Aging and neurodegeneration
In the Kahn lab, we use animal models to study brain changes that occur in normal aging, as well as in neurodegenerative disorders. As we age, natural changes in the brain lead to a level of normal and expected cognitive decline over time. However, a subset of individuals will develop neurodegenerative disorders in old age that present a much more rapid and severe decline in cognitive ability.
High-order cognitive processes and goal-directed behavior in learning and memory
The lab studies high-order cognitive processes supporting learning and memory, with a focus on active sensing mechanisms as a way to understand the underlying processes. We use olfaction in mice as a model to study active sensing and have developed an experimental setup to monitor sniffing behavior non-invasively in behaving mice to examine brain-wide responses during learning.
Motor behaviors
The ability to learn and perform goal-directed, motor actions is essential for adaptive behavior and survival. Efforts to dissect motor function suggest dissociable roles for basal ganglia and cerebellum. The current consensus view is that the former reinforces goal-directed actions while the latter refines actions using error signals. Each circuit has been thoroughly studied, yet an understanding of how reward-related signals dynamically modulate the contributions of these circuits is lacking.
Neural mechanisms underlying flexible decision-making
A baseball player who takes a risk by swinging at a bad pitch in an early inning would likely not swing at the same pitch when the game is on the line. How does the brain perform such context-dependent associations between sensory stimuli and motor actions?
Over the past two decades the most important revolution in human brain research took place due to the availability of non-invasive imaging methods allowing to evaluate the structure and function of the brain. Structural imaging using magnetic resonance imaging (MRI) allows us to assess structural changes that occur as the brain develops when we are young and deteriorate as we age. When disease processes attack the brain, atrophy or other structural changes occurs at a rapid rate. MRI allows us to precisely assess these changes. Further, it is now possible to measure the activity of brain cells using functional MRI (fMRI). Brain cells compute and communicate using electrical signals. This activity requires oxygen, the brain’s energy source, and the intricate and precise supply of oxygen to the brain can be measured with fMRI, providing us a map of brain activity.
In the lab we seek to understand the relation between the brain’s structure and function in health and disease. We aspire to understand how brain structure and activity give rise to various aspects of behavior. To that end, we use fMRI in humans and mice to understand the basic principles of brain function as well as detect brain regions that are not working normally, follow them carefully and try novel first-in-class therapeutic approaches to alleviate brain disorders.
We measure activity in multiple brain systems simultaneously, looking at the interactions between regions of the brain. We attempt to characterize changes in activity that can be used to identify populations or individuals at risk. Namely, we look for changes that precede and predict diseases. In doing so we open a time window for prevention and/or early therapeutic intervention programs that may benefit people that seem to be on a trajectory to develop a brain disorder.
Although using MRI in humans allows us to develop approaches to diagnose brain pathologies, it is not sufficient to help us understand the underlying mechanisms of the biological processes in health and disease. This is because MRI and other tools available to use in humans are too crude to measure pathological changes (for example, deficiency in proteins the brain needs for normal function or toxins killing brain cells). In order to understand what goes wrong we need the tools of cellular biology. Such tools can only be used in animals. Currently, the lab mouse is the primary animal used in biomedical research. Studying mice we can figure out the biological mechanisms in detail. Moreover, many findings from studies concerning the mouse brain (but not all) give us insight about brain structure and function of all mammals and particularly to humans.
In summary, our approach is to first diagnose disruptions or pathologies in humans using fMRI. Then, using fMRI in mice that we engineered to have the pathology of neurodegenerative diseases or that are old, we are testing whether they show the same phenomenology found in humans. For the phenomena that are well replicated, we now use systems neuroscience tools (electrophysiology, cellular imaging, pharmacology, etc) to develop therapeutic targets and test them.
We aspire to advance both the field of medicine and neuroscience. Our hope is that the research conducted in our lab will:
- Advance the understanding of the biological processes that take place in the brain, from genes to behavior.
- Help find and define specific signatures of various brain pathologies to enable a diagnosis that relies more on objective measurements rather than on reported symptoms.
- Develop diagnostic imaging approaches that will open opportunities for prevention and more meaningful intervention programs.