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Abstract

We performed a whole-brain fMRI imaging in the rat under urethane anesthesia and studied BOLD responses induced by electrical stimulation of the brain stem noradrenergic nucleus Locus Coeruleus (LC). The rat was implanted with a MRI-compatible custom-made iridium electrode into LC under electrophysiological guidance. A 7T (300 MHz) magnet with a 30-cm horizontal bore (Bruker BioSpec 70/30, Ettlingen, Germany) equipped with a 20cm inner diameter gradient (Bruker BGA-20S Ettlingen, Germany) was used for MRI scanning. The experimental paradigm consisted of 6s baseline sampling, followed by 4s of unilateral LC stimulation and 10s of post-stimulus sampling. Biphasic square pulses (0.05-0.4mA) were delivered to LC at 20-100Hz either continuously for 4s or grouped in 100-500ms trains. These stimulation parameters were efficient in eliciting LC burst firing bilaterally. We also collected BOLD responses induced by peripheral sensory stimulation in the same animal and using the same experimental design (6/4/10s). For visual stimulation we used a luminance flicker presented to both eyes at 16Hz and delivered via fiber optic cables. A mild electrical stimulation (1-5mA) of a forepaw was used as somatosensory stimulation. The fMRI images were collected with spatial resolution of 0.4x0.4x1.0mm and temporal resolution of 1s. BOLD maps were generated by using GLM with standard (HRF-convolved boxcar functions) or neural regressors. We observed a remarkable dichotomy between BOLD responses of cortical and subcortical structures. Specifically, LC stimulation produced positive BOLD responses in the majority of structures belonging to metencephalon, mesencephalon and diencephalon, while negative BOLD responses in the entire neocortex. The robust neuronal activation in thalamic projections of LC was further confirmed by electrophysiological recordings. The cortical inhibition as a result of LC stimulation and associated NE release in cortical targets of LC has been reported in earlier studies. The peripheral sensory stimulation evoked both sensory-specific and non-specific activation/deactivation pattern. Strikingly, the regions of non-specific BOLD responses were common for both sensory modalities and largely overlapped with brain regions that showed responses to LC stimulation. We hypothesize that sensory stimulation activates modality-specific sensory pathways along with LC-NE system; and the LC co-activation produces the observed non-specific BOLD responses.