Unraveling the neural basis of female aggression and dementia-related aggression: a systems biology approach.

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Project Summary Males and females elicit aggressive behavior for resources and survival. Male aggression has been well studied in many species. However, not much is known about female aggression. I identified a small female-specific subgroup of cells in the pC1 brain region (pC1α neurons), that triggered females to fight at extremely high intensity levels when activated. My work serves as a “point-of-entry” to map out the rest of the circuitry that governs female aggression. Aim 1 will continue to map pC1α neuron circuitry. My independent research program will incorporate novel genetic and computational tools that I learned during my K99 phase and will continue interrogating the neural circuitry underlying female aggression in health and disease. Severe behavioral disturbances of aggression and agitation have been reported to be increasingly common during the progression of Alzheimer's disease and other related dementias. The reasons for this are completely unknown. Moreover, there is a dearth of understanding of how changes in neurons, during neurodegeneration, lead to specific behavioral defects. Aim 2 will address what happens to aggression in the early and late stages of neurodegenerative disease. I will shift my focus to looking at aggression in neurodegenerative disease models and begin my efforts by elucidating the contribution of neuronal protein aggregates of Aβ-42 to aggression. Based on my preliminary findings, I hypothesize Aβ-42 overexpression induced aggression is due to altered excitability of key aggression promoting neurons. I plan to use diverse and integrative systems approaches (learned from my mentored phase). I will lead a multi-pronged research effort to understand the mechanisms by which neurons regulate their normal function or in the presence of a neurodegenerative disease state and how these changes affect circuit pathways and ultimately aggression. I anticipate that our studies will uncover novel principles of brain function and also provide a platform for developing therapeutic targets that can mitigate disease-related behavioral deficits. McLean Hospital and Harvard Medical School will provide the necessary resources and support, and offer an ideal environment for carrying out the proposed project and establishing an independent research program.