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Brain-wide signatures of visual experience in development and disease
L'Esperance, Oliver James
L'Esperance, Oliver James
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Abstract
Sensory dependent changes in neuronal function are often investigated via cellular resolution measurements on a local scale (voltage changes, calcium flux reporter fluorescence) or at lower resolution on a brain-wide scale (functional magnetic resonance imaging, positron emission tomography). However, leveraging immediate early gene expression allows for brain-wide investigation of neuromodulation at the microscale, avoiding the tradeoff between resolution and measurement area common to other methods. Here, we employ multiple approaches to label neurons expressing c-Fos, a widely expressed immediate early gene with sensitivity to sensory stimuli, in the presence and absence of visual experience. Using a newly developed pharmacogenetic system, we label the somata and presynaptic termini of c-Fos-expressing neurons across the brain during normal visual experience or visual deprivation at initial eye opening in developing mice. With high-resolution multiphoton imaging and microscale voxel-wise analysis, we show that the c-Fos-expressing neurons and their presynaptic termini are modulated by visual experience versus its absence in areas far beyond the initial visual relay system. We also find that visual experience-modulated somata and termini tend to lie in different brain regions, highlighting the utility of parallel screens to differentiate areas with cellular versus synaptic modulation. We additionally investigate brain-wide visual experience-dependent c-Fos protein expression and functional network alterations in an amyloidosis mouse model of early Alzheimer’s disease. In non-pathological mice, visual deprivation induces widespread increases in c-Fos expression and sharp increases in functional connectivity, phenomena that are both stunted in Alzheimer’s disease model mice. In non-pathological mice, the primary visual cortex features a high degree of functional connectivity to other brain regions, a factor that correlates with aberrantly dense c-Fos expression during normal visual experience in Alzheimer’s disease model mice. In these mice, the visual cortex additionally shows neuromodulation deficit during visual deprivation and excitatory cortico-cortical presynaptic terminal loss. We additionally show that the relationship between a region’s degree of functional connectivity and its vulnerability to c-Fos hyperexpression during normal visual experience and reduced modulation capacity during visual deprivation are both generalizable across the brain.
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Date
2025-05-31
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University of Kansas
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Keywords
Neurosciences, Alzheimer's disease, c-Fos, functional connectivity, presynaptic terminals, visual experience, visual system