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Abstract

Introduction: The level of norepinephrine (NE) in the brain modulates a variety of cognitive processes such as attention, perception, learning and memory. Accordingly, 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. The LC phasic response to a salient stimulus is thought to beneficially contribute to attention, working memory, or behavioral flexibility by affecting the prefrontal NE neurotransmission [1-4]. Recently, some advances have been done on the study of the effects of phasic NE release on the responsiveness of mPFC cortical areas; although to have a more complete understanding of the widespread projections of LC we will need a multimodal approach. Here we set out to investigate the effects of LC phasic discharge on ongoing and sensory-evoked cortical activity, by combining LC direct electrical stimulation (LC-DES) [5] 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 norepinephrine modulation. Methods: We have begun to study the effects of ongoing cortical state in prefrontal (mPFC) and somatosensory (S1) cortex during NE manipulation. Specifically, in a series of experiments, we stimulate the LC (directly through DES or indirectly through foot shock, FS) while recording its responses in the mPFC and S1 cortices. The activity of the NE system is expected to strongly contribute to the modulation of the cortical state [6]. Cortical recordings are used to determine both the network state prior to stimulation and the neurophysiological responses to FS or LC-DES. The fMRI combined with electrophysiological recordings and microstimulation capitalizes on previous approaches conducted in the lab [7] and is continuously optimized for the specific requirements of this project. Results: 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 [8] in the 5-sec interval preceding stimulation. In Fig.1 it is plotted the distributions of a lower (a) and a higher (b) synchronization index for the same FS condition. Subsequently, we looked at the associated FS response dependency on cortical synchronization. Fig.2 shows the Z-score of the BOLD time course difference between the SI distributions of Fig.1 (a) and (b). 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). Fig.3 shows the fraction of positively and negatively activated regions of interest (ROIs) for the same LC-DES condition averaged over sessions.