Multiscale physiology and causal mechanisms of slow network fluctuations

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ABSTRACT: The overarching goal of Project (P) 3 is subsumed under Center Aim 3: Advance the physiological interpretation of macroscale findings using meso- and microscale measures in humans and NHPs. To do so, P3 will rely on NHPs as an animal model system to inform the interpretation of human macroscale neuroimaging (P1) and mesoscale intracranial recording studies (P2) and the biophysical modeling (P4). NHP work will provide, 1) simultaneous scalp EEG/fMRI, behavioral-cognitive and autonomic data under three common tasks and conditions: intermodal attention, movie watching and rest, 2) brush and laminar array recordings to define the microscopic cell circuits and physiological processes, and 3) targets for chemogenetic manipulation. Aim 1 will link the macroscale measures of P1 meso- and microscale physiology of slow brain network fluctuations (SBNFs), by defining SBNFs across distributed brain areas, including both the interoceptive system and a classic exteroceptive system, the thalamocortical auditory system. Proposed studies will include simultaneous recordings from multiple sites within and across task positive and task negative networks. This will allow testing the hypothesis that SBNFs entail opposing unit and LFP activation levels in task positive and task negative networks, with the anterior insular cortex a key site associated with SBNF network switching from ‘restive’ to more task engaged activation patterns. Aim 2 will define processes and structures triggering and modulating SBNF dynamics. Here, we will first pharmacologically increase arousal via Methylphenidate as a direct link to human studies in P1. We will also electrically stimulate the Vagus Nerve which impacts on neural networks including cholinergic and dopaminergic system and the interoceptive system. Finally, after initial range-finding studies using electrical µ-stimulation, we will conduct reversible chemogenetic inactivation of anterior insular cortex (AIC) projections to the anterior cingulate cortex (ACC) and nucleus basalis (NB) to test hypotheses on the roles of these pathways in control of SBNF dynamics. P3 will provide crucial information from neurophysiological neuronal recordings to EEG and fMRI informing the detailed cell-circuit and network modeling in P4 and the human studies in P1 and P2.