Jae-Eun Kang Miller, PhD - US grants

DESCRIPTION (provided by applicant): The cerebral cortex, the primary site for our perception, memory, and language, is spontaneously active. While this intrinsic activity is often considered noise, recent work suggests that it holds a key secret for understanding cortical function. Remarkably, in thalamocortical slices the spatiotemporal patterns of spontaneous cortical activity are similar to the patterns triggered by thalamic input. This result suggests tha intrinsic cortical connectivity primarily drives the pattern of the cortical response. External inpt may then release this intrinsic activity pattern. However, it is crucial to validate this model in ivo where entire brain circuits are intact. The proposed Aim 1 will determine the spatiotemporal patterns of spontaneous cortical activity in the intact brain. Determining the pattern of spontaneous activity in vivo will be a starting point for future studies dissecting the microcircuiry that generates and modulates this activity. Aim 2 will address how the spontaneous activity pattern is related to the cortical response to sensory input. To achieve these aims, we will utilize a head-fixed mouse on an air-floating spherical treadmill to image neural activity in awake behaving mice. We will use fast two-photon calcium imaging to measure the activity of large populations of neurons in vivo with unprecedented precision. To deliver external inputs, visual stimulation will be generated in Matlab using the Psychophysics Toolbox. This work will help to distinguish between two views of the cortex: either primarily driven by external inputs or primarily driven by internal circuitry. This will be an advance in basic neuroscience and also relevant to human disease. As the site of so many of the brain functions that humans hold dear, the cortex is also the target of many devastating neurologic and psychiatric diseases. By increasing our understanding of cortical function, this project will help lay the foundation for understanding the cortical dysfunction that underlies so much human suffering.

DESCRIPTION (provided by applicant): Experience-dependent plasticity is a prominent feature of the sensory cortices and occurs throughout one's lifetime by a variety of sensory experiences. Investigating the neural mechanisms of perceptual learning will enhance our understanding of plasticity in the adult brain and provide novel insights into learning disabilitie. Although the functional advantage is obvious, precisely what kinds of neural changes lead to improved perception is still under debate. The proposed career development plan aims to gain fundamental insights into the neural network-level mechanisms of visual perceptual learning, while establishing an independent academic career in a university setting. The candidate has considerable experience studying cortical function in awake behaving mice monitoring patterned activity in hundreds of neurons simultaneously using advanced optical techniques. She now proposes to undergo new training in rodent behavior and cutting-edge optical stimulation tools, to reach her long-term goal of becoming an independent scientist studying network-level plasticity in the adult cortex in healthy and diseased states. She will carry out the mentored phase under the guidance of Dr. Rafael Yuste, a world expert in developing optical methods and applying them to investigation of the structure and function of cortical microcircuit. Using two-photon calcium imaging to measure network activity from hundreds of neurons simultaneously in the primary visual cortex of awake mice, the candidate recently discovered that specific visual stimuli evoke distinct sets of neuronal ensembles and these ensembles respond far more reliably to visual stimuli than individual neurons. Furthermore, the same neuronal ensembles are activated spontaneously and in response to visual stimulation, suggesting that the cortical representation of visual attributes is built out of intrinsic activity patterns. The candidate now proposes to apply novel optical imaging and manipulation techniques to understand the mechanisms of how network-level activity is modified by sensory experience. During the mentored phase, she will use fast imaging and optogenetic techniques to understand the circuit mechanisms of perceptual learning during visual stimulation as well as during spontaneous activity following a perceptual learning task. In the independent phase of the award the candidate will use these newly acquired technical skills to determine the distinct roles of basal forebrain cholinergic and GABAergic inputs to V1 ensemble activity during perceptual learning. Training in novel optical methods and rodent behavior as outlined in the research plan will equip the candidate to embark on a comprehensive and fruitful research program as an independent researcher. The proposed studies will become a foundation for future studies on adult plasticity in other sensory modalities and will provide novel insights into how learned information is encoded throughout the cerebral cortex.