Brain Plasticity

Thirty years ago, the working assumption in neuroscience was this: People are born with a set number of neurons, hardwired in a certain way, and brain function is essentially all downhill from there. We spend our lifetimes losing connections and neurons—the brain slowly falling apart until we die.

Except it is not true. In 1998, Fred “Rusty” Gage, working out of the Laboratory of Genetics at the Salk Institute, showed that the human brain can and does produce new nerve cells into adulthood (Eriksson et al., 1998). In mice, he showed that exercise could increase the rate of neurogenesis, showing that the system is not fixed, but responds itself to experience and the outside world. The discovery of neurogenesis and an improved understanding of neuroplasticity—the ability of the brain to shape, form, eliminate, and strengthen new connections throughout life—has completely recast the question of nature versus nurture.

“Neurons can change their connectivity,” explained Blakemore. “They can change the strength of their connections. They can change the morphology of their connections. They can do it not necessarily just in early stages of life, although that is especially exaggerated, but probably throughout life responding to new environments and experiences.”

New research shows, for instance, that the number and strength of connections we have in the brain is determined by how often those connections are stimulated. The brain, if you will, has a “use it or lose it” approach to neurological maintenance.

Genetic programming also plays a key role. In most cases, the initial formation of a synapse occurs independent of stimulation. But if that synapse is not used, the brain will “prune” or eliminate it. Conversely, the more often a connection is used, the stronger it becomes in a physical sense, with more dendritic spines connecting to one another and a stronger net connection over time.

On the developmental side, researchers now understand the critical role that sensory input plays in shaping the wiring of the brain from the earliest days. Blakemore discussed work in his lab on the development of neural wiring in mice. Researchers have known since the 1960s that the neurons connected to the ultrasensitive whiskers of mice align themselves in a format called “barrel fields.” Each of these barrel fields is connected to a single whisker, although how or why they influence function is unknown. Blakemore showed that if you removed a clump of whiskers at an early age, the segment of the brain linked to that area never develops the barrel structure.

Similar research has shown in mice that if you tape one eye shut from birth, the mouse never gains the ability to see from that eye—it needs the stimulation to develop. However, if you tape shut the eye of an adult mouse for a similar period of time, vision is not affected.

All this seems to point the finger toward experience, but of course, the system really works as a complete feedback loop.

“We used to think . . . that the capacity of the brain to change its connections was an entirely independent process from the genetic regulation of structure,” said Blakemore. “But, of course, that cannot be the case. If adaptive change is possible, that must be the consequence of having molecular mechanisms that mediate those changes. Plasticity is a characteristic that has been selected for, so there must be genes for plasticity.”

In the case of barrel fields, Blakemore’s lab and other investigators have identified a number of molecules and genes that appear to be involved in mediating between incoming information for the whiskers and the anatomical changes necessary to produce the barrel field.

Understanding how this interplay works has huge implications for understanding how our brain develops and changes over time, and raises a number of interesting questions. Marder, for instance, asked how the brain can be so plastic and yet still retain memories over time.

Plasticity, however, is just one half of the equation; the underlying genetics are critically important, and new techniques and technologies make this a particularly interesting time to address these questions. For instance, modern, high-throughput gene-profiling technologies allow researchers to figure out all of the underlying transcriptions in a neuron, and see how these are manifest in the body.

Understanding the interplay of biology and experience on learning and development will surely require understanding the biological processes that cause changes in individual neurons and synapses. But this is only part of the puzzle. We must also understand the control of learning processes at a system-wide level in the brain. How does the brain orchestrate the right set of neural synaptic updates based on training experiences we encounter over our lifetime? Given the tremendous number of synapses in the brain, it is unlikely that a purely bottom-up approach will suffice to answer this question.

A complementary approach to studying experience-based learning at a system level relies on machine learning algorithms that have been developed to allow robots to learn from experience, described Mitchell. One intriguing study has shown that temporal-difference learning algorithms, which enable robots successfully to learn control strategies such as how to fly helicopters autonomously, can be used to predict the neural activity of dopamine-based systems in the human brain that are involved in reward-based learning (Schultz et al., 1997; Seymour et al., 2004; Doya, 2008). The integration of such system-level computational models alongside new research into synaptic plasticity offers an opportunity to examine the interplay of biology and experience on learning and development from multiple perspectives.

New tools will allow researchers to understand how variability between different genes and neurons and neuronal activity could influence behavior and capabilities across different people, the researchers said. Who we are is not only influenced by the yes/no expression of genes, but also the specific levels of expression among different genes, which in turn influences neuronal activity.

Gene-Environment Interactions

Nature and nurture are not simply additive interactions that result in a particular behavior, but rather a complex interplay of many factors. Nature includes not only the usual factors—parents, homes, what people learn—but also many other factors that individuals are exposed to routinely in their daily environments. As Marder emphasized, we cannot simply assume that gene X produces behavior Y. Instead as Bialek described, there are often many additional factors that directly and indirectly interact with gene X and ultimately influence variants in behavior. These variants define individuality.

As previously described, it has been known for almost 50 years that experience from the outside environment shapes our brain. This comes initially from the original work of Nobel Laureates David Hubel and Torsten Wiesel who studied how information is sensed and processed in the part of the brain responsible for vision. As Greenberg commented, the field is now at a point where we could in the next 10 years attain a significant mechanistic understanding of how the environment impinges directly on our genes to give rise to a malleable organ that allows us to adapt and change.

Huge Clinical Importance

Multiple participants at the workshop—including Nora Volkow, director of the National Institute on Drug Abuse; Joseph Takahashi, investigator of the Howard Hughes Medical Institute and Northwestern University; Lichtman; and Coyle—highlighted the role of genetics in shaping the brain as one of the fundamental challenges for neuroscience, both for its basic scientific interest and for its practical applications: Understanding how genes and experience come together to impact the brain could significantly alter how we think about treating neurological disease. Many of the most common neurological and mental health disorders—schizophrenia, bipolar disorder, autism, Parkinson’s disease, multiple sclerosis, Alzheimer’s disease—are complex genetic disorders that are influenced by environmental factors.

Alcino Silva, professor in the Departments of Neurobiology, Psychiatry and Psychology at the University of California, Los Angeles, showcased research from his lab showing he could treat and reverse developmental disorders in adult mice. This finding is worth repeating because it is so contrary to our general thinking on developmental disorders: Scientists working out of Silva’s lab have been able to reverse the impacts of the developmental disorder NF-1 (Neurofibromatosis type 1), which is caused by genetic malfunction, by treating the pathology of the disease in adult mice. These mice, which have obvious cognitive deficits, regain mental function when treated; Silva has advanced the study into human clinical trials.

The applications of this vein of study extend beyond developmental disorders. A growing body of evidence is revealing a massive feedback loop among genetics, neurological structure, experience, and disease. You are three times more likely to die from a heart attack if you are depressed than if you are not, for instance, and depression has a huge impact on diabetes as well, stated Coyle.

Taking a step backward, clinical data also show that people who experience multiple stressful episodes in their lives tend to suffer from clinical depression. But there is tremendous variation: Some people are resistant to stress and others are not.

“It turns out that the pattern is correlated with a polymorphic variation in one particular gene, the gene for the transporter for serotonin, a transmitter which is known to be involved in regulating mood,” explained Blakemore.

How do genes work in the brain to determine our resilience to stress, and how can those capabilities be monitored and modulated for better health?

The Way Forward

Asking these kinds of questions was not realistic 10 or even 5 years ago. The advent of high-throughput gene profiling and the growing sophistication of our ability to manipulate genes in animal models lets us, for the first time, explore the role that genes play in both creating and modulating our neural structures. At the same time, new imaging techniques and technologies like channel rhodopsin “light switches” let us better characterize neural systems and their response to the world around us, and to begin to plumb the tremendous feedback loop among genes, experience, and the physical activity in the brain.

Until quite recently, these have remained philosophical questions, commented Marder. However, the field of neuroscience is now in a position—through all the molecular, connectomics, and technological advances—to put these questions on firm mechanistic, biological bases, and to attack them scientifically.