How to Prevent Recurrent Stress from Damaging the Brain

Zhen Yan, Ph.D., Professor of Physiology and Neuroscience at the State University of New York at Buffal,o Stress Expert
Zhen Yan, Ph.D.

NARSAD Young and Independent Investigator Grantee Zhen Yan, Ph.D., Professor of Physiology and Neuroscience at the State University of New York at Buffalo, discovered that repeated stress dampens the activity of excitatory neurons in a part of the brain called the prefrontal cortex, or PFC. Excitatory neurons make up the majority of nerve cells in the brain, and are responsible for the transmission of neural messages from one cell to another within complex neural circuits. The PFC is a crucial brain region that controls high-level “executive” functions, including working memory and decision making.  

Prior research in adult rodents had revealed that chronic stress causes structural remodeling of the PFC, leading to behavioral changes in adults.  It had also shown that adrenal corticosterone—the major stress hormone that mammals secrete in response to stressful situations—can cause long-lasting changes in cognitive and emotional processes.

The results of recent research by Dr. Yan and her team, published on March 8, 2012 in the journal Neuron, take the prior research findings further by beginning to explain how the stress-induced changes in the brain happen and to identify possible pathways to prevent the damage from occurring. In earlier work published in the 2009 Proceedings of the National Academy of Sciences and in the 2011 Molecular Psychiatry, the team had discovered that acute stress—a traumatic, one-time shock to the system—induces elevated and sustained transmission of glutamate, the main excitatory neurotransmitter, in the PFC of rats. Interestingly, this had a beneficial effect on the rats’ working memory.  In certain circumstances and at certain levels, the reaction to acute stress can actually help the brain.

Not so, however, when stress recurs. This is one of the conclusions of the team’s new work.  They carefully traced how repeated, “sub-chronic” stress disturbed glutamate signaling in juvenile animals, which are especially vulnerable as their brains mature. They found that repeated stress significantly impaired the young rats’ temporal order recognition memory, which is controlled by the PFC.

The team also deduced two important biological mechanisms behind the disturbance in glutamate signaling: the first is that there are significant reductions in the responses mediated by NMDA- (N-methyl-D-aspartate) and AMPA- (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors at the point of tiny gaps between neurons called synapses; and the second is that there are fewer total numbers of glutamate receptors. Both of these mechanisms depend on activation of receptors of glucocorticoid stress hormones. Such activation, they specifically discovered, had the effect of eliminating ‘subunits’, or functional modules, of the glutamate receptors where excitatory neurotransmitters ‘dock’.

Perhaps most exciting: the team was able to experimentally prevent the loss of those glutamate receptor ‘subunits’. By preventing the loss of the subunits, the loss of glutamatergic responses and of recognition memory in stressed animals was also prevented. With this important stream of new discoveries, the team suggests that use of an existing class of medications called proteasome inhibitors might be “a potential approach to block the detrimental effects of repeated stress”.