Stress can have a negative influence on the human brain, but increasingly it is the ability to withstand severe stress that is the focus of research.
Daniela Kaufer has a personal interest in the effects of stress. “My mum’s family had a very traumatic experience when their mother died in childbirth,” she explains. The three children grew up motherless, in 1950s war-torn Israel, but there was a marked difference in how well the siblings coped. “My mum had an extremely difficult early life,” she says. “Yet she is extremely resilient.” Kaufer, who is a neuroscientist at the University of California, Berkeley, says that why her mother in particular coped so well has fascinated her.
Research into how people react to early trauma began in earnest after the Second World War. Distressing events such as the death of a parent have been found to increase children’s short-term risk of major depression, anxiety disorders and post-traumatic stress disorder (PTSD). With advances in techniques to study genes and to explore the brain, the neurobiological study of stress is undergoing a revolution — and our view of the stress response is changing. Until about 20 years ago, the absence of a severe negative reaction such as PTSD was thought to be a lack of response. Instead, “resilience is now viewed as a reactive response”, says Kaufer.
What resilience means in terms of gene expression, numbers of cells and brain networks is now the focus of research. “Years ago, most would have thought that resilient individuals escape some of the bad things that stress induces in the brains of more susceptible individuals,” explains neurobiologist Eric Nestler at Mount Sinai School of Medicine, New York. “Now we believe susceptible individuals lack some of the more adaptive changes that occur in the resilient brain.”
Stress is an unavoidable component of life, and the stress response is a crucial survival mechanism. “The brain is a detector of threatening information,” says neuropsychologist Sonia Lupien at the University of Montreal, Canada. “This is its most important job if you want to survive.” Acute stress readies us for action, but chronic stress wears us down, altering the brain genetically and neurologically and priming us for mental health problems. Whether a person is resilient to stress depends heavily on their life history. Understanding the effects of early-life difficulties could provide new ways to treat or prevent mental illnesses such as severe depression or PTSD in susceptible individuals.
Stress in the brain
Confronted with a life-threatening situation, hormones and neurotransmitters prep us for action. Specific stress hormones — cortisol in primates, corticosterone in most rodents — are released, some of which surge across the blood–brain barrier. Stress gets everywhere: all our cells host receptors for the hormone. “Every brain area has something happen to it,” says Kaufer. The human brain has two types of receptor for cortisol. One has a six to tenfold higher affinity for the molecule than the other, and so is activated earlier, by smaller amounts of cortisol.
The hippocampus (which is pivotal for memory) and the amygdala (the centre for emotions) contain lots of the high-affinity receptors, and are, therefore, activated by slight rises in the hormone. The frontal lobe, which is involved in executive planning and control, has only the low-affinity receptor, and is activated later, after the tide has risen. And, as Lupien and colleagues found, both memory formation and recall in adults can be influenced by cortisol1.
The existence of two receptor types means that response to stress is not linear. “The relationship between circulating stress hormone and memory is an inverted U-shape function,” Lupien explains. “Up to a certain level, stress hormones are good for your memory” — when the cortisol binds only to the high-affinity receptors, the ability to lay down and retrieve memory is enhanced. When the low-affinity receptors are activated, the relationship enters the right-hand side of the U-shape and the response shifts, she adds.
The duration of stress is also important. A transient bout of stress causes a proliferation of neural stem cells and a spike in numbers of new neurons, which take at least two weeks to mature. The brain seems to be preparing itself in case a second stressor comes calling. Chronic stress is not so beneficial. It slashes investment in new neurons, prunes the tree-like shape of existing ones, and suppresses new connections.
If stress hormones remain elevated for months or years, they can stimulate physiological changes: the hippocampus shrinks and the amygdala grows, for example. Eventually, the complex feedback system that suppresses the excess secretion of cortisol is disturbed. Once this happens, the capacity to discriminate between threat levels falls away. Either everything seems threatening (anxiety) or else nothing does (depression or burnout).
Old ideas that certain individuals have an inherent ‘hardiness’ or an innate ability to bounce back from severe stress have fallen by the wayside. Instead, resilience and our response to trauma are recognized as being more dynamic, changing throughout life. It’s a complicated milieu, but one of the main ways that stress marks the brain is through epigenetics. This does not change genes, but it can change their expression by attaching methyl groups to DNA or associated proteins.
At McGill University in Montreal, neuroscientist Michael Meaney’s group has been exploring the stress response in rats. It found that high-licking and low-licking grooming strategies in mother rats gave rise to different offspring2. The lesser-grooming mums produced pups with high anxiety, poor stress-recovery and low cognitive performance. The pups’ brain circuits that switch off stress were sluggish, owing to higher DNA methylation and lower expression of the ‘off’ receptors in the hippocampus. Well-groomed pups showed the opposite.
People might be tempted to label high-groomers as better mothers, says Kaufer. “But it is not ‘good mums’ or ‘bad mums’, just a different parenting style.” Parenting style can reflect the environment and prepare the offspring, she explains. Being a cautious, worried rat — the offspring of a less-thorough groomer — makes sense if you live in an alley full of cats.
Nature 531, S18–S19 (03 March 2016)
Published online 02 March 2016