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Application towards Neurological
Disorders and Disease

Adult neurogenesis occurs broadly across animals including humans, both as a natural process and as a response to damage or disease. Aberrations in adult neurogenesis are tightly associated with mental disorders, which themselves can manifest independently or in conjunction with other neurodegenerative diseases. Mental disorders cost nearly $2.5 trillion each year and account for ~10% of the global burden of disease. Yet, there has been stagnation in the development of new drugs to combat such disorders. This likely reflects a limited repertoire of model systems and a near-exclusive focus on neurons rather than the many supporting cell types that contribute to circuit integrity and function. Progress in understanding and treating mental disorders could benefit from a paradigm shift away from a “rodent neuron-centric” view towards a holistic view that embraces promising non-traditional models and the complex orchestration of neural plasticity and function across cell types.

To understand mechanisms underlying plasticity in cellular composition and resulting impacts on behavioral motivation and performance, we exploit the natural, robust changes in cellular content of the adult songbird brain. Songbirds have a unique ability to regenerate a brain region responsible for song learning and production, called “HVC”. In the spring, when day length is long, the gonads increase testosterone synthesis, which promotes the addition of new HVC neurons and astrocytes. As HVC adds neurons, songbirds increase the quantity and quality of singing to attract mates and defend their territories9. In autumn when day length decreases, the gonads decrease testosterone production, a large number of HVC neurons die rapidly, and birds stop singing. 

Using Gambel’s white-crowned sparrow (Zonotrichia leucophrys gambelli) we investigate: i) the role of astrocytes in stabilizing song circuit architecture and function following degeneration and regrowth using surgically targeted infusions of pharmacological inhibitors, ii) the cellular and molecular mechanisms driving interactions among dying neurons, astrocytes and stem or progenitor cells using single-nuclei-RNA-sequencing with analyses to identify critical signaling within and between cell types, and iii) high resolution ex vivo imaging of the intact song circuit to observe, in live time, cellular behaviors regulating cell death, debris removal, inflammatory responses, and cellular proliferation.

Understanding how plasticity in the adult brain arrises evolutionarily and how this plasticity at cellular and circuit levels impacts behavioral outcomes is vital to developing a more holistic understanding of and treatments for mental disorders. 

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