Navigation Links
Resilience factor low in depression, protects mice from stress

This release is available in Chinese.

Scientists have discovered a mechanism that helps to explain resilience to stress, vulnerability to depression and how antidepressants work. The new findings, in the reward circuit of mouse and human brains, have spurred a high tech dragnet for compounds that boost the action of a key gene regulator there, called deltaFosB.

A molecular main power switch called a transcription factor inside neurons, deltaFosB turns multiple genes on and off, triggering the production of proteins that perform a cell's activities.

"We found that triggering deltaFosB in the reward circuit's hub is both necessary and sufficient for resilience; it protects mice from developing a depression-like syndrome following chronic social stress," explained Eric Nestler, M.D., of the Mount Sinai School of Medicine, who led the research team, which was funded by the National Institute of Health's National Institute of Mental Health (NIMH).

"Antidepressants can reverse this social withdrawal syndrome by boosting deltaFosB. Moreover, deltaFosB is conspicuously depleted in brains of people who suffered from depression. Thus, induction of this protein is a positive adaptation that helps us cope with stress, so we're hoping to find ways to tweak it pharmacologically," added Nestler, who also directs the ongoing compound screening project.

Nestler and colleagues report the findings that inspired the hunt online May 16 2010 in the journal Nature Neuroscience.

"This search for small molecules that augment the actions of deltaFosB holds promise for development of a new class of resilience-boosting treatments for depression," said NIMH director Thomas R. Insel. "The project, funded under the American Recovery and Reinvestment Act of 2009, is a stunning example of how leads from rodent experiments can be quickly followed up and translated into potential clinical applications."

DeltaFosB is more active in the reward hub, called the nucleus accumbens (see diagram below), than in any other part of the brain. Chronic use of drugs of abuse or even natural rewards like excess food, sex or exercise can gradually induce increasing levels of this transcription factor in the reward hub. Nestler and colleagues have shown that this increase in deltaFosB can eventually lead to lasting changes in cells that increase rewarding responses to such stimuli, hijacking an individual's reward circuitry addiction.

The new study in mice and human post-mortem brains confirms that the same reward circuitry is similarly corrupted (though to a lesser degree than with drugs of abuse) in depression via effects of stress on deltaFosB.

Depressed patients often lack motivation and the ability to experience reward or pleasure and depression and addiction often go together. Indeed, mice susceptible to the depression-like syndrome show enhanced responses to drugs of abuse, the researchers have found.

But the similarity ends there. For, while an uptick in deltaFosB promotes addiction, the researchers have determined that it also protects against depression-inducing stress. It turns out that stress triggers the transcription factor in a different mix of nucleus accumbens cell types working through different receptor types than do drugs and natural rewards, likely accounting for the opposite effects.

The researchers explored the workings of deltaFosB in a mouse model of depression. Much as depressed patients characteristically withdraw from social contact, mice exposed to aggression by a different dominant mouse daily for 10 days often become socially defeated; they vigorously avoid other mice, even weeks later.

Among key findings in the brain's reward hub:

  • The amount of deltaFosB induced by the stress determined susceptibility or resilience to developing the depression-like behaviors. It counteracted the strong tendency to learn an association, or generalize, the aversive experience to all mice.
  • Induction of deltaFosB was required for the antidepressant fluoxetine (Prozac) to reverse the stress-induced depression-like syndrome.
  • Prolonged isolation from environmental stimuli reduced levels of deltaFosB, increasing vulnerability to depression-like behaviors.
  • Among numerous target genes regulated by deltaFosB, a gene that makes a protein called the AMPA receptor is critical for resilience or protecting mice from the depression-like syndrome. The AMPA receptor is a protein on neurons that boosts the cell's activity when it binds to the chemical messenger glutamate.
  • Increased activity of neurons triggered by heightened sensitivity of AMPA receptors to glutamate increased susceptibility to stress-induced depression-like behavior.
  • Induction of deltaFosB calmed the neurons and protected against depression by suppressing AMPA receptors' sensitivity to glutamate.
  • Post-mortem brain tissue of depressed patients contained only about half as much deltaFosB as that of controls, suggesting that poor response to antidepressant treatment may be traceable, in part, to weak induction of the transcription factor.

Reduced deltaFosB in the reward hub likely helps to account for the impaired motivation and reward behavior seen in depression, said Nestler. Boosting it appears to enable an individual to pursue goal-directed behavior despite stress.

The high-tech screening for molecules that boost DeltaFosB, supported by the Recovery Act grant, could lead to development of medications that would help people cope with chronic stress. The molecules could also potentially be used as telltale tracers in brain imaging to chart depressed patients' treatment progress by reflecting changes in deltaFosB, said Nestler.


Contact: Jules Asher
NIH/National Institute of Mental Health

Related biology news :

1. New brain nerve cells key to stress resilience, UT Southwestern researchers find
2. Hormone levels contribute to stress resilience
3. Long-term recovery of reefs from bleaching requires local action to increase resilience
4. Resilience in an aging society: GSA showcases cutting-edge meeting topics
5. Resilience concepts poised to aid management of coastal marine ecosystems
6. ORNL resilience plan to help Tennessee, Mississippi and South Carolina communities beat disaster
7. BIO-key(R) Delivers FBI-Compliant 2 Factor Authentication Solution for First Responders
8. Grapes reduce risk factors for heart disease and diabetes, U-M animal study shows
9. Duke, LabCorp combine forces to create the Biomarker Factory
10. Study pins factors behind geography of human disease
11. CNIC and Banco Santander set up research project on early cardiovascular risk factors
Post Your Comments:
Related Image:
Resilience factor low in depression, protects mice from stress
(Date:11/16/2015)... Calif. , Nov 16, 2015  Synaptics ... of human interface solutions, today announced expansion of ... TouchView ™ touch controller and display driver ... revolution of smartphones. These new TDDI products add ... TD4100 (HD resolution), TD4302 (WQHD resolution), and TD4322 ...
(Date:11/12/2015)... 11, 2015   Growing need for low-cost, ... has been paving the way for use of ... discrete analytes in clinical, agricultural, environmental, food and ... used in medical applications, however, their adoption is ... to continuous emphasis on improving product quality and ...
(Date:11/10/2015)... , Nov. 10, 2015 ... behavioral biometrics that helps to identify and verify ... Signature is considered as the secure and accurate ... identification of a particular individual because each individual,s ... accurate results especially when dynamic signature of an ...
Breaking Biology News(10 mins):
(Date:11/26/2015)... , England , November 26, 2015 ... Lightpoint Medical, an innovative medical device company specializing in imaging ... grant from the European Commission as part of the Horizon ... the company to carry out a large-scale clinical trial in ... -->      (Logo: , --> ...
(Date:11/25/2015)... , November 25, 2015 2 ... première fois les différences entre les souches bactériennes ... celles des êtres humains . Ces recherches ... et envisager la prise en charge efficace de ... diagnostiqués chez les chats .    --> ...
(Date:11/25/2015)... 25, 2015  Neurocrine Biosciences, Inc. (Nasdaq: NBIX ... and CEO of Neurocrine Biosciences, will be presenting at ... New York . .   ... approximately 5 minutes prior to the presentation to download ... presentation will be available on the website approximately one ...
(Date:11/25/2015)... , Nov. 25, 2015 Orexigen® Therapeutics, Inc. ... participate in a fireside chat discussion at the Piper ... York . The discussion is scheduled for Wednesday, ... .  A replay will be available for ... Stilwell  , Julie NormartVP, Corporate Communications and Business ...
Breaking Biology Technology: