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. Recently, my work 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. For the K99 phase, I will build on my previous work and elaborate on the pC1α neurons circuitry under the mentorship of Dr. E. Kravitz, a well-renowned expert in aggression and Drosophila genetics. Aim 1 is concerned with determining the pre- and post-synaptic partners of the pC1α neurons. For this aim, I will work with my co-mentor, Dr. R. Wilson, to determine pre- and post- synaptic partners and design transgenic fly lines to target these areas. Based on my preliminary data of electron microscopy tracings, I hypothesize that, a)SAG neurons provide inputs to pC1α neurons; and b) pC1α neurons project dendritic outputs to PVL04om_pct neurons in areas previously identified in aggression such as Posterior Lateral Protocerebrum. I anticipate that both up- and down-stream pC1α neurons partners will induce high intensity female aggression. Aim 2 will investigate the role of candidate aggression-associated genes in pC1α neurons. I will train in single-cell profiling methods (used by the Kravitz lab) and address the hypothesis that genes overexpressed in male aggression mediating neurons also play key role in pC1α neuron function. In collaboration with co-mentor Dr. B de Bivort, I will also use neural network-based body part tracking software to train a classifier to automatically label aggressive behaviors. This will allow me to use machine-learning algorithms to capture multi-dimensional representations of the phenotypic differences among fly lines with mutations and transgenic effectors that target aggression circuits (e.g, activating and inhibiting a neuron or overexpressing aggregating proteins). The trainings acquired in my mentored K99 phase will facilitate my transition to independent research studying age-related diseases and behavior. 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. For the R00 phase, 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. My preliminary data indicates that overexpression of human Aβ-42 in using a (pan-neuronal driver) in males and (cholinergic driver) in females induces heightend levels of aggression. Based on these 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 in the presence of an aging and or neurodegenerative disease state and how these changes affect circuit pathways and ultimately aggression.

Project Narrative Aggression accompanies a number of common human neurodegenerative disorders (e.g. Alzheimer's and other related dementias), with little understanding of how cognitive and aggression symptoms may be linked at the neuronal level. Aggression has been extensively studied in males of many species, but neglected in females (likewise, the interaction of sex and age is neglected). The objective of this research program is to identify the neural circuitry that governs female aggression (K99- mentored phase) and later transition (R00- independent phase) into discovering mechanisms of dementia-related pathology and how these changes affect aggression.