But how stress accomplishes its sinister work on a cellular level has remained mysterious. Neuroscientists at a UC Berkeley lab have uncovered evidence that a well-known stress hormone trips a switch in stem cells in the brain, causing them to produce a white matter cell that ultimately can change the way circuits are connected in the brain. This key step toward hardening wires, the researchers found, may be at the heart of the hyper-connected circuits associated with prolonged, acute stress, according to the study published online Tuesday in the journal Molecular Psychiatry. The findings strengthen an emerging view that cells once written off as little more than glue, insulation and scaffolding may regulate and reorganize the brain’s circuitry. Researchers examined a population of stem cells in the brain’s hippocampus, an area critical to fusing emotion and memory, and one that has been known to shrink under the effects of prolonged acute stress. Under normal circumstances, these cells form new neurons or glia, a type of white matter. But the stress hormone corticosterone (the rodent equivalent of cortisol in humans) can trip up that programming. Instead, the stem cells produce an abundance of oligodendrocytes, cells that help coat long fibers of neurons, known as axons, with a protective sheath. That sheath, made of myelin, is critical for the transmission of electrochemical signals that are the essence of our central nervous system. “Usually the brain doesn’t make much oligodendrocytes in adulthood from those neural stem cells,” said UC Berkeley neuroscientist Daniela Kaufer, lead investigator of the study. In fact, a recent study suggested these cells were incapable of producing oligodendrocytes, which are somewhat like a vine spreading out and wrapping around axons, both insulating and supporting them. “It’s pretty much true, in a regular situation,” Kaufer said of the previous study’s conclusions. “But under stress, all of a sudden, you discover they are making those cells” that insulate axons, she added. Researchers stressed out rodents by either immobilizing them in a straitjacket for three hours a day, seven days a week, or injecting them with corticosterone. “When we looked afterwards at their brain, we saw there was a decrease in the amount of neurons made from those cells; that was well known,” Kaufer said. “But then it occurred to me that nobody ever looked at the other cells that those cells can make.” Another UC Berkeley lab investigating traumatic epilepsy had been working for some time on searching out these other cells, categorized as glia, Latin for glue. These woefully misnamed cells were on Kaufer’s mind, but more importantly, the lab equipment to find and quantify them also was readily at hand. Lab members scooped out the oligodendrocytes from the rodent brains, put them in a dish, added corticosterone and then took the equivalent of an inventory. They found fewer neurons and a big increase in oligodendrocytes. And by blocking the corticosterone receptors, they discovered the process was tied to that stress hormone. “This was absolutely not what we were expecting to find,” Kaufer said. “But those are always the best discoveries.” The last element of the puzzle still loomed: How was this stress hormone changing the fate of these stem cells? They looked at transcriptional programming – the proteins that bind to DNA and regulate genes that drive whether the cells become neurons. Fewer cells from the stressed rodents were programmed to become neurons, while many were set on the path to becoming insulation-generating cells, the data showed. “The cell re-programs changes its fate, from wanting to become a neuron to wanting to become an oligodendrocyte,” Kaufer said. Further data not included in the published study suggest that these cells go on to produce more insulation, known as a myelin sheath, Kaufer said. That sheath is vital to human brains – babies must develop it as they mature, because it helps neurons propagate the electrochemical signals toward synapses that connect to neighboring neurons. Insufficient myelination lies at the heart of developmental disorders as well as addiction, studies have shown. But myelin formation can be good or bad, depending on time or place, Kaufer said. Better sheathing could, for instance, bolster the connection between the amygdala and hippocampus, enhancing our fight/flight response, which is beneficial in a war zone, but can be maladaptive on the home front. Relatively weaker sheathing, meanwhile, could prevent the frontal cortex from countering the fight/flight response of the hippocampus with a rational assessment of the threat. The ensuing hypervigilant loop features prominently in PTSD. Those hypotheses, however, remain to be examined further, Kaufer noted. But it is intriguing, she added, that a broad array of neurological disorders involve anomalies in white matter connectivity. Kaufer’s team is examining how early trauma might set the fate of white matter, and ultimately the form and function of the developing brain. Moderate stress – such as produced by studying for an exam or competing in the Olympic Games – can build stronger circuitry and a more resilient brain, she noted. But acute, prolonged stress can wreak havoc, as the study suggests. “You’re creating a brain that’s either resilient or very vulnerable to mental disease, based on the patterning of white matter you get early in life,” said Kaufer.
20 Feb 2014
February 20, 2014
By Geoffrey MohanFebruary 11, 2014, 6:27 p.m. http://www.latimes.com/
Stress can damage the brain. The hormones it releases can change the way nerves fire, and send circuits into a dangerous feedback loop, leaving us vulnerable to anxiety, depression and post-traumatic stress disorder.