Jonathan Rochus Reinwald1, Robert Becker2, Anne Stephanie Mallien3, Claudia Falfan-Melgoza2, Markus Sack2, Christian Clemm von Hohenberg4, Urs Braun5, Alejandro Cosa Linan6, Natalia Gass2, Andrei-Nicolae Vasilescu7, Fabian Tollens2, Philipp Lebhardt2, Natascha Pfeiffer3, Dragos Inta8, Andreas Meyer-Lindenberg9, Peter Gass7, Alexander Sartorius4, Wolfgang Weber-Fahr2. 1. Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. Electronic address: jonathan.reinwald@zi-mannheim.de. 2. Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. 3. Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. 4. Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. 5. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Research Group Systems Neuroscience in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. 6. Research Group In Silico Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. 7. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. 8. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Psychiatry, University of Basel, Basel, Switzerland. 9. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
Abstract
BACKGROUND: To explore the domain-general risk factor of early-life social stress in mental illness, rearing rodents in persistent postweaning social isolation has been established as a widely used animal model with translational relevance for neurodevelopmental psychiatric disorders such as schizophrenia. Although changes in resting-state brain connectivity are a transdiagnostic key finding in neurodevelopmental diseases, a characterization of imaging correlates elicited by early-life social stress is lacking. METHODS: We performed resting-state functional magnetic resonance imaging of postweaning social isolation rats (N = 23) 9 weeks after isolation. Addressing well-established transdiagnostic connectivity changes of psychiatric disorders, we focused on altered frontal and posterior connectivity using a seed-based approach. Then, we examined changes in regional network architecture and global topology using graph theoretical analysis. RESULTS: Seed-based analyses demonstrated reduced functional connectivity in frontal brain regions and increased functional connectivity in posterior brain regions of postweaning social isolation rats. Graph analyses revealed a shift of the regional architecture, characterized by loss of dominance of frontal regions and emergence of nonfrontal regions, correlating to our behavioral results, and a reduced modularity in isolation-reared rats. CONCLUSIONS: Our result of functional connectivity alterations in the frontal brain supports previous investigations postulating social neural circuits, including prefrontal brain regions, as key pathways for risk for mental disorders arising through social stressors. We extend this knowledge by demonstrating more widespread changes of brain network organization elicited by early-life social stress, namely a shift of hubness and dysmodularity. Our results highly resemble core alterations in neurodevelopmental psychiatric disorders such as schizophrenia, autism, and attention-deficit/hyperactivity disorder in humans.
BACKGROUND: To explore the domain-general risk factor of early-life social stress in mental illness, rearing rodents in persistent postweaning social isolation has been established as a widely used animal model with translational relevance for neurodevelopmental psychiatric disorders such as schizophrenia. Although changes in resting-state brain connectivity are a transdiagnostic key finding in neurodevelopmental diseases, a characterization of imaging correlates elicited by early-life social stress is lacking. METHODS: We performed resting-state functional magnetic resonance imaging of postweaning social isolation rats (N = 23) 9 weeks after isolation. Addressing well-established transdiagnostic connectivity changes of psychiatric disorders, we focused on altered frontal and posterior connectivity using a seed-based approach. Then, we examined changes in regional network architecture and global topology using graph theoretical analysis. RESULTS: Seed-based analyses demonstrated reduced functional connectivity in frontal brain regions and increased functional connectivity in posterior brain regions of postweaning social isolation rats. Graph analyses revealed a shift of the regional architecture, characterized by loss of dominance of frontal regions and emergence of nonfrontal regions, correlating to our behavioral results, and a reduced modularity in isolation-reared rats. CONCLUSIONS: Our result of functional connectivity alterations in the frontal brain supports previous investigations postulating social neural circuits, including prefrontal brain regions, as key pathways for risk for mental disorders arising through social stressors. We extend this knowledge by demonstrating more widespread changes of brain network organization elicited by early-life social stress, namely a shift of hubness and dysmodularity. Our results highly resemble core alterations in neurodevelopmental psychiatric disorders such as schizophrenia, autism, and attention-deficit/hyperactivity disorder in humans.
Authors: Natalia Gass; Robert Becker; Jonathan Reinwald; Alejandro Cosa-Linan; Markus Sack; Wolfgang Weber-Fahr; Barbara Vollmayr; Alexander Sartorius Journal: Transl Psychiatry Date: 2019-06-28 Impact factor: 6.222
Authors: Jonathan R Reinwald; Natalia Gass; Anne S Mallien; Wolfgang Weber-Fahr; Peter Gass; Alexander Sartorius; Robert Becker; Markus Sack; Claudia Falfan-Melgoza; Christian Clemm von Hohenberg; Damiana Leo; Natascha Pfeiffer; Anthonieke Middelman; Andreas Meyer-Lindenberg; Judith R Homberg Journal: Mol Psychiatry Date: 2022-03-04 Impact factor: 13.437
Authors: Andreas Meyer-Lindenberg; Natalia Gass; Jonathan R Reinwald; Alexander Sartorius; Wolfgang Weber-Fahr; Markus Sack; Robert Becker; Michael Didriksen; Tine B Stensbøl; Adam J Schwarz Journal: Transl Psychiatry Date: 2020-03-13 Impact factor: 6.222
Authors: Veronica Begni; Alice Sanson; Natascha Pfeiffer; Christiane Brandwein; Dragos Inta; Steven R Talbot; Marco Andrea Riva; Peter Gass; Anne Stephanie Mallien Journal: PLoS One Date: 2020-10-27 Impact factor: 3.240