Despite its high prevalence and harm, the pathobiology of anxiety and depression remain poorly understood. Psychiatric disorders complexity and their polygenic nature complicate their genetic analyses, which often not only reveal disorder-specific genes, but also show significant genetic overlap and cross-disorder heritability (Murphy et al. 2003, Ivleva et al. 2010, Cross-Disorder Group of the Psychiatric Genomics et al. 2013, Ikeda et al. 2013, Schizophrenia Working Group of the Psychiatric Genomics 2014 et al. 2014). To resolve some of the complications resulting from this ‘spectum’ nature of the CNS pathogenesis, the domain interplay and “interlinking” genes concepts were proposed previously by our team (Kalueff et al., 2008, 2014). We proposed that the interaction between the disordered endophenotypes (or their domains) can be based on both 1) shared molecular pathways and 2) specific ‘crosstalk’ mechanisms that, although not influencing the phenotypes by themselves, can modulate their interrelatedness during pathogenesis. To test this theory experimentally in a rodent model, we used chronic social defeat stress model in C57BL/6J mice, according to Kudryavtseva et al. (1994, 1996). Changes in gene expression, set enrichment and topology of differentially expressed genes and proteins connections, were examined in prefrontal cortex and hippocampus on different modeling stages of the disease progression, including well-validated anxious stage (10 days of social defeat), transitional stage (15 days of social defeat) and depressed stage (20 days). Observed changes that were conservative between brain regions can be described as follows: major disruption of neurotransmitter signaling in ‘anxious’ mouse group, followed by astrocyte function downregulation in ‘transitional’ group and ended by differential tissue-specific reactions in the ‘depressed’ group. These changes are mostly mediated by various patterns of signaling pathways downregulation, and were usually accompanied with changes in cell adhesion, inflammation and ion transport systems. These pilot experimental results strongly support the proposed interlinking genes that seem to play a key role in integrating anxiety and depression pathogenesis in vivo, and also additionally highlight the role of astrocyte pathology in major depressive disorder pathogenesis.