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110. Early Life Adversity Associates with Altered Oligodendrocyte Function and Decreased Myelination in the Anterior Cingulate Cortex of Depressed Suicides
Biological Psychiatry
Thursday Abstracts
CRF neurons. Ongoing experiments are evaluating potential sex differences in the organization and function of this circuit. Supported By: K99AA023559 Keywords: Alcohol, CRF
SYMPOSIUM Negative Affect and Regional Network Alterations: Recent Advances in Translational Research Thursday, May 18, 2017, 3:00 PM - 5:00 PM Aqua D Chair: Jean-Luc Martinot Co-Chair: Monique Ernst
sex-dependent, structural connectivity changes in limbic networks. Supported By: ERA_NET Neuron, Labex Biopsy, ANR Keywords: Animal Model, white matter, Connectivity, Adolescent Depression, Diffusion Tensor Imaging (DTI)
110. Early Life Adversity Associates with Altered Oligodendrocyte Function and Decreased Myelination in the Anterior Cingulate Cortex of Depressed Suicides Naguib Mechawar1, Pierre-Éric Lutz1, Arnaud Tanti1, Alicja Gasecka2, John Kim1, Marina Wakid1, Daniel Côté2, and Gustavo Turecki1 1
109. From Early Life Adversity to Adolescence Depression: White Matter Remodelling in a Translational Animal Model Severine Farley1, Julien Grenier2, Victor Gorgievski1, Alexandre Barbe1, Wojciech Jaworski1, Ariane Bochereau1, Carlos Macedo1, Said Ghandour3, Neele Huebner4, Thomas Bienert4, Jurgen Henning4, Charbel Massaad2, Bruno Giros1, Laura Harsan5, and Eleni Tzavara1 Inserm, 2University Paris Descartes, 3Strasbourg University, 4Uniklinik Freiburg, 5Strasbourg University, Uniklinik Freiburg
1
Background: In recent years, the pathophysiology of affective disorders has increasingly been related to structural brain circuit remodelling and organizational changes, based on imaging studies in depressed adolescent patients. Myelination was proposed as one of the main mechanisms. However, no study has prospectively examined behavior, white matter imaging, and concomitant molecular changes in animal models of adolescent depression. Methods: We established a novel mouse model of adolescent depression after early life adversity. Animals were assessed longitudinally, in a sex-dependent manner from weaning through early adulthood for several translational behavioral dimensions. The model was used to identify imaging and molecular biomarkers associated with depressive-like behavior. Myelin genes, myelin microenvironment markers and signaling pathways were investigated longitudinally, in selected regions of interest. DTI imaging was performed in adolescence, at a validated time-point of behavioral and molecular alterations. Results: A strong phenotype of depression-like behaviors emerged in both sexes, in early adolescence. There was a clear-cut sexual dimorphism in predominant traits. DTI imaging showed widespread alterations of myelin integrity measures in limbic tracts, and in key-regions inside networks associated with negative and positive affect, cognitive control, salience, anxiety and threat. Alterations in oligodendrocyte markers and in myelin protein (MBP, PLP) expression were consistent with imaging findings. The behavioral sexual dimorphism was mirrored at the molecular/imaging level. Conclusions: We validate a first systematic translational animal model of adolescent depression, and show functionally relevant,
S46
Douglas Institute, 2IUSMQ
Background: Early life adversity (ELA) is a major risk factor for psychopathologies and suicide. The increasing number of neuroimaging studies reporting white matter alterations in adults having suffered from ELA suggests that child abuse can have a lasting impact on brain connectivity. However, the underlying cellular and molecular features of such white matter changes remain to be described. Methods: To gain insight into the neurobiological impact of ELA, we performed a transcriptome-wide analysis of gene expression in samples of dorsal anterior cingulate cortex (dACC) from depressed suicides with or without a history of ELA, and psychiatrically healthy controls with no history of ELA. These well-characterized brain samples were obtained from the Douglas-Bell Canada Brain Bank. Furthermore, we used high throughput, high resolution myelin imaging by Coherent anti-Stokes Raman Scattering (CARS) to investigate myelination of individual axons within dACC white matter. Results: Using RNA-sequencing followed by Nanostring validation, we found that a large number of genes related to myelin and oligodendrocyte function were specifically downregulated as a function of ELA. The ultrastructural analysis of white matter axons revealed that small caliber axons were less myelinated in depressed suicides with a history of ELA compared to healthy controls and to depressed suicides without ELA. Conclusions: These results converge to highlight that ELA leads to a global and long-term impairment of oligodendrocyte function in the dACC. Considering the critical role of myelination in normal brain development, this may represent a key mechanism by which ELA may have lifelong consequences on mood and behavior. Supported By: ERA-NET NEURON; AFSP Keywords: child abuse, white matter, Major Depression, Suicide
111. White Matter Microstructural Variations in Adolescents with Affective Symptoms Marie-Laure Paillere Martinot1, Helene Vulser2, Eric Artiges2, Nadege Bourvis1, Jean-Pierre Benoit1, Marie Douniol3, Richard Delorme1, David Cohen1,
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
Thursday Abstracts
CRF neurons. Ongoing experiments are evaluating potential sex differences in the organization and function of this circuit. Supported By: K99AA023559 Keywords: Alcohol, CRF
SYMPOSIUM Negative Affect and Regional Network Alterations: Recent Advances in Translational Research Thursday, May 18, 2017, 3:00 PM - 5:00 PM Aqua D Chair: Jean-Luc Martinot Co-Chair: Monique Ernst
sex-dependent, structural connectivity changes in limbic networks. Supported By: ERA_NET Neuron, Labex Biopsy, ANR Keywords: Animal Model, white matter, Connectivity, Adolescent Depression, Diffusion Tensor Imaging (DTI)
110. Early Life Adversity Associates with Altered Oligodendrocyte Function and Decreased Myelination in the Anterior Cingulate Cortex of Depressed Suicides Naguib Mechawar1, Pierre-Éric Lutz1, Arnaud Tanti1, Alicja Gasecka2, John Kim1, Marina Wakid1, Daniel Côté2, and Gustavo Turecki1 1
109. From Early Life Adversity to Adolescence Depression: White Matter Remodelling in a Translational Animal Model Severine Farley1, Julien Grenier2, Victor Gorgievski1, Alexandre Barbe1, Wojciech Jaworski1, Ariane Bochereau1, Carlos Macedo1, Said Ghandour3, Neele Huebner4, Thomas Bienert4, Jurgen Henning4, Charbel Massaad2, Bruno Giros1, Laura Harsan5, and Eleni Tzavara1 Inserm, 2University Paris Descartes, 3Strasbourg University, 4Uniklinik Freiburg, 5Strasbourg University, Uniklinik Freiburg
1
Background: In recent years, the pathophysiology of affective disorders has increasingly been related to structural brain circuit remodelling and organizational changes, based on imaging studies in depressed adolescent patients. Myelination was proposed as one of the main mechanisms. However, no study has prospectively examined behavior, white matter imaging, and concomitant molecular changes in animal models of adolescent depression. Methods: We established a novel mouse model of adolescent depression after early life adversity. Animals were assessed longitudinally, in a sex-dependent manner from weaning through early adulthood for several translational behavioral dimensions. The model was used to identify imaging and molecular biomarkers associated with depressive-like behavior. Myelin genes, myelin microenvironment markers and signaling pathways were investigated longitudinally, in selected regions of interest. DTI imaging was performed in adolescence, at a validated time-point of behavioral and molecular alterations. Results: A strong phenotype of depression-like behaviors emerged in both sexes, in early adolescence. There was a clear-cut sexual dimorphism in predominant traits. DTI imaging showed widespread alterations of myelin integrity measures in limbic tracts, and in key-regions inside networks associated with negative and positive affect, cognitive control, salience, anxiety and threat. Alterations in oligodendrocyte markers and in myelin protein (MBP, PLP) expression were consistent with imaging findings. The behavioral sexual dimorphism was mirrored at the molecular/imaging level. Conclusions: We validate a first systematic translational animal model of adolescent depression, and show functionally relevant,
S46
Douglas Institute, 2IUSMQ
Background: Early life adversity (ELA) is a major risk factor for psychopathologies and suicide. The increasing number of neuroimaging studies reporting white matter alterations in adults having suffered from ELA suggests that child abuse can have a lasting impact on brain connectivity. However, the underlying cellular and molecular features of such white matter changes remain to be described. Methods: To gain insight into the neurobiological impact of ELA, we performed a transcriptome-wide analysis of gene expression in samples of dorsal anterior cingulate cortex (dACC) from depressed suicides with or without a history of ELA, and psychiatrically healthy controls with no history of ELA. These well-characterized brain samples were obtained from the Douglas-Bell Canada Brain Bank. Furthermore, we used high throughput, high resolution myelin imaging by Coherent anti-Stokes Raman Scattering (CARS) to investigate myelination of individual axons within dACC white matter. Results: Using RNA-sequencing followed by Nanostring validation, we found that a large number of genes related to myelin and oligodendrocyte function were specifically downregulated as a function of ELA. The ultrastructural analysis of white matter axons revealed that small caliber axons were less myelinated in depressed suicides with a history of ELA compared to healthy controls and to depressed suicides without ELA. Conclusions: These results converge to highlight that ELA leads to a global and long-term impairment of oligodendrocyte function in the dACC. Considering the critical role of myelination in normal brain development, this may represent a key mechanism by which ELA may have lifelong consequences on mood and behavior. Supported By: ERA-NET NEURON; AFSP Keywords: child abuse, white matter, Major Depression, Suicide
111. White Matter Microstructural Variations in Adolescents with Affective Symptoms Marie-Laure Paillere Martinot1, Helene Vulser2, Eric Artiges2, Nadege Bourvis1, Jean-Pierre Benoit1, Marie Douniol3, Richard Delorme1, David Cohen1,
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal