Grant: Project Grant

Maintaining the balance between excitation and inhibition is a fundamental attribute of brain function that is necessary for information processing and higher functions, such as affect and cognition. The maintenance of this balance occurs through the constant fine-tuning of excitatory and inhibitory neurotransmission on multiple time scales, from milliseconds to weeks and months. Much has been learned about short-term functional adaptations (seconds to hours) at the cell contact level; however how the different cell types of brain microcircuits synchronize their functions on longer time-scales (weeks to months) to maintain optimal function, while allowing plasticity, is less well-known. Our data suggest a predominant role for inhibitory cells in mediating adaptive changes during brain aging. We and others show similar inhibitory changes, albeit out of synchrony or exaggerated, in the context of depression, schizophrenia and Alzheimer's disease. Hence we predict that (1) changes in gene function, specifically in inhibitory neurons, maintain long-term adaptations during life-long brain aging, and that (2) changes in the same cell-dependent gene programs occur in several brain disorders. Using molecular biology and computational methods, we will test this hypothesis directly in the human post-mortem brain, using samples from midlife and older subjects. Similar approaches will be used in rodent models to investigate mechanisms and conservation of processes across species. We will then determine the extent of changes in the same cells and pathways in the context of diseases, using human samples from bipolar depression, schizophrenia and Alzheimer's patients. This novel dimensional approach across species, lifespan and brain disorders has the potential to reveal the molecular mechanisms and rules that govern long-term homeostatic processes across the main cell types of brain cell microcircuits in health and brain diseases.