Evidence Grows for Brain Benefits of Enriched Environments in Normal Aging and Disease - 2006

by Brenda Patoine

Humans can learn a lot from fun-loving rodents.  Mice and rats that spend their days twirling in running wheels, nosing their way through elaborate tunnels, negotiating obstacle courses, or just hanging out with their four-legged friends have provided neuroscience with some of the best evidence yet for how to keep brains healthy.  While the overall message – that stimulating and challenging the brain reaps rewards – is not new, the evidence supporting this message is stronger than ever.

Examining the neural effects of “environmental enrichment” (EE) is a growing sector of neuroscience research, one with profound implications for human brain health from birth to death.  Most recently, a spate of peer-reviewed papers has suggested that the benefits of a “complex” environment go beyond the realm of normal development and aging, pointing to a potential role in preventing or mitigating a range of brain disorders.  The list includes the major neurodegenerative diseases (Alzheimer’s, Parkinson’s and Huntington’s); neurological injuries like stroke, head injury and epilepsy, and addictive disorders including fetal alcohol syndrome and cocaine or amphetamine addiction.

Granted, the vast majority of scientific research on the brain and behavioral impact of enriched environments is being done in laboratory animals, and neuroscientists are typically cautious about connecting the dots back to humans and making broad recommendations for two-legged mammals based on results in the four-legged variety.  Still, at least at the cellular and molecular level, human brains and rodent brains are remarkably similar.  As Dana Alliance member Marilyn Albert, director of cognitive neuroscience at Johns Hopkins, points out, the rationale for looking at animals in the first place came from human studies that suggested physically and mentally active lifestyles afford health and brain benefits.

“There have now been a number of large epidemiological studies, involving many thousands of people in many locations around the world, and they keep coming up with the same findings,” says Albert.  The strongest human data, she says, come from studies identifying predictive factors of cognitive maintenance in normal aging and delay of onset of Alzheimer’s disease.  In these areas at least, the animal data have supported the conclusions from human studies.

Unraveling Mechanisms
Importantly, the animal studies, coupled with the sophisticated tools of modern neuroscience – molecular biology, gene screens, and cellular imaging among them – have enabled scientists to tease apart the physiological mechanisms involved, a critical step to developing targeted therapies that might enhance or mimic specific brain processes.

“The importance of the animal studies is that they give you a sense of what the underlying mechanisms might be,” says Albert.  “To me, it’s the combination of the human data with the animal models that makes you think there is something meaningful to the findings.”

William Greenough, a Dana Alliance member and director, Center for Advanced Study at the University of Illinois at Urbana-Champaign, has been studying animals raised in enriched environments for three decades.  “I think the weight of the evidence in both animals and humans says that complex, demanding interventions that force one to both learn new things with intention and to be physically active have enormous potential therapeutically, particularly for nervous systems that are somewhat debilitated either because of age or pathology,” he says.

The next hurdle is to prove the findings in well-controlled clinical trials – a high hurdle, given the recent history of large clinical trials that have contradicted the findings of epidemiological results (the Women’s Health Initiative has taught this lesson repeatedly, for example).  And while researchers obviously can’t strictly mimic animal EE studies in humans – keeping people in cages full of toys, friends, and exercise equipment, and then systematically examining their skills and their brains, just isn’t possible – a few pioneering scientific teams have begun to apply the principles of environmental enrichment to studies in human volunteers with or without neurological disease.  Such investigations are still preliminary, but early results seem to support the notion of cognitive benefits.

A Rich History
Modern-era research on environmental enrichment can be traced back to the 1940s, when the Canadian psychologist Donald O. Hebb observed anecdotally that the laboratory rats he took home and kept as pets had behavioral improvements over their littermates who remained in standard cages in the laboratory.  In the decades since, scientists have applied all manner of behavioral, anatomical, and physiological assessments to understand precisely how “enriched” animals are different. 

In the 1960s, Mark Rosenzweig, Edward Bennett and colleagues at the University of California-Berkeley found changes in neuroanatomy and neurochemistry in rats exposed to enriched environments, including a thicker and more weighty cortex.  In the 1970s, Greenough and others added to the evidence, finding greater synapse density, glial cell proliferation, and structural changes in nerve cells including increased dendritic branching.  In the 1990s Alliance member Fred Gage, Professor at the Laboratory of Genetics at the Salk Institute, and his colleagues showed that enrichment also increases the survival of new nerve cells in the hippocampus.

The findings have evolved in line with the evolution of molecular techniques and tools to study brain tissue.  Scientists can now track changes in gene expression for neurotrophic factors and neurotransmitters, the brain chemicals that support and nourish neurons and help them communicate with one another.  Recent studies, for example, have found increases in levels of acetylcholine, a neurotransmitter involved in cognition, and in the neurotrophins BDNF (brain-derived neurotrophic factor), GDNF (glial-derived neurotrophic factor) and NGF (nerve growth factor) following environmental enrichment.

What Matters Most?
One of the big questions is which aspect of the enriched environment is most critical.  The typical “enriched” cage for rodents is larger than the standard housing, and is stocked with exercise devices, tunnels, obstacles, and various toys, all of which may or may not be replaced or reconfigured periodically.  In many studies, enriched animals are housed in groups, affording them plenty of opportunities for intermingling and socialization.  Whatever the variation, the goal is to provide stimulation and challenge, with the fundamental elements being physical activity, social interaction, and mental stimulation by way of exploratory play that presumably involves some degree of experiential learning.

By no coincidence, this triad of lifestyle elements has emerged over two decades of epidemiologic research as fundamental tenets of a brain-healthy lifestyle that affords the best hope of maintaining cognitive integrity with age.  Along with minimizing cardiovascular risk factors such as hypertension, high cholesterol, diabetes, and obesity, each factor is important by itself, but the benefits are most likely additive, Albert says.

This notion was supported by a study published last year by Alliance member Carl Cotman, director of the Institute for Brain Aging and Dementia at the University of California, Irvine, and colleagues.  In it, the researchers exposed beagles of various ages to enrichment protocols that included one or more of the following: play time with other dogs; access to a variety of stimulating toys; exercise; and an antioxidant-rich diet.  Each enrichment improved cognitive skills by itself, but the combination of all four provided the most consistent improvements.

Greenough and others are trying to sort out which element of enrichment is most critical.  His team has designed studies in a model of Fetal Alcohol Syndrome that attempt to dissociate the effects of physical activity from learning, by forcing the animals to learn how to negotiate a complicated obstacle course but otherwise limiting their physical activity.  The results suggest that “exercise is good, but learning is better,” he says.  “You get more bang for the buck, both behaviorally and in terms of brain measures, when plastic brain mechanisms are engaged by using a skill acquisition task.”

In his group’s study, exposing newborn mice to alcohol kills the large output neurons of the cerebellar cortex.   “When we then rehabilitate the animals with motor skill learning, the neurons that remain gain more synapses, a change that parallels behavioral recovery,” he says.

Improved learning and memory has been a consistent finding in EE studies of animals.  In 1997, Gage and colleague Gerd Kempermann reported that rats living in complex environments were able to learn their way to a submerged platform in a standard water maze test significantly faster than rats housed normally.  Cognitive improvements correlated with increased neurogenesis in the hippocampus, suggesting but not proving a possible mechanism.  More recently, Yale researcher Karyn Frick and colleagues have shown that mice given 24-hour access to cognitively stimulating toys and running wheels for four months performed better on a water maze navigating test than non-enriched mice, and middle-aged mice seemed to reap the most benefits.

Disease-Fighting Potential?
The newest wave of EE research is investigating its potential therapeutic value in an array of brain disorders.  In the last year alone, researchers have published papers suggesting benefits in animal models of Alzheimer’s, Parkinson’s, and traumatic brain injury recovery, which build on earlier data in a longer list of brain disorders. 

For example, Dana Alliance member, professor Sangram Sisodia and colleagues at the University of Chicago reported in March 2005 that mice genetically altered to develop Alzheimer’s had lower levels of amyloid peptides and plaques following exposure to an enriched environment.  The results contrast with earlier work by Joanna Jankowsky of Johns Hopkins, who found an increase in amyloid in Alzheimer’s mice raised in complex settings.  Jankowsky’s team found improvements in memory in the EE mice, while Sisodia didn’t measure cognitive skills.  Meanwhile, Gary Arendash and coworkers at the University of South Florida have found that Alzheimer’s mice raised in an enriched environment are protected from cognitive impairment later in life. The contradictory findings point to the need for more work.

In Parkinson’s disease, two recent reports add to earlier data suggesting that EE mice may be more resistant to a Parkinson-like syndrome used as a model for the disease.  The first, by St. Jude’s Children’s Hospital researcher Richard Smeyne and colleagues, found that an enriched environment during adulthood “totally protects” mice from the Parkinson symptoms that usually result from injections of MPTP, a toxic chemical that destroys dopamine neurons.  The second, by Andreas Kupsch of Charite University in Berlin, which used a different model (6-OHDA) for inducing parkinsonism, found improved motor behavior along with increased numbers of neurons and glial cells in Parkinson’s rats that lived in enriched cages for seven weeks.

In an animal model of Traumatic Brain Injury, a team of German researchers led by Marc Maegele found that placing rats into an enriched environment immediately after TBI effectively reversed motor and cognitive dysfunction, compared to controls.  The effects were even greater when EE rats also received multi-modal sensory stimulation.

Earlier reports have shown benefits of environmental enrichment in animal models of Huntington’s disease, epileptic seizure, stroke recovery, cocaine and amphetamine addiction, and lead exposure.

Given the growing literature suggesting a therapeutic benefit, why don’t we see more “EE therapy” for humans?  “Good question,” says Greenough, who adds that “people are moving in that direction.”  Many organizations serving older people, he points out, have recommended that people “keep your body alive and your mind alive.”  The Alzheimer’s Association, for example, has launched an initiative called “Maintain Your Brain,” which encourages physical activity, mental stimulation and social interaction, as well as the prevention of cardiovascular risk factors, as strategies to preserve cognitive health.  The AARP, in collaboration with the Dana Foundation, have “Staying Sharp,” a program that encourages brain health through lifelong learning and other cognitive enrichments.

Tango Anyone?
A few controlled studies are applying what might be called “enrichment” to humans and tracking the effects on behavior and, to a lesser extent, the brain.  Albert points to an ongoing study at Johns Hopkins led by Linda Fried, in which older adults volunteer to mentor young students in public schools, which increases the volunteers’ social, physical, and cognitive activity.  Preliminary results have found improved cognitive skills in the volunteers compared to those on a waiting list for the program, and the analysis of benefits is continuing.  A small subset of the active group has undergone functional MRI (fMRI) scans, which according to Albert, have shown increased brain activity in areas of the brain linked to attention. 

And in the newest twist, Patricia McKinley of McGill University found that older adults who learned the Argentine tango, which combines social interaction with physical exercise and mental challenge (learning complicated dance steps), had better cognition and were better able to perform day-to-day tasks than controls. Previous reports have linked cognitive improvements with group dance lessons, and it’s possible that other activities that involve skill learning and exercise in a social setting – tai chi, for example – may afford similar benefits, Albert hypothesizes.

Several research groups are looking at physical activity alone, which is emerging as a critical factor in brain health.  Art Kramer at the University of Illinois at Champaign-Urbana has reported cognitive improvements among older adults involved in a cardiovascular fitness program.  Functional MRI scans of the volunteers identified increased activity in the hippocampus, a brain structure involved in memory and learning.  Michael Zigmond at the University of Pittsburgh has begun a clinical trial to assess whether a structured exercise program can help people with Parkinson’s, as a small pilot study in humans as well as animal studies have suggested.

A Looming Crisis of Cognition?
With America’s – and indeed the world’s – population aging, cognitive health and maintenance is beginning to assume a more prominent role in public health messages.  The National Institutes of Health has just released an initial report from its Cognitive and Emotional Health Project detailing the evidence for “predictive factors” for maintaining cognitive faculties and setting a roadmap for future research.  The Centers for Disease Control and Prevention is also joining in, with the initiation of a public health program that aims to translate scientific findings into strategies people can use to preserve and protect brain health.  These initiatives, along with recognition of the increasing toll memory loss and brain disorders take on health, society and individual families, are likely to fuel a new wave of research about how we can enrich the environment we live in for better brain health.

Published in 2006