Stress-Induced Depressive-Like Symptoms Controlled by Networks of Genes

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Manipulating gene networks across distinct brain regions in mice affects susceptibility or resilience to depression-like behavior.

Various networks of genes across distinct brain regions in mice affect both stress-induced susceptibility and resilience to depression-like behavior, according to a study published in Neuron.1

It is evident that depression is caused by a complex interplay between genetic and environmental components. Because genome-wide association studies and epidemiologic analyses are unable to detect causative biological mechanisms that underlie its development, nonhuman animal models are essential to address the biological basis of affective disorders.

New evidence indicates that susceptibility to depression may involve stress-induced changes in networks of genes across interconnected brain regions and structures. One such brain part, the nucleus accumbens (NAC), integrates diverse information from various structures such as the prefrontal cortex (PFC), amygdala (AMY), and ventral hippocampus (VHIP) and is primarily associated with mediating reward.2 In addition, it is known that these brain structures are involved in emotional regulation and stress-related behaviors. Aside from driving motivated behavior, the NAC mediates a variety of other behaviors including susceptibility and resilience to depression following stress exposure.3 In murine models of depression-like behavior, chronic social defeat stress (CSDS) is commonly employed as an environmental stressor because of its etiologic and ethologic validity.4

In the present study, a group of investigators affiliated with the Icahn School of Medicine at Mount Sinai, New York, exposed mice to CSDS in order to induce 2 distinct behavioral phenotypes: stress susceptible (~67%) and stress resilient (~33%).  Following the stress exposure, they profiled gene expression in 4 brain regions (NAC, VHIP, AMY, and PFC) in order to identify networks of genes within distinct circuits that regulate stress-induced susceptibility or resilience to depressive-like symptoms. The data obtained from mice in the 2 experimental groups were then compared to those from naive, nonstressed control animals.1

In line with previous reports, the circuit-wide transcriptional profiles indicate that susceptibility to stress-induced depressive-like behavior is characterized by a significant overlap in upregulated genes between PFC and VHIP, whereas resilience is characterized by a significant overlap in gene expression between PFC and NAC. Following additional analyses, “susceptibility associates with much larger changes in network connectivity than resilience, which suggests that coexpression changes may be most relevant in susceptibility,” the authors noted.

They also validated the RNA-seq findings in vivo by overexpressing a key gene (Sdk1) in the VHIP or PFC to induce a stress-susceptible or stress-resilient behavioral phenotype in adult mice, respectively. “Sdk1 showed a particularly striking phenotype: its overexpression in PFC versus VHIP induced opposite behavioral effects … and also increased synaptic transmission in VHIP, a potential cellular mechanism by which Sdk1 regulates increased susceptibility in the brain region,” the authors concluded.

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1. Bagot RC, Cates HM, Purushothaman I, et al. Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility. Neuron. 2016. doi: 10.1016/j.neuron.2016.04.015. [Epub ahead of print]

2. Salgado S, Kaplitt MG. The nucleus accumbens: a comprehensive review. Stereotact Funct Neurosurg. 2015;93:75-93.

3. Bagot RC, Parise EM, Peña CJ, et al. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nat Commun. 2015;6:7062.

4. Hammels C, Pishva E, De Vry J, et al. Defeat stress in rodents: from behavior to molecules. Neurosci Biobehav Rev. 2015;59:111-140.