Abstract:
Brain states, which indicate degrees of arousal during wakefulness, sleep, or anesthesia, have been long investigated over the last decades. The dynamics of distinct brain states are conserved across different species of animals and tightly linked to physiological be- haviors (e.g., pupil size modulation) and specific brain network activity. Both pupil size and brain states are substantially regulated by neuromodulators originating from the brainstem and subcortical structures through interactions with the cerebral cortex, partly sharing common regulatory pathways. For this reason, pupil size and neuronal activities of arousal-regulating brain regions demonstrate high correlations. However, the correlation emerges with high variability across recording trials, indicating a possible involvement of complex pupil- and brain state- regulatory pathways, including brain re- gions of the lateral hypothalamus (LH) and anterior cingulate cortex (ACC) that could induce the varied correlation properties. In this dissertation, I aim to shed light on neural pathways regulating the brain state and pupil size variations using a multi-modal experimental design in three research protocols. The first goal was to demonstrate a platform to bridge the fields of functional magnetic resonance imaging (fMRI), pupil- lometry, and fiber photometry neuronal Ca2+ recordings in anesthetized animals and evaluate brain state dynamics from across-scale recordings. Using the information from Ca2+ signals, we first distinguished different brain states. In each of these brain states, different correlation features between fMRI signal and pupil size changes appeared, e.g., strong positive correlations in the A5 region where noradrenergic neurons are located. The second goal was to assess cross-scale brain dynamics in electrophysiology, fMRI, pupillometry, and fiber photometry Ca2+ recordings for specifying different brain states under anesthesia based on the lateral hypothalamic (LH) activity. Across multi-scale recording trials, both local field potential (LFP) and fMRI signals detected in the LH presented distinct brain states with consistent distribution patterns of positive and neg- ative correlations with pupil dynamics. The association of different pupil dynamics to a distinct brain state was further verified by neuronal activity coupling between the LH and anterior cingulate cortex (ACC), indicating the LH-ACC circuit-specific regulation of pupil dynamics. The third goal was to demonstrate the properties of the LH regarding pupil size and brain state regulations using optogenetics, pupillometry, and electrophys- iology. Optogenetic stimulation of the LH in anesthetized animals evoked pupil dilation and LFP delta power reduction. These changes showed an exponential relationship with respect to the stimulation frequency. Moreover, the exponential feature was observed only under one specific underlying brain state for LFP delta power reduction but under all brain states for pupil dilation. These observations suggested that the LH mediates pupil size independently of the underlying brain state variations. Overall, these studies identified several important features of pupil-regulatory circuits underlying brain-state transitions under anesthesia. The complex signal interdependence shown here indicated that the brain state is orchestrated in multiple regions (especially the LH and ACC) and at multiple scales (frequency and amplitude of neuronal firing, inter-region corre- lation with pupil size, neurovascular coupling, etc.). This dissertation presents a novel way to track brain state transitions by connecting pupillary signals and their variable
relationship with the whole brain signal and offers a reference framework to understand the LH-ACC relationship. We demonstrate that LH/ACC activity provides a strong indication of different vigilance levels and may become a useful approach to evaluate the ongoing brain states in arousal-related clinical research.
Brain states
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