Supported Projects

Centralized alignment database

We will develop a centralized database to integrate data produced by the various Simons Collaboration on Plasticity and the Aging Brain projects. This type of database is essential because different species and individuals within a species follow different trajectories of brain aging, and researchers need a reference framework to link them. The framework we develop will include surface features of aging, such as life span, behavior, and gross morphological and functional changes, as well as deep features, such as shifts in cell states, emergence and attenuation of signaling pathways, and accumulation of underlying genetic and cellular damage. The overarching goal is to develop a database and interfaces that align knowledge about brain aging across model systems and humans.

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Conserved regulatory pathways in age-related loss of plasticity and cognitive function

As we age, our ability to learn and remember starts to decline, even in the absence of age-related dementia. We haven’t identified the critical molecular changes that occur in the aging brain or how these changes affect plasticity, the brain’s ability to rewire its connections. To develop interventions to slow or reverse this decline, scientists must first characterize these changes at the molecular and cellular levels and identify the key genes that regulate these processes in the brain. Both of these tasks are challenging. We will leverage the genetic similarities between humans and many different organisms, ranging from worms to fish to mice to nonhuman primates, to examine how these organisms’ ability to learn, a behavioral measure of plasticity, changes with age. This approach can identify a set of core hubs of plasticity in the aging brain that are conserved across species, as well as species-specific changes. We will assess how much these regulators are conserved across different cell types, across individuals of the same species and across species. The promising potential therapeutic targets are those that are shared across species, and using multiple model systems and integrating the information across species will yield information that is greater than the sum of the individual systems.

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Discovering neural underpinnings of age-related changes in perceptual and value-based decision-making

Our ability to learn, remember and make decisions changes with age. Older mice, for example, take longer to learn new tasks and don’t perform as well as their younger counterparts. We aim to discover how the neural circuits that support learning, attention and decision-making evolve with age and how these changes contribute to age-related changes in behavior. Our hypothesis is that many age-related differences in behavior and learning capacity arise not from neurodegeneration but from active remodeling of neural circuits. To test this hypothesis, we will track age-related changes in mice all the way from gene expression to complex behavior. We will use an automated system to characterize spontaneous behavior and to measure learning and expert performance on two complementary tasks that have already been thoroughly tested in young adult animals. Next, we will measure and manipulate neural activity in both cortical and subcortical structures to determine which brain areas mirror changes in behavior and when these changes are most prominent during the life span. We will also track the synaptic, cellular and wiring changes that occur in these brain areas during healthy aging. In addition to exploring neural changes, we will examine how glial cells contribute to age-related decline. Previous research in our group has shown that a set of genes active in glia may drive some of these changes. We will determine if silencing these genes can prevent age-related decline in learning and decision-making. Taken together, these approaches will greatly advance our understanding of the neural underpinnings of age-related changes in synapses, circuits and behavior.

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Glial mechanisms by which sleep preserves cognitive function and plasticity in aging

Aging is accompanied by a striking reduction in deep sleep and sleep structure. Because sleep plays several essential roles in the brain, loss of sleep with age may contribute to cognitive decline — for example, sleep loss predicts individual memory ability in older adults. During sleep, glial cells and the lymphatic system help remove metabolic waste that accumulates in brain cells when we’re awake, reducing inflammation and restoring a healthy neural environment. Sleep is also crucial for regulating neural plasticity. During wakefulness, the size and number of synapses and overall excitability in the brain rises. Sleep restores the baseline and prevents the brain from becoming hyperexcitable.

It’s unclear exactly how age-related sleep decline disrupts cognitive function. We hypothesize that worsening sleep quality impairs waste removal, triggering low-grade neuroinflammation, slowing the birth of new brain cells and dampening synaptic plasticity. Our collaboration will identify how glial function during sleep changes with age in fish, mice and humans and how these changes influence inflammation and neural plasticity. We will determine if improving the quality of sleep and enhancing glial waste-removal systems makes animals more resilient to age-related cognitive decline. We will search for mechanisms that impair waste removal and determine how modulating these mechanisms influences plasticity, memory and the birth of new neurons. The results will highlight potential biomarkers that can be used to assess sleep-related damage with age, as well as targets for slowing sleep-related cognitive decline.

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Linking molecules, circuits and behavior to promote plasticity and memory in the aging brain

Advances in disease prevention and therapeutics have enabled humans to live longer than ever before. We now face the challenge of increasing health span in a comparable manner. How can we help people maintain the normal mental function needed to support multifaceted, independent lifestyles for as long as possible? The cognitive changes that develop with normal advanced aging are poorly understood, and we currently lack effective therapies to slow decline. We know that age-related changes in the brain occur at the molecular, circuit and behavioral levels, so we must investigate each of these scales and understand how changes at one level relate to changes at others. We aim to understand the links between molecular, circuit and behavioral alterations that occur with age, with a longer-term goal of developing effective treatments that will help maintain cognitive function during aging.

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Male Human Sex Chromosomes X and Y (Pair 23), scanning electron micrograph (SEM). There are 23 pairs of chromosomes in most normal human cells. These are allocated pairs 1 - 22 with pair 23 being the sex chromosomes, either xx for females and xy for males. Magnification x17500 at 10 cm wide.
Sex-specific differences in cognitive and brain aging

The world’s population is rapidly aging. Age-related cognitive decline is a major biomedical challenge with no effective medical treatments. However, aging affects men and women differently on average — most women live longer than men worldwide and in many populations appear to experience less cognitive decline and to lose less brain tissue over time. However, many women undergo dramatic loss of sex hormones compared to men, which may make their decline different from men’s. Sex chromosomes and sex hormones are likely involved, but the exact mechanisms that underlie these fundamental differences in brain aging and cognitive decline — both between the sexes and within each sex — remain largely unknown. Understanding what makes one sex more vulnerable or resilient to aging will reveal novel targets for treatment that could benefit everyone.

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Understanding how bloodborne factors improve the function of the aging brain

Cognitive function declines with age, reflecting a complex and interrelated set of changes in neurons, neural stem cells, glia and vascular cells. This complexity presents a formidable challenge to neuroscientists studying the aging brain. However, a series of surprising observations has provided an exciting path forward. We have discovered that blood contains proteins that can restore some age-related cognitive decline. For example, giving old mice factors found in young blood can enhance the birth of new neurons, which typically slows with age. Blood proteins from younger animals can also restore declining blood vessel function in older animals, improving blood flow and the delivery of key nutrients to brain cells.

We have identified several different components in blood that have this effect, each of which appears to act differently. Certain factors appear to cross the blood-brain barrier and bind directly to receptors on neural and glial cells. Other factors may act on vascular cells, boosting neural function via better blood flow or by increasing the vascular system’s secretion of neuroactive factors.

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