Amalia Floriou-Servou1, Lukas von Ziegler2, Luzia Stalder3, Oliver Sturman1, Mattia Privitera1, Anahita Rassi4, Alessio Cremonesi4, Beat Thöny5, Johannes Bohacek6. 1. Laboratory of Molecular and Behavioral Neuroscience, Department of Health Science and Technology of ETH Zurich, Institute for Neuroscience, Neuroscience Center Zurich, Zurich, Switzerland. 2. Laboratory of Molecular and Behavioral Neuroscience, Department of Health Science and Technology of ETH Zurich, Institute for Neuroscience, Neuroscience Center Zurich, Zurich, Switzerland; Laboratory of Neuroepigenetics, Medical Faculty of the University Zürich and Department of Health Science and Technology of the ETH Zürich, Zurich, Switzerland. 3. Laboratory of Neuroepigenetics, Medical Faculty of the University Zürich and Department of Health Science and Technology of the ETH Zürich, Zurich, Switzerland. 4. Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland. 5. Division of Metabolism, University Children's Hospital Zurich, Zurich, Switzerland. 6. Laboratory of Molecular and Behavioral Neuroscience, Department of Health Science and Technology of ETH Zurich, Institute for Neuroscience, Neuroscience Center Zurich, Zurich, Switzerland. Electronic address: johannes.bohacek@hest.ethz.ch.
Abstract
BACKGROUND: Acutely stressful experiences can trigger neuropsychiatric disorders and impair cognitive processes by altering hippocampal function. Although the intrinsic organization of the hippocampus is highly conserved throughout its long dorsal-ventral axis, the dorsal (anterior) hippocampus mediates spatial navigation and memory formation, whereas the ventral (posterior) hippocampus is involved in emotion regulation. To understand the molecular consequences of stress, detailed genome-wide screens are necessary and need to distinguish between dorsal and ventral hippocampal regions. While transcriptomic screens have become a mainstay in basic and clinical research, proteomic methods are rapidly evolving and hold even greater promise to reveal biologically and clinically relevant biomarkers. METHODS: Here, we provide the first combined transcriptomic (RNA sequencing) and proteomic (sequential window acquisition of all theoretical mass spectra [SWATH-MS]) profiling of dorsal and ventral hippocampus in mice. We used three different acute stressors (novelty, swim, and restraint) to assess the impact of stress on both regions. RESULTS: We demonstrated that both hippocampal regions display radically distinct molecular responses and that the ventral hippocampus is particularly sensitive to the effects of stress. Separately analyzing these structures greatly increased the sensitivity to detect stress-induced changes. For example, protein interaction cluster analyses revealed a stress-responsive epigenetic network around histone demethylase Kdm6b restricted to the ventral hippocampus, and acute stress reduced methylation of its enzymatic target H3K27me3. Selective Kdm6b knockdown in the ventral hippocampus led to behavioral hyperactivity/hyperresponsiveness. CONCLUSIONS: These findings underscore the importance of considering dorsal and ventral hippocampus separately when conducting high-throughput molecular analyses, which has important implications for fundamental research as well as clinical studies.
BACKGROUND: Acutely stressful experiences can trigger neuropsychiatric disorders and impair cognitive processes by altering hippocampal function. Although the intrinsic organization of the hippocampus is highly conserved throughout its long dorsal-ventral axis, the dorsal (anterior) hippocampus mediates spatial navigation and memory formation, whereas the ventral (posterior) hippocampus is involved in emotion regulation. To understand the molecular consequences of stress, detailed genome-wide screens are necessary and need to distinguish between dorsal and ventral hippocampal regions. While transcriptomic screens have become a mainstay in basic and clinical research, proteomic methods are rapidly evolving and hold even greater promise to reveal biologically and clinically relevant biomarkers. METHODS: Here, we provide the first combined transcriptomic (RNA sequencing) and proteomic (sequential window acquisition of all theoretical mass spectra [SWATH-MS]) profiling of dorsal and ventral hippocampus in mice. We used three different acute stressors (novelty, swim, and restraint) to assess the impact of stress on both regions. RESULTS: We demonstrated that both hippocampal regions display radically distinct molecular responses and that the ventral hippocampus is particularly sensitive to the effects of stress. Separately analyzing these structures greatly increased the sensitivity to detect stress-induced changes. For example, protein interaction cluster analyses revealed a stress-responsive epigenetic network around histone demethylase Kdm6b restricted to the ventral hippocampus, and acute stress reduced methylation of its enzymatic target H3K27me3. Selective Kdm6b knockdown in the ventral hippocampus led to behavioral hyperactivity/hyperresponsiveness. CONCLUSIONS: These findings underscore the importance of considering dorsal and ventral hippocampus separately when conducting high-throughput molecular analyses, which has important implications for fundamental research as well as clinical studies.
Authors: Lívia Ramos-da-Silva; Pamela T Carlson; Licia C Silva-Costa; Daniel Martins-de-Souza; Valéria de Almeida Journal: Complex Psychiatry Date: 2021-07-09
Authors: Maria A Samara; George D Oikonomou; George Trompoukis; Georgia Madarou; Maria Adamopoulou; Costas Papatheodoropoulos Journal: Brain Neurosci Adv Date: 2022-06-24
Authors: Kimberly L Kraus; Arihant P Chordia; Austin W Drake; James P Herman; Steve C Danzer Journal: J Comp Neurol Date: 2022-04-09 Impact factor: 3.028
Authors: Remzi Karayol; Lucian Medrihan; Jennifer L Warner-Schmidt; Ben W Fait; Meghana N Rao; Eva B Holzner; Paul Greengard; Nathaniel Heintz; Eric F Schmidt Journal: Mol Psychiatry Date: 2021-01-13 Impact factor: 13.437