Depression Susceptibility Controlled By Gene Networks

Depression involves alterations in coordinated networks of hundreds of genes across key brain circuits, suggests a study from the Icahn School of Medicine at Mount Sinai.

Earlier research suggested that multiple brain regions play a role in depression, but the exact mechanism behind gene activity control of brain circuits had not been investigated. Most studies looked only at how the activity of individual genes is increased or decreased in isolated brain areas in depression without investigating how the relationship between groups of genes is regulated.

The Mount Sinai study homes in on identifying how groups of genes operate in functional clusters or ‘gene networks’ to control communication across distinct areas in the brain or ‘brain circuits’ that are changed in depression. Rosemary C. Bagot, PhD, a postdoctoral researcher in the Nestler Laboratory of Molecular Psychiatry at Mount Sinai, said:

By considering both activity of individual genes and the relationship between groups of genes in several brain regions, our team found that depression may reflect fundamental changes in the architecture of gene networks, rather than just simple increases or decreases in the activity of genes.“

Master Regulator Genes

The research team found large gene networks that are altered in depression-like states, focusing on three specific genes that were “master regulators” of the gene networks. None of these genes had previously been linked to depression.

The team demonstrated that manipulating the master regulator genes that control these networks could make mice susceptible or resilient to chronic stress.

Using a mouse model of human depression, the team examined the multifaceted dysregulation of gene networks within several inter-connected brain regions implicated in depression:

  • the nucleus accumbens (NAc)

  • the prefrontal cortex

  • the amygdala

  • the ventral hippocampus

The brain areas studied form a circuit with the NAc at its center, integrating diverse input from the other three regions to drive motivated behavior.

The nucleus accumbens receives information about executive control and attention from the prefrontal cortex; context, space and emotional data from the ventral hippocampus; and information about both learned associations and emotion from the amygdala.

RNA sequencing created a complete picture of gene expression in these interconnected brain regions. The study team found a striking difference in patterns of gene expression between resilient and susceptible mice.

Specifically, researchers found an opposing relationship between the prefrontal cortex and the ventral hippocampus. By manipulating master regulators of key gene networks within each of these brain regions, they found a key role for the ventral hippocampus in making mice susceptible to depression, whereas the prefrontal cortex was important in making mice resilient.

Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience and Director of the Friedman Brain Institute at Mount Sinai, said:

This study’s findings suggest that we need drugs that can alter how clusters of genes function within brain circuits. Depression is a circuit-level disorder and needs to be understood and treated at that level.“

Study: Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility. Neuron, May 2016 DOI: 10.1016/j.neuron.2016.04.015

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