Many neurological diseases occur in the absence of neurodegenerative pathology, such as neurotransmission disorders. Deficient neurotransmission is a hallmark of many neurological diseases, such as depression, schizophrenia and autism. Moreover, deterioration in synaptic function also appears during ageing, accompanied by a decline in cognitive and behavioral function. Synaptic strength and plasticity, important in cognitive functions such as memory, are affected by synaptic activity. However, the regulators of synaptic strength, either activity-dependent or independent, are far from understood. Here, I propose to explore how environmental cues and ageing can affect synaptic morphology in the nematode C. elegans, and how this correlates to synaptic function and activity. In C. elegans, which is an excellent model for neuroscience, synaptic sites can be observed with fluorescent fusion proteins. However, fluorescently labeled synaptic sites are small and faint, and obtaining large number of high-content data poses many experimental limitations. The main goal of this proposal is to elucidate regulators of synaptic function through multidimensional morphological profiling of synaptic sites. This work is composed of a mentored and an independent research phase. During the mentored phase, I will develop tools that allow high-throughput quantitative multidimensional profiling of synaptic morphology in large populations of animals. These tools are based on combining microfluidics, automation, and computer vision methods for image analysis, which enable streamlined quantitative morphological characterization of synaptic sites. In addition to this, tools to determine synaptic function in the motor circuit through the quantification of locomotive activity and controlled stimulation of excitatory neurons will be developed to correlate synaptic morphology to function. The mentored phase will also include extensive training in various aspects: technology development, biology and neuroscience, and career development. The scientific environment at the institution of the mentored phase is highly collaborative and provides excellent support in terms of facilities and intellectual opportunities. During the independent research phase, I plan to apply the developed tools during the mentored phase to uncover how environmental cues can affect synaptic function through activity dependent or independent mechanisms. I will also utilize these tools to study synaptic decline during aging, and how exposure to environmental regulators of synaptic function during development can alter synaptic decline during aging. In this way, we will be able to address a biological question unapproachable with conventional methods. This approach is innovative not only because the technology developed will greatly increase the throughput and quality of characterization, but also because it proposes studying the links between form and function in synaptic sites. This project is significant because it will enable streamlined morphological studies in neuroscience, which should lead to uncovering pathways, genes and potential therapies for synaptic function deficiencies due to disease or age-related decline.

Public Health Relevance

Defective neurotransmission is the cause of many neurological diseases ranging from depression to autism. Understanding the regulators of synaptic strength can shed light on pathways that play a role in establishing healthy synaptic function, and treatments for neurotransmission-related diseases.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Career Transition Award (K99)
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National Institute on Aging Initial Review Group (NIA)
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Wise, Bradley C
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Georgia Institute of Technology
Engineering (All Types)
Schools of Engineering
United States
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San-Miguel, Adriana; Kurshan, Peri T; Crane, Matthew M et al. (2016) Deep phenotyping unveils hidden traits and genetic relations in subtle mutants. Nat Commun 7:12990