusammenfassung der Projektergebnisse
Chronic, uncontrollable stress can result in major depressive disorder (MDD) in humans and mam‐ malian disease models. In our chronic stress paradigm, Drosophila flies are subjected to 3 days of repetitive phases of 300 Hz vibrations combined with overcrowding and food deprivation. This treat‐ ment induces depression‐like behavioral alterations accompanied by changes in biogenic amine levels in the adult brain. Voluntary activity is reduced, including the motivation to climb wide gaps (risk taking) and to stop for sweets (anhedonia), suggesting a depression‐like state (DLS). It is correlated with decreased serotonin release to the α‐lobes of the mushroom body (MB), a major behavioral control center in the central brain of flies. Stressed flies are relieved from the DLS, e.g. by feeding the anti‐depressant serotonin precursor 5‐HTP or the selective serotonin reuptake inhibitor fluoxetine. Notably, feeding sucrose to stressed flies results in elevated serotonin levels in the brain and amel‐ iorates the DLS. In the DFG‐funded project, we analyzed the sugar relief pathway. The neurotransmitter octopamine released from ventral unpaired medial neurons located in the subesophageal ganglion signals the sweet taste. The signal is transmitted to the MB via the dopaminergic PAM neurons. Neuronal silencing experiments reveal that the serotonergic dorsal paired medial (DPM) neurons innervating the MB are essential for sugar relief. Conversely, thermogenetic or optogenetic activation of DPMs can replace sweet sensation, elucidating that serotonergic signaling from DPMs takes part in positively modulating DLS‐related behavioral changes. We probed further into the network and activated MB output neurons (MBONs) by thermogenetic means, either acutely or for 5h prior to behavioral testing. Eighteen of 19 MBONs reduced the climbing activity under one or both of the treatments, suggesting a complex output network of the MBs. We employed the fly depression paradigm for a genome‐wide association study of 172 lines of the Drosophila Genetic Reference Panel and found interpretable gene variants, e.g. Ork1, coding for a potassium channel with high homology to mammalian TREK1 or KCNK2, a target in depression. We used the Drosophila depression paradigm to study the mode of action of the Lithium Chloride (LiCl) therapy of MDD. Practiced for more than 50 years, its complex action in the vertebrate brain is far from understood. Similar to sucrose, we have shown that feeding low concentrations (5mM) of LiCl overnight can relief stressed flies from DLS, whereas high levels (50mM) induce excessive climbing behavior in stressed and control flies. We could establish that manic climbing behavior is mediated by inhibition of the GSK3‐β protein kinase Shaggy (Sgg) function in the MB α/β‐neurons. In contrast, first results for the relief from DLS after low LiCl treatment hint towards the IP3 signaling pathway (IP3 depletions hypothesis). Surprisingly, sleep deprivation did not result in a DLS in the flies, but in exhaustion, which we were unable to alleviate with antidepressants. In contrast, feeding L‐dopa, the precursor of dopamine, to flies resulted in a DLS that can be counteracted by feeding antidepressants. We employed the Drosophila depression paradigm to investigate whether plants known from tra‐ ditional medicine like Withania somnifera or Centella asiatica (CA) can improve depression‐associated symptoms like anhedonia and decreased climbing activity. We found that a water extract of CA provides resilience to stress‐induced phenotypes and that this effect is primarily due to mono‐caffe‐ oylquinic acids found in CA. We show that chlorogenic acid acts via calcineurin, a multifunctional phosphatase that can regulate synaptic transmission and plasticity and is involved in neuronal maintenance.
Projektbezogene Publikationen (Auswahl)
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Antidepressant action of sugar treatment is dependent on octopaminergic signaling to the serotonergic system in Drosophila melanogaster. Neuroforum Suppl. 25, T24‐5B
Hermanns, T.; Ries, A.‐S.; Poeck, B. & Strauss, R.
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The Neuromodulator Octopamine Mediates Sugar Relief from a Chronic Stress‐Induced Depression‐Like State (DLS) in Drosophila. Neuroforum Suppl.
Boxhorn, S.; Herrmans, T.; Poeck, B. & Strauss R.
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Octopamine mediates sugar relief from a chronic-stress-induced depression-like state in Drosophila. Current Biology, 32(18), 4048-4056.e3.
Hermanns, Tim; Graf-Boxhorn, Sonja; Poeck, Burkhard & Strauss, Roland
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Phytopharmaceuticals can ameliorate a depression‐like state in Drosophila melanogaster. Neurofly, Saint Malo
Holvoet, H.; Poeck, B.; Kretzschmar, D.; Soumyanath, A. & Strauss, R.
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Withania somnifera Extracts Promote Resilience against Age-Related and Stress-Induced Behavioral Phenotypes in Drosophila melanogaster; a Possible Role of Other Compounds besides Withanolides. Nutrients, 14(19), 3923.
Holvoet, Helen; Long, Dani M.; Law, Alexander; McClure, Christine; Choi, Jaewoo; Yang, Liping; Marney, Luke; Poeck, Burkhard; Strauss, Roland; Stevens, Jan F.; Maier, Claudia S.; Soumyanath, Amala & Kretzschmar, Doris
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Botanicals Can Induce Resilience to a Depression‐Like State in Drosophila melanogaster. NWG Göttingen T13‐5A
Holvoet, H.; Poeck, B.; Kretzschmar, D.; Soumyanath, A. & Strauss, R.
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Chlorogenic Acids, Acting via Calcineurin, Are the Main Compounds in Centella asiatica Extracts That Mediate Resilience to Chronic Stress in Drosophila melanogaster. Nutrients, 15(18), 4016.
Holvoet, Helen; Long, Dani M.; Yang, Liping; Choi, Jaewoo; Marney, Luke; Poeck, Burkhard; Maier, Claudia S.; Soumyanath, Amala; Kretzschmar, Doris & Strauss, Roland
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Der Einfluss von Dopamin auf den depressionsähnlichen Zustand bei Drosophila melanogaster. Dissertation, Universität Mainz.
Sonja Boxhorn
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Modulation des Verhaltensantriebs und dessen neuronaler Substrate bei Drosophila melanogaster. Dissertation, Universität Mainz
Hermanns, Tim
