TY - JOUR

T1 - CNS genomic profiling in the mouse chronic social stress model implicates a novel category of candidate genes integrating affective pathogenesis

AU - Demin, Konstantin A.

AU - Smagin, Dmitry A.

AU - Kovalenko, Irina L.

AU - Strekalova, Tatyana

AU - Galstyan, David S.

AU - Kolesnikova, Tatyana O.

AU - De Abreu, Murilo S.

AU - Galyamina, Anna G.

AU - Bashirzade, Alim

AU - Kalueff, Allan V.

N1 - Funding Information: The study was supported by the Russian Foundation for Basic Research (RFBR) grant 16-04-00851 to AVK . The authors thank Prof. N.N. Kudryavtseva very much for her long-standing support, expert methodological consultations on the chronic social defeat stress model and invaluable first-hand assistance with data interpretation and analyses. Dr. V. Babenko is also acknowledged for his valuable assistance with data interpretation. AVK is supported by the School of Pharmacy of the Southwest University (Chongqing, China). He is the President of the International Stress and Behavior Society (ISBS, www.stress-and-behavior.com ) that coordinated this collaborative project. Prof. N.N. Kudryavtseva's laboratory was supported by the Russian Science Foundation (RSF) grant 19-15-00026 . KAD is supported by the Fellowship of the President of Russia, and the Special Rector's Fellowship for St. Petersburg State University PhD Students. The laboratory is supported by the budgetary state funding for basic research from St. Petersburg State University (project 51130521 ). AB is supported by the budgetary state funding for basic research from the Institute of Physiology and Basic Medicine (Novosibirsk, Russia). The funders had no role in the design, analyses and interpretation of the submitted study, or decision to publish. Publisher Copyright: © 2020 Elsevier Inc. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2021/3/8

Y1 - 2021/3/8

N2 - Despite high prevalence, medical impact and societal burden, anxiety, depression and other affective disorders remain poorly understood and treated. Clinical complexity and polygenic nature complicate their analyses, often revealing genetic overlap and cross-disorder heritability. However, the interplay or overlaps between disordered phenotypes can also be based on shared molecular pathways and ‘crosstalk’ mechanisms, which themselves may be genetically determined. We have earlier predicted (Kalueff et al., 2014) a new class of ‘interlinking’ brain genes that do not affect the disordered phenotypes per se, but can instead specifically determine their interrelatedness. To test this hypothesis experimentally, here we applied a well-established rodent chronic social defeat stress model, known to progress in C57BL/6J mice from the Anxiety-like stage on Day 10 to Depression-like stage on Day 20. The present study analyzed mouse whole-genome expression in the prefrontal cortex and hippocampus during the Day 10, the Transitional (Day 15) and Day 20 stages in this model. Our main question here was whether a putative the Transitional stage (Day 15) would reveal distinct characteristic genomic responses from Days 10 and 20 of the model, thus reflecting unique molecular events underlining the transformation or switch from anxiety to depression pathogenesis. Overall, while in the Day 10 (Anxiety) group both brain regions showed major genomic alterations in various neurotransmitter signaling pathways, the Day 15 (Transitional) group revealed uniquely downregulated astrocyte-related genes, and the Day 20 (Depression) group demonstrated multiple downregulated genes of cell adhesion, inflammation and ion transport pathways. Together, these results reveal a complex temporal dynamics of mouse affective phenotypes as they develop. Our genomic profiling findings provide first experimental support to the idea that novel brain genes (activated here only during the Transitional stage) may uniquely integrate anxiety and depression pathogenesis and, hence, determine the progression from one pathological state to another. This concept can potentially be extended to other brain conditions as well. This preclinical study also further implicates cilial and astrocytal mechanisms in the pathogenesis of affective disorders.

AB - Despite high prevalence, medical impact and societal burden, anxiety, depression and other affective disorders remain poorly understood and treated. Clinical complexity and polygenic nature complicate their analyses, often revealing genetic overlap and cross-disorder heritability. However, the interplay or overlaps between disordered phenotypes can also be based on shared molecular pathways and ‘crosstalk’ mechanisms, which themselves may be genetically determined. We have earlier predicted (Kalueff et al., 2014) a new class of ‘interlinking’ brain genes that do not affect the disordered phenotypes per se, but can instead specifically determine their interrelatedness. To test this hypothesis experimentally, here we applied a well-established rodent chronic social defeat stress model, known to progress in C57BL/6J mice from the Anxiety-like stage on Day 10 to Depression-like stage on Day 20. The present study analyzed mouse whole-genome expression in the prefrontal cortex and hippocampus during the Day 10, the Transitional (Day 15) and Day 20 stages in this model. Our main question here was whether a putative the Transitional stage (Day 15) would reveal distinct characteristic genomic responses from Days 10 and 20 of the model, thus reflecting unique molecular events underlining the transformation or switch from anxiety to depression pathogenesis. Overall, while in the Day 10 (Anxiety) group both brain regions showed major genomic alterations in various neurotransmitter signaling pathways, the Day 15 (Transitional) group revealed uniquely downregulated astrocyte-related genes, and the Day 20 (Depression) group demonstrated multiple downregulated genes of cell adhesion, inflammation and ion transport pathways. Together, these results reveal a complex temporal dynamics of mouse affective phenotypes as they develop. Our genomic profiling findings provide first experimental support to the idea that novel brain genes (activated here only during the Transitional stage) may uniquely integrate anxiety and depression pathogenesis and, hence, determine the progression from one pathological state to another. This concept can potentially be extended to other brain conditions as well. This preclinical study also further implicates cilial and astrocytal mechanisms in the pathogenesis of affective disorders.

KW - Animal models

KW - Anxiety

KW - Depression

KW - Genomics

KW - Molecular mechanisms

KW - SEROTONIN TRANSPORTER

KW - OXIDATIVE STRESS

KW - MAJOR DEPRESSION

KW - ANXIETY-LIKE BEHAVIOR

KW - ESTROGEN-RECEPTOR

KW - POSITIVE FIGHTING EXPERIENCE

KW - AGONISTIC INTERACTIONS

KW - NEUROPSYCHIATRIC DISORDERS

KW - TRANSPORTER KNOCKOUT MICE

KW - INTERMEDIATE PHENOTYPES

UR - http://www.scopus.com/inward/record.url?scp=85094958084&partnerID=8YFLogxK

U2 - 10.1016/j.pnpbp.2020.110086

DO - 10.1016/j.pnpbp.2020.110086

M3 - Article

C2 - 32889031

AN - SCOPUS:85094958084

VL - 105

JO - Progress in Neuro-Psychopharmacology and Biological Psychiatry

JF - Progress in Neuro-Psychopharmacology and Biological Psychiatry

SN - 0278-5846

M1 - 110086

ER -