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Optogenetic functional MRI
Recent work has revealed that optogenetic strategies, using activation of channelrhodopsin-2 (ChR2), a light-gated cation channel, as well as other opsins can be employed with functional magnetic resonance imaging (fMRI) to evoke blood oxygenation-level dependent signals in the rodent. Leveraging optogenetic fMRI we, as well as others, have shown that activity is observed locally and downstream of the light activated target in a brain wide network with known anatomical connections to the driven site. Using behavioral manipulations combined with optogenetic control we sought to understand functional connections between regions, and highlight response properties in parts of the network unstudied so far. This approach, when combined with whole-brain functional imaging provided initial insights into the neural underpinnings of perception and goal-directed behavior. Further, in this project we established the precise protocols necessary to carry out awake behaving mouse fMRI combined with optogenetic control and external sensory stimulus delivery as well as detecting mouse behavioral responses. Together, this work set the stage to conduct behavioral studies combined with optogenetic control with whole-brain high-resolution fMRI.
The research program was designed so we will be able to make progress in parallel on all aims. All the goals required development of technologies which we have made progress according to the proposed outline. In the following summary of the results the different technologies developed and state of experimentation using them is described.
Several basic technologies were required to allow awake mouse fMRI, an approach adopted by only a handful of laboratories across the world. We developed a specialized cradle allowing us to restrain the animal in the MRI while still being able to attach surface and phased-array receive coils for high-resolution imaging. Further, this cradle allows to input sensory stimuli and apply optogenetic (fiber-optic driven light to the brain) control and record the animal's responses and collection of reward. Specifically, we developed visual stimulation procedure, non-invasive optogenetic drive of the facial nucleus to control artificial whisking, effectively allowing somatosensory stimulation, and an olfactometer combined with non-invasive sniff detection. The mouse responses are recorded via a lick detector and reward is provided via a port on the lick detector. Finally, we developed a holographic-based light delivery system allowing patterned optical brain stimulation. In parallel we have accommodated previously used acclimation protocols and were able to image a head-restrained animal in baseline levels of stress for over an hour on mulitple occasions and across a period spanning weeks to months. Using these methods we acquired whole-brain high-resolution maps of the entire somatomotor system in awake animals, and recorded basic perceptual detection behavior in the MRI.
The core achievements of the project: (1) We developed and validated a full platform to carry out whole-brain imaging at high-resolution (150 μm × 150 μm × 300 μm) of a behaving mouse; (2) We demonstrated a strict structure-function relation of sensory regions, identifying a core feature of mammalian cortical organization with implications to understanding the role of association regions and hippocampus in sensory processing. These results demonstrate the utility of whole-brain imaging using fMRI to understanding the basic neural mechanisms underlying perception and more broadly as a complementary tool for optical and electrophysiological techniques.

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