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Abstract:
The level of norepinephrine (NE) in the brain modulates a variety of cognitive processes such as attention, perception, learning and memory. Stimulation of the Locus Coeruleus (LC), the major source of NE in the forebrain, can change spontaneous and task-related neuronal discharge in a large number of LC projection-targets. Few advances have been done on the study of the effects of phasic NE release on the responsiveness of mPFC cortical areas. In order to have a more complete understanding of the widespread projections of LC we need a multimodal approach. Here, we investigate the effects of LC discharge on ongoing and sensory-evoked cortical activity, by combining LC direct electrical stimulation (LC-DES) with multisite extracellular recordings and whole-brain fMRI in rats under anesthesia. The combination of these methods allows the acquirement of a richer dataset which carries unique insight into the mechanism of large scale NE modulation. The aim of this project is to combine multi-site extracellular recordings, DES and functional MRI techniques in an attempt to define brain “states” and their conditional probabilities with respect to the LC activity level and salient external events. The activity of the noradrenergic system is expected to strongly contribute to the modulation of the cortical state [Neuron 69:1061-1068, 2011]. The cortical recordings, from mPFC, are used to determine the network state prior to sensory stimulation and the neurophysiological responses to sensory stimuli with or without LC stimulation. In order to characterize the different cortical states induced by the anesthesia level and classify its maps accordingly, we computed a cortical synchronization index (SI) proxy [J Neurosci 29: 10600-10612, 2009] using the baseline preceding stimulation. We obtained representations for the distributions of a lower (a) and a higher (b) synchronization index during the same foot-shock (FS) condition. Subsequently, we looked at the cortical state-dependent effect of the FS stimulation, which shows the Z-score of the BOLD time course difference between the SI distributions. Furthermore, fMRI maps for LC-DES have shown to produce an interesting dichotomy between BOLD responses of cortical and subcortical structures (belonging to metencephalon, mesencephalon and diencephalon cortices). Namely, they show the fraction of positively and negatively activated ROIs for the same LC-DES condition averaged over 10 sessions. This study suggests that it is possible to map the whole brain noradrenergic system by characterizing the FS or LC-DES stimuli responses and contextualize it according to the endogenous cortical synchronization state.
