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Jonathan D. Cohen - One of the best experts on this subject based on the ideXlab platform.
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pupil diameter tracks changes in control state predicted by the adaptive gain theory of Locus Coeruleus function
Cognitive Affective & Behavioral Neuroscience, 2010Co-Authors: Mark S Gilzenrat, Sander Nieuwenhuis, Marieke Jepma, Jonathan D. CohenAbstract:An important dimension of cognitive control is the adaptive regulation of the balance between exploitation (pursuing known sources of reward) and exploration (seeking new ones) in response to changes in task utility. Recent studies have suggested that the Locus Coeruleus-norepinephrine system may play an important role in this function and that pupil diameter can be used to index Locus Coeruleus activity. On the basis of this, we reasoned that pupil diameter may correlate closely with control state and associated changes in behavior. Specifically, we predicted that increases in baseline pupil diameter would be associated with decreases in task utility and disengagement from the task (exploration), whereas reduced baseline diameter (but increases in task-evoked dilations) would be associated with task engagement (exploitation). Findings in three experiments were consistent with these predictions, suggesting that pupillometry may be useful as an index of both control state and, indirectly, Locus Coeruleus function.
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decision making the p3 and the Locus Coeruleus norepinephrine system
Psychological Bulletin, 2005Co-Authors: Sander Nieuwenhuis, Gary Astonjones, Jonathan D. CohenAbstract:Psychologists and neuroscientists have had a long-standing interest in the P3, a prominent component of the event-related brain potential. This review aims to integrate knowledge regarding the neural basis of the P3 and to elucidate its functional role in information processing. The authors review evidence suggesting that the P3 reflects phasic activity of the neuromodulatory Locus Coeruleus–norepinephrine (LC-NE) system. They discuss the P3 literature in the light of empirical findings and a recent theory regarding the information-processing function of the LC-NE phasic response. The theoretical framework emerging from this research synthesis suggests that the P3 reflects the response of the LC-NE system to the outcome of internal decision-making processes and the consequent effects of noradrenergic potentiation of information processing.
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Locus Coeruleus and regulation of behavioral flexibility and attention
Progress in Brain Research, 2000Co-Authors: Gary Astonjones, J Rajkowski, Jonathan D. CohenAbstract:Publisher Summary Recent work on the Locus Coeruleus-norepinephrine (LC-NE) system has led us to hypothesize that it plays a central role in regulating this balance between focused vs. flexible responding, or selective vs. scanning attention. This chapter discusses previous work on the LC system relevant to understanding its role in cognitive activity and attention, and then describes the recent neurophysiology in behaving monkeys and modeling work aimed at understanding the mechanisms by which this neuromodulatory brain system operates, and how it regulates behavior. The present analysis indicates that the LC system could play a role not only in the regulation of attentional stability and responsiveness, but also in disorders of attention. The results indicate that attention deficit-hyperactivity disorder (ADHD) may result, at least in part, from an overly tonic LC mode. That is, ADHD may occur in subjects whose LC neurons exhibit the tonic mode inappropriately in many contexts, and only infrequently transition to the phasic mode.
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the role of Locus Coeruleus in the regulation of cognitive performance
Science, 1999Co-Authors: Marius Usher, Jonathan D. Cohen, J Rajkowski, David Servanschreiber, Gary AstonjonesAbstract:Noradrenergic Locus Coeruleus (LC) neurons were recorded in monkeys performing a visual discrimination task, and a computational model was developed addressing the role of the LC brain system in cognitive performance. Changes in spontaneous and stimulus-induced patterns of LC activity correlated closely with fluctuations in behavioral performance. The model explains these fluctuations in terms of changes in electrotonic coupling among LC neurons and predicts improved performance during epochs of high coupling and synchronized LC firing. Cross correlations of simultaneously recorded LC neurons confirmed this prediction, indicating that electrotonic coupling in LC may play an important role in attentional modulation and the regulation of goal-directed versus exploratory behaviors.
Luis De Lecea - One of the best experts on this subject based on the ideXlab platform.
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in vivo cell type specific crispr knockdown of dopamine beta hydroxylase reduces Locus Coeruleus evoked wakefulness
Nature Communications, 2018Co-Authors: Hiroshi Yamaguchi, Woodward F. Hopf, Luis De LeceaAbstract:Locus Coeruleus (LC) neurons in the brainstem have long been associated with attention and arousal. Optogenetic stimulation of LC-NE neurons induces immediate sleep-to-wake transitions. However, LC neurons also secrete other neurotransmitters in addition to NE. To interrogate the role of NE derived from the LC in regulating wakefulness, we applied in vivo cell type-specific CRISPR/Cas9 technology to disrupt the dopamine beta hydroxylase (dbh) gene selectively in adult LC-NE neurons. Unilateral dbh gene disruption abolished immediate arousal following optogenetic stimulation of LC. Bilateral LC-specific dbh disruption significantly reduced NE concentration in LC projection areas and reduced wake length even in the presence of salient stimuli. These results suggest that NE may be crucial for the awakening effect of LC stimulation and serve as proof-of-principle that CRISPR gene editing in adult neurons can be used to interrogate gene function within genetically-defined neuronal circuitry associated with complex behaviors. Neurons of the Locus Coeruleus (LC) are implicated in attention and arousal. Here the authors use CRISPR/Cas9 to disrupt dopamine beta hydroxylase in LC neurons and see this reduces LC-evoked sleep-to-wake transitions and wake length.
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In vivo cell type-specific CRISPR knockdown of dopamine beta hydroxylase reduces Locus Coeruleus evoked wakefulness
Nature Publishing Group, 2018Co-Authors: Hiroshi Yamaguchi, Woodward F. Hopf, Luis De LeceaAbstract:Neurons of the Locus Coeruleus (LC) are implicated in attention and arousal. Here the authors use CRISPR/Cas9 to disrupt dopamine beta hydroxylase in LC neurons and see this reduces LC-evoked sleep-to-wake transitions and wake length
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tuning arousal with optogenetic modulation of Locus Coeruleus neurons
Nature Neuroscience, 2010Co-Authors: Matthew E Carter, Karl Deisseroth, Ofer Yizhar, Sachiko Chikahisa, Hieu Nguyen, Antoine Roger Adamantidis, Seiji Nishino, Luis De LeceaAbstract:Neural activity in the noradrenergic Locus Coeruleus correlates with periods of wakefulness and arousal. However, it is unclear whether tonic or phasic activity in these neurons is necessary or sufficient to induce transitions between behavioral states and to promote long-term arousal. Using optogenetic tools in mice, we found that there is a frequency-dependent, causal relationship among Locus Coeruleus firing, cortical activity, sleep-to-wake transitions and general locomotor arousal. We also found that sustained, high-frequency stimulation of the Locus Coeruleus at frequencies of 5 Hz and above caused reversible behavioral arrests. These results suggest that the Locus Coeruleus is finely tuned to regulate organismal arousal and that bursts of noradrenergic overexcitation cause behavioral attacks that resemble those seen in people with neuropsychiatric disorders.
Jerome M Siegel - One of the best experts on this subject based on the ideXlab platform.
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increased and decreased muscle tone with orexin hypocretin microinjections in the Locus Coeruleus and pontine inhibitory area
Journal of Neurophysiology, 2001Co-Authors: Boris Y Mileykovskiy, Lyudmila I Kiyashchenko, Jerome M SiegelAbstract:Orexin-A (OX-A) and orexin-B (OX-B) (hypocretin 1 and hypocretin 2) are synthesized in neurons of the perifornical, dorsomedial, lateral, and posterior hypothalamus. The Locus Coeruleus (LC) receiv...
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Locus Coeruleus neurons cessation of activity during cataplexy
Neuroscience, 1999Co-Authors: Ming-fung Wu, Seema Gulyani, B Phan, Emmanuel Mignot, Jerome M SiegelAbstract:Cataplexy, a symptom of narcolepsy, is a loss of muscle tone usually triggered by sudden, emotionally significant stimuli. We now report that Locus Coeruleus neurons cease discharge throughout cataplexy periods in canine narcoleptics. Locus Coeruleus discharge rates during cataplexy were as low as or lower than those seen during rapid-eye-movement sleep. Prazosin, an a1 antagonist, and physostigmine, a cholinesterase inhibitor, both of which precipitate cataplexy, decreased Locus Coeruleus discharge rate. Our results are consistent with the hypothesis that Locus Coeruleus activity contributes to the maintenance of muscle tone in waking, and that reduction in Locus Coeruleus discharge plays a role in the loss of muscle tone in cataplexy and rapid-eye-movement sleep. Our results also show that the complete cessation of Locus Coeruleus activity is not sufficient to trigger rapid-eye-movement sleep in narcoleptics. © 1999 IBRO. Published by Elsevier Science Ltd.
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Locus Coeruleus neurons cessation of activity during cataplexy
Neuroscience, 1999Co-Authors: Seema Gulyani, B Phan, Emmanuel Mignot, Jerome M Siegel, E YauAbstract:Cataplexy, a symptom of narcolepsy, is a loss of muscle tone usually triggered by sudden, emotionally significant stimuli. We now report that Locus Coeruleus neurons cease discharge throughout cataplexy periods in canine narcoleptics. Locus Coeruleus discharge rates during cataplexy were as low as or lower than those seen during rapid-eye-movement sleep. Prazosin, an alpha1 antagonist, and physostigmine, a cholinesterase inhibitor, both of which precipitate cataplexy, decreased Locus Coeruleus discharge rate. Our results are consistent with the hypothesis that Locus Coeruleus activity contributes to the maintenance of muscle tone in waking, and that reduction in Locus Coeruleus discharge plays a role in the loss of muscle tone in cataplexy and rapid-eye-movement sleep. Our results also show that the complete cessation of Locus Coeruleus activity is not sufficient to trigger rapid-eye-movement sleep in narcoleptics.
Gary Astonjones - One of the best experts on this subject based on the ideXlab platform.
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decision making the p3 and the Locus Coeruleus norepinephrine system
Psychological Bulletin, 2005Co-Authors: Sander Nieuwenhuis, Gary Astonjones, Jonathan D. CohenAbstract:Psychologists and neuroscientists have had a long-standing interest in the P3, a prominent component of the event-related brain potential. This review aims to integrate knowledge regarding the neural basis of the P3 and to elucidate its functional role in information processing. The authors review evidence suggesting that the P3 reflects phasic activity of the neuromodulatory Locus Coeruleus–norepinephrine (LC-NE) system. They discuss the P3 literature in the light of empirical findings and a recent theory regarding the information-processing function of the LC-NE phasic response. The theoretical framework emerging from this research synthesis suggests that the P3 reflects the response of the LC-NE system to the outcome of internal decision-making processes and the consequent effects of noradrenergic potentiation of information processing.
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Locus Coeruleus and regulation of behavioral flexibility and attention
Progress in Brain Research, 2000Co-Authors: Gary Astonjones, J Rajkowski, Jonathan D. CohenAbstract:Publisher Summary Recent work on the Locus Coeruleus-norepinephrine (LC-NE) system has led us to hypothesize that it plays a central role in regulating this balance between focused vs. flexible responding, or selective vs. scanning attention. This chapter discusses previous work on the LC system relevant to understanding its role in cognitive activity and attention, and then describes the recent neurophysiology in behaving monkeys and modeling work aimed at understanding the mechanisms by which this neuromodulatory brain system operates, and how it regulates behavior. The present analysis indicates that the LC system could play a role not only in the regulation of attentional stability and responsiveness, but also in disorders of attention. The results indicate that attention deficit-hyperactivity disorder (ADHD) may result, at least in part, from an overly tonic LC mode. That is, ADHD may occur in subjects whose LC neurons exhibit the tonic mode inappropriately in many contexts, and only infrequently transition to the phasic mode.
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the role of Locus Coeruleus in the regulation of cognitive performance
Science, 1999Co-Authors: Marius Usher, Jonathan D. Cohen, J Rajkowski, David Servanschreiber, Gary AstonjonesAbstract:Noradrenergic Locus Coeruleus (LC) neurons were recorded in monkeys performing a visual discrimination task, and a computational model was developed addressing the role of the LC brain system in cognitive performance. Changes in spontaneous and stimulus-induced patterns of LC activity correlated closely with fluctuations in behavioral performance. The model explains these fluctuations in terms of changes in electrotonic coupling among LC neurons and predicts improved performance during epochs of high coupling and synchronized LC firing. Cross correlations of simultaneously recorded LC neurons confirmed this prediction, indicating that electrotonic coupling in LC may play an important role in attentional modulation and the regulation of goal-directed versus exploratory behaviors.
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afferent projections to the rat Locus Coeruleus demonstrated by retrograde and anterograde tracing with cholera toxin b subunit and phaseolus vulgaris leucoagglutinin
Neuroscience, 1995Co-Authors: Pierre-hervé Luppi, Gary Astonjones, Hideo Akaoka, Guy Chouvet, M JouvetAbstract:Abstract The aim of this study was to examine the afferents to the rat Locus Coeruleus by means of retrograde and anterograde tracing experiments using cholera-toxin B subunit and phaseolus leucoagglutinin. To obtain reliable injections of cholera-toxin B in the Locus Coeruleus, electrophysiological recordings were made through glass micropipettes containing the tracer and the noradrenergic neurons of the Locus Coeruleus were identified by their characteristic discharge properties. After iontophoretic injections of cholera-toxin B into the nuclear core of the Locus Coeruleus, we observed a substantial number of retrogradely labeled cells in the lateral paragigantocellular nucleus and the dorsomedial rostral medulla (ventromedial prepositus hypoglossi and dorsal paragigantocellular nuclei) as previously described. 6 We also saw a substantial number of retrogradely labeled neurons in (1) the preoptic area dorsal to the supraoptic nucleus, (2) areas of the posterior hypothalamus, (3) the Kolliker-Fuse nucleus, (4) mesencephalic reticular formation. Fewer labeled cells were also observed in other regions including the hypothalamic paraventricular nucleus, dorsal raphe nucleus, median raphe nucleus, dorsal part of the periaqueductal gray, the area of the noradrenergic A5 group, the lateral parabrachial nucleus and the caudoventrolateral reticular nucleus. No or only occasional cells were found in the cortex, the central nucleus of the amygdala, the lateral part of the bed nucleus of the stria terminalis, the vestibular nuclei, the nucleus of the solitary tract or the spinal cord, structures which were previously reported as inputs to the Locus Coeruleus. 10,13 Control injections of cholera-toxin B were made in areas surrounding the Locus Coeruleus, including (1) Barrington's nucleus, (2) the mesencephalic trigeminal nucleus, (3) a previously undefined area immediately rostral to the Locus Coeruleus and medial to the mesencephalic trigeminal nucleus that we named the peri-mesencephalic trigeminal nucleus, and (4) the medial vestibular nucleus lateral to the caudal tip of the Locus Coeruleus. These injections yielded patterns of retrograde labeling that differed from one another and also from that obtained with cholera-toxin B injection sites in the Locus Coeruleus. These results indicate that the area surrounding the Locus Coeruleus is divided into individual nuclei with distinct afferents. These results were confirmed and extended with anterograde transport of cholera-toxin B or phaseolus leucoagglutinin. Injections of these tracers in the lateral paragigantocellular nucleus, preoptic area dorsal to the supraoptic nucleus, the ventrolateral part of the periaqueductal gray, the Kolliker-Fuse nucleus yielded a substantial to large number of labeled fibers in the nuclear core of the Locus Coeruleus. Anterograde transport of cholera-toxin B or phaseolus leucoagglutinin from the posterior hypothalamic areas yielded a moderate to small number of labeled fibers in the nuclear core of the Locus Coeruleus. These anterograde tracing experiments confirm that these areas send direct projections to the rat Locus Coeruleus. Importantly, fiber labeling from each of these areas was in most cases much denser in areas immediately surrounding the Locus Coeruleus than in the Locus Coeruleus proper. In particular, the lamina and the periaqueductal gray medial to the Locus Coeruleus where many dendrites of Locus Coeruleus noradrenergic cells are located contained a large number of fibers. These data might indicate that a large number of the afferents to the noradrenergic neurons of the Locus Coeruleus terminate on dendrites outside the dense core of the nucleus. Further electrophysiological as well as ultrastructural studies are necessary to test this hypothesis.
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response of Locus Coeruleus neurons to footshock stimulation is mediated by neurons in the rostral ventral medulla
Neuroscience, 1993Co-Authors: C Chiang, Gary AstonjonesAbstract:Abstract While it is well documented that Locus Coeruleus neurons are potently activated by footpinch or sciatic nerve stimulation, little is known about the circuit producing this sensory response. Previous work in our laboratory has identified the medullary nucleus paragigantocellularis as a major excitatory afferent to the Locus Coeruleus. Here, we use local microinjections into the paragigantocellularis to test whether this nucleus is a link in the pathway mediating the activation of Locus Coeruleus neurons by subcutaneous footpad stimulation, or footshock, in anesthetized rats. Lidocaine HCl microinjected into the paragigantocellularis reversibly attenuated footshock-evoked activation of 50 out of 56 Locus Coeruleus cells, with responses in 20 cells completely blocked. Microinjections of GABA into the paragigantocellularis reduced the footshock-evoked responses of 17 out of 27 Locus Coeruleus cells (seven complete blocks); microinjections of the GABAB agonist baclofen had no effect (0 out of 11 cells blocked). Microinjections of a synaptic decoupling cocktail of manganese and cadmium also attenuated Locus Coeruleus activation in eight out of nine cells with two complete blocks. With each agent, the most effective injection placement for complete blockade of responses was the ventromedial paragigantocellularis; injections bordering this region attenuated responses, while those outside of the paragigantocellularis (dorsal medullary reticular formation, nucleus tractus solitarius, or facial nucleus), or vehicle injections, were ineffective. These results are consistent with previous findings that pharmacologie blockade of paragigantocellularis-evoked Locus Coeruleus activity also blocks footshock-evoked responses of Locus Coeruleus neurons [ Ennis and Aston-Jones (1988) J. Neurosci.8, 3644–3657], and support the view that this somatosensory response, and perhaps other sensory-evoked responses of Locus Coeruleus neurons, involve the nucleus paragigantocellularis.
M Jouvet - One of the best experts on this subject based on the ideXlab platform.
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afferent projections to the rat Locus Coeruleus demonstrated by retrograde and anterograde tracing with cholera toxin b subunit and phaseolus vulgaris leucoagglutinin
Neuroscience, 1995Co-Authors: Pierre-hervé Luppi, Gary Astonjones, Hideo Akaoka, Guy Chouvet, M JouvetAbstract:Abstract The aim of this study was to examine the afferents to the rat Locus Coeruleus by means of retrograde and anterograde tracing experiments using cholera-toxin B subunit and phaseolus leucoagglutinin. To obtain reliable injections of cholera-toxin B in the Locus Coeruleus, electrophysiological recordings were made through glass micropipettes containing the tracer and the noradrenergic neurons of the Locus Coeruleus were identified by their characteristic discharge properties. After iontophoretic injections of cholera-toxin B into the nuclear core of the Locus Coeruleus, we observed a substantial number of retrogradely labeled cells in the lateral paragigantocellular nucleus and the dorsomedial rostral medulla (ventromedial prepositus hypoglossi and dorsal paragigantocellular nuclei) as previously described. 6 We also saw a substantial number of retrogradely labeled neurons in (1) the preoptic area dorsal to the supraoptic nucleus, (2) areas of the posterior hypothalamus, (3) the Kolliker-Fuse nucleus, (4) mesencephalic reticular formation. Fewer labeled cells were also observed in other regions including the hypothalamic paraventricular nucleus, dorsal raphe nucleus, median raphe nucleus, dorsal part of the periaqueductal gray, the area of the noradrenergic A5 group, the lateral parabrachial nucleus and the caudoventrolateral reticular nucleus. No or only occasional cells were found in the cortex, the central nucleus of the amygdala, the lateral part of the bed nucleus of the stria terminalis, the vestibular nuclei, the nucleus of the solitary tract or the spinal cord, structures which were previously reported as inputs to the Locus Coeruleus. 10,13 Control injections of cholera-toxin B were made in areas surrounding the Locus Coeruleus, including (1) Barrington's nucleus, (2) the mesencephalic trigeminal nucleus, (3) a previously undefined area immediately rostral to the Locus Coeruleus and medial to the mesencephalic trigeminal nucleus that we named the peri-mesencephalic trigeminal nucleus, and (4) the medial vestibular nucleus lateral to the caudal tip of the Locus Coeruleus. These injections yielded patterns of retrograde labeling that differed from one another and also from that obtained with cholera-toxin B injection sites in the Locus Coeruleus. These results indicate that the area surrounding the Locus Coeruleus is divided into individual nuclei with distinct afferents. These results were confirmed and extended with anterograde transport of cholera-toxin B or phaseolus leucoagglutinin. Injections of these tracers in the lateral paragigantocellular nucleus, preoptic area dorsal to the supraoptic nucleus, the ventrolateral part of the periaqueductal gray, the Kolliker-Fuse nucleus yielded a substantial to large number of labeled fibers in the nuclear core of the Locus Coeruleus. Anterograde transport of cholera-toxin B or phaseolus leucoagglutinin from the posterior hypothalamic areas yielded a moderate to small number of labeled fibers in the nuclear core of the Locus Coeruleus. These anterograde tracing experiments confirm that these areas send direct projections to the rat Locus Coeruleus. Importantly, fiber labeling from each of these areas was in most cases much denser in areas immediately surrounding the Locus Coeruleus than in the Locus Coeruleus proper. In particular, the lamina and the periaqueductal gray medial to the Locus Coeruleus where many dendrites of Locus Coeruleus noradrenergic cells are located contained a large number of fibers. These data might indicate that a large number of the afferents to the noradrenergic neurons of the Locus Coeruleus terminate on dendrites outside the dense core of the nucleus. Further electrophysiological as well as ultrastructural studies are necessary to test this hypothesis.
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Afferent projections to the rat Locus Coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin
Neuroscience, 1995Co-Authors: Pierre-hervé Luppi, Hideo Akaoka, Guy Chouvet, G. Aston-jones, M JouvetAbstract:The aim of this study was to examine the afferents to the rat Locus Coeruleus by means of retrograde and anterograde tracing experiments using cholera-toxin B subunit and phaseolus leucoagglutinin. To obtain reliable injections of cholera-toxin B in the Locus Coeruleus, electrophysiological recordings were made through glass micropipettes containing the tracer and the noradrenergic neurons of the Locus Coeruleus were identified by their characteristic discharge properties. After iontophoretic injections of cholera-toxin B into the nuclear core of the Locus Coeruleus, we observed a substantial number of retrogradely labeled cells in the lateral paragigantocellular nucleus and the dorsomedial rostral medulla (ventromedial prepositus hypoglossi and dorsal paragigantocellular nuclei) as previously described. We also saw a substantial number of retrogradely labeled neurons in (1) the preoptic area dorsal to the supraoptic nucleus, (2) areas of the posterior hypothalamus, (3) the Kölliker-Fuse nucleus, (4) mesencephalic reticular formation. Fewer labeled cells were also observed in other regions including the hypothalamic paraventricular nucleus, dorsal raphe nucleus, median raphe nucleus, dorsal part of the periaqueductal gray, the area of the noradrenergic A5 group, the lateral parabrachial nucleus and the caudoventrolateral reticular nucleus. No or only occasional cells were found in the cortex, the central nucleus of the amygdala, the lateral part of the bed nucleus of the stria terminalis, the vestibular nuclei, the nucleus of the solitary tract or the spinal cord, structures which were previously reported as inputs to the Locus Coeruleus. Control injections of cholera-toxin B were made in areas surrounding the Locus Coeruleus, including (1) Barrington's nucleus, (2) the mesencephalic trigeminal nucleus, (3) a previously undefined area immediately rostral to the Locus Coeruleus and medial to the mesencephalic trigeminal nucleus that we named the peri-mesencephalic trigeminal nucleus, and (4) the medial vestibular nucleus lateral to the caudal tip of the Locus Coeruleus. These injections yielded patterns of retrograde labeling that differed from one another and also from that obtained with cholera-toxin B injection sites in the Locus Coeruleus. These results indicate that the area surrounding the Locus Coeruleus is divided into individual nuclei with distinct afferents. These results were confirmed and extended with anterograde transport of cholera-toxin B or phaseolus leucoagglutinin. Injections of these tracers in the lateral paragigantocellular nucleus, preoptic area dorsal to the supraoptic nucleus, the ventrolateral part of the periaqueductal gray, the Kölliker-Fuse nucleus yielded a substantial to large number of labeled fibers in the nuclear core of the Locus Coeruleus.(ABSTRACT TRUNCATED AT 400 WORDS)
