@Article{ EschenkoENBML2011,
title = {Tracing of noradrenergic projections using manganese-enhanced MRI},
journal = {NeuroImage},
year = {2012},
month = {2},
volume = {59},
number = {4},
pages = {3252–3265},
abstract = {We examined the applicability of manganese-enhanced MRI (MEMRI) to the in vivo tracing of diffuse neuromodulatory projections by means of simultaneous iontophoretic injections of an extremely low, non-toxic concentration of MnCl2 (10 mM) and fluorescent dextran in the locus coeruleus (LC) in the rat. We validated the use of the iontophoretic injection by reproducing previously reported results from pressure injections of MnCl2 in primary somatosensory cortex. Twenty four hours after injection in LC, Mn2 + labeling was detected in major cortical and subcortical targets of LC projections including predominantly ipsilateral primary motor and somatosensory cortices, hippocampus and amygdala. Although the injections were in most cases centered in the core of LC, the pattern of Mn2 + labeling greatly varied across rats. In addition, despite a certain degree of overlap of the labeling obtained with both MEMRI and classical tracing, MEMRI tracing consistently failed to reliably label not only several minor but also major targets of LC, notably the thalamus. The lack of Mn2 + labeling in thalamus possibly reflected a weaker functional connectivity within coeruleothalamic projections that could not be predicted by anatomical tracing. Inversely, a number of brain regions, particularly contralateral motor cortex, that were not or only sparsely labeled with fluorescent dextran were strongly labeled by Mn2 +. This discrepancy could be partly due to both the activity-dependent and transsynaptic nature of Mn2 + transport. The overall labeling produced using MEMRI with iontophoretic injections in LC indicates that the Mn2 + imaging of highly diffuse projections is in principle feasible. However, the labeling pattern of each individual case needs to be carefully interpreted particularly before submitting data for group analysis or in the case of longitudinal examination of discrete changes in functional connectivity under various physiological or behavioral conditions.},
web_url = {http://www.sciencedirect.com/science/article/pii/S1053811911013127},
state = {published},
DOI = {10.1016/j.neuroimage.2011.11.031},
author = {Eschenko O{oeschenko}{Department Physiology of Cognitive Processes}, Evrard HC{evrard}{Department Physiology of Cognitive Processes}, Neves RM{ricardo}{Department Physiology of Cognitive Processes}, Beyerlein M{bayo}{Department Physiology of Cognitive Processes}, Murayama Y{yusuke}{Department Physiology of Cognitive Processes} and Logothetis NK{nikos}{Department Physiology of Cognitive Processes}}
}

@Poster{ NevesvLE2012,
title = {Locus coeruleus noradrenergic system mediates the transient cortical activation evoked by nociceptive stimulation},
year = {2012},
month = {10},
volume = {42},
number = {674.16},
abstract = {It is well-established that electrical or pharmacological activation of several nuclei in the reticular formation elicits cortical arousal which is reflected in the EEG as low amplitude and high frequency, or ‘desynchronized’, activity pattern. Among the ascending reticular activating system (ARAS) is the noradrenergic locus coeruleus (LC), which is critically involved in regulation of the sleep-wake cycle. Local activation of LC, as well as stimulation of its afferents, has been reported to induce cortical desynchronization. Interestingly, several nuclei of the ARAS have been shown to have either anatomical connections with LC or their activation showed impact on activity of LC neurons. Therefore, we hypothesized that the LC is a primary hub component in the ARAS. In order to test this hypothesis, we stimulated LC directly, by applying brief (100-200ms) trains of electrical pulses, or indirectly, by electrical stimulation of contralateral limb paw and simultaneously recorded local field potential (LFP) from multiple cortical and subcortical brain regions in urethane anesthetized rats. Both stimulation paradigms evoked transient (1-2 sec) desynchronization of the cortical LFP in all recorded sites, which were characterized by decreased LFP signal power within low frequency (1-8 Hz) and increased in high frequency range (>20 Hz). Foot shock evoked LFP desynchronization was completely abolished in all recording sites including the hid paw representation of the primary somatosensory cortex after bilateral, but not unilateral, selective inhibition of LC neurons by means of local iontophoretic injection of α2-agonist clonidine. Cortical desynchronization to nociceptive stimulation is used as an indicator of efficiency of analgesic treatment. Furthermore, clonidine is known to possess antinociceptive properties when used as additive in anesthetics. Therefore, our results demonstrate that LC is tightly involved in mediating nociception. The well-known antinociceptive property of α2-agonists in the peripheral nervous system is likely due to decreased levels of noradrenaline as result of the activation of presynaptic negative feedback of α2-receptors. The brain regions that mediate LC-dependent cortical desynchronization are yet to be identified.},
web_url = {http://www.sfn.org/am2012/},
event_name = {42nd Annual Meeting of the Society for Neuroscience (Neuroscience 2012)},
event_place = {New Orleans, LA, USA},
state = {published},
author = {Neves RM{ricardo}{Department Physiology of Cognitive Processes}, van Keulen S{svankeulen}{Department Physiology of Cognitive Processes}, Logothetis NK{nikos}{Department Physiology of Cognitive Processes} and Eschenko O{oeschenko}{Department Physiology of Cognitive Processes}}
}

@Poster{ NevesEEBL2010,
title = {Mapping noradrenergic projections from locus coeruleus using classical fluorescent tracer and MRI-visible contrast agent},
year = {2010},
month = {7},
volume = {7},
number = {087.13},
abstract = {We examined anterograde labeling of noradrenergic terminals originating from the neurons of brain stem neuromodulatory nucleus Locus Coeruleus (LC), a major course of noradrenaline in the rat forebrain, by means of simultaneous iontophoretic injection of paramagnetic (Mn2+) and classical (fluorescent dextran) tracers in the LC. In order to detect Mn2+ transport, MRI scanning was performed in each rat before and 24h after injection and, subsequently, MR images were compared using voxel-based t-test (voxel size: 0.25x0.25x0.25mm). Fluorescent dextran monosynaptic anterograde transport was analysed 5 days after injection. Iontophoretic injection of Mn2+ did not produce neurotoxic effects as there were no signs of neuronal death or glial inflammatory reaction at the injection site 5 days after injection. Both methods revealed reliable labeling in major subcortical terminal fields of LC neurons (Swanson and Hartman, 1975; Ungerstedt, 1971) including central nucleus of amygdala, internal capsule, anterior part of bed nucleus of the stria terminalis, and mesencephalic region. Consistent with previous studies, labeling was predominantly ipsilateral to the injection site. Classical tracer readily detected terminals like fibers of passage typical for noradrenergic innervation of cortical regions. In contrast, manganese-enhanced MRI (MEMRI) method failed to visualize such dispersed noradrenergic innervation in the cortex. On the other hand, MEMRI might be more sensitive for detecting patterns of functional connectivity. Consistent and strong Mn-labeling in hippocampus was observed, which was not proportional to anatomical connectivity labeled by dextran. Thus, the tract-tracing using MEMRI preferentially maps the target sites of rather strong and highly concentrated projections, but not dispersed terminal fields. Despite the relatively low resolution of MEMRI technique compared to florescent microscopy, this novel tract-tracing method can be successfully applied for visualization of major neural pathways and their reorganization in the same animal in longitudinal studies including those concentrating on development, aging, plasticity, or disease-related neurodegeneration.},
web_url = {http://fens2010.neurosciences.asso.fr/},
event_name = {7th Forum of European Neuroscience (FENS 2010)},
event_place = {Amsterdam, Netherlands},
state = {published},
author = {Neves RM{ricardo}{Department Physiology of Cognitive Processes}, Eschenko O{oeschenko}{Department Physiology of Cognitive Processes}, Evrard H{evrard}{Department Physiology of Cognitive Processes}, Beyerlein M{bayo}{Department Physiology of Cognitive Processes} and Logothetis NK{nikos}{Department Physiology of Cognitive Processes}}
}

@Poster{ NevesEEBL2009,
title = {Anterograde analysis of noradrenergic projections in the rat forebrain using classical and manganese-enhanced MRI (MEMRI) tract-tracing},
year = {2009},
month = {11},
volume = {10},
number = {10},
pages = {29},
abstract = {We examined anterograde labeling of noradrenergic terminals originating from the neurons of brain stem neuromodulatory nucleus Locus Coeruleus (LC), a major course of noradrenaline in the rat forebrain, by means of simultaneous iontophoretic injection of paramagnetic
(Mn2 +) and classical (fluorescent dextran) tracers in the LC. Both MEMRI and fluorescent microscopy revealed anterograde labeling in major terminal fields of LC neurons
(Swanson and Hartman, 1975; Ungerstedt, 1971) 24 h and 5 d after injection, respectively. Predominantly ipsilateral labeling of thalamic nuclei, primary sensory cortices, medial prefrontal cortex, and olfactory bulbs reflected previously demonstrated monosynaptic projections of
the LC neurons in multiple target brain regions. The labeling patterns of both paramagnetic and classical tracers were strikingly similar. Importantly, iontophoretic injection of Mn2+ did not produce neurotoxic effects as there were no signs of neuronal death or glial inflammatory
reaction at the injection site 5 days after injection. The reported results further validate MEMRI tract-tracing technique allowing visualization a highly distributed and distal efferent projections arising from the brain stem nucleus. Thus, MEMRI may be used for mapping convergent target brain regions of different neuromodulatory systems in the same animal and their functional reorganization in longitudinal studies.},
web_url = {http://www.neuroschool-tuebingen-nena.de/},
event_name = {10th Conference of Junior Neuroscientists of Tübingen (NeNa 2009)},
event_place = {Ellwangen, Germany},
state = {published},
author = {Neves RM{ricardo}{Department Physiology of Cognitive Processes}, Eschenko O{oeschenko}{Department Physiology of Cognitive Processes}, Evrard H{evrard}{Department Physiology of Cognitive Processes}, Beyerlein M{bayo}{Department Physiology of Cognitive Processes} and Logothetis NK{nikos}{Department Physiology of Cognitive Processes}}
}