NEUROBIOLOGICAL CIRCUIT FUNCTION AND COMPUTATION OF THE SEROTONERGIC AND RELATED SYSTEMS Topic Editors Kae Nakamura and KongFatt Wong-Lin INTEGRATIVE NEUROSCIENCE Frontiers in Integrative Neuroscience February 2015 | Neurobiological circuit function and computation of the serotonergic and related systems | 1 ABOUT FRONTIERS Frontiers is more than just an open-access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. 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Cover image provided by Ibbl sarl, Lausanne CH ISSN 1664-8714 ISBN 978-2-88919-384-4 DOI 10.3389/978-2-88919-384-4 Frontiers in Integrative Neuroscience February 2015 | Neurobiological circuit function and computation of the serotonergic and related systems | 2 Topic Editors: Kae Nakamura, Kansai Medical University, Japan KongFatt Wong-Lin, University of Ulster, UK Serotonin is one of the oldest neurotransmitters in evolutionary terms, and the serotonergic system is complex and multifaceted. Serotonin-producing neurons in the raphe nuclei provide serotonin innervations throughout various parts of the brain, modulating cellular excitability and network properties of targeted brain areas, and regulating mood, cognition and behavior. Dysfunctions of the serotonergic system are implicated in neuropsychiatric disorders including depression, schizophrenia, and drug abuse. Although the system has been studied for many years, an integrative account of its functions and computational principles remains elusive. This is partly attributed to the high variability and heterogeneity in terms of neuronal properties and receptor types, and its extensive connections with other brain regions. This Frontiers Research Topic e-book is a collection of recent experimental and computational work and approaches at multiple scales that provide the latest information regarding the integrated functions of the serotonergic system. The contributed papers include a variety of experimental and computational work, and human clinical studies. NEUROBIOLOGICAL CIRCUIT FUNCTION AND COMPUTATION OF THE SEROTONERGIC AND RELATED SYSTEMS Frontiers in Integrative Neuroscience February 2015 | Neurobiological circuit function and computation of the serotonergic and related systems | 3 Table of Contents 05 Functions and Computational Principles of Serotonergic and Related Systems at Multiple Scales Kae Nakamura and KongFatt Wong-Lin 07 Biological Implications of Coeruleospinal Inhibition of Nociceptive Processing in the Spinal Cord Masayoshi Tsuruoka, Junichiro Tamaki, Masako Maeda, Bunsho Hayashi and Tomio Inoue 17 Serotonin Modulation of Cortical Neurons and Networks Pau Celada, M. Victoria Puig and Francesc Artigas 37 Reward Prediction-Related Increases and Decreases in Tonic Neuronal Activity of the Pedunculopontine Tegmental Nucleus Ken-Ichi Okada and Yasushi Kobayashi 51 Modulation of Firing and Synaptic Transmission of Serotonergic Neurons by Intrinsic G Protein-Coupled Receptors and Ion Channels Takashi Maejima, Olivia A. Masseck, Melanie D. Mark and Stefan Herlitze 66 Computational Studies of the Role of Serotonin in the Basal Ganglia Michael C. Reed, H. Frederik Nijhout and Janet Best 74 Monitoring Serotonin Signaling on a Subsecond Time Scale Elyse C. Dankoski and R. Mark Wightman 87 Comodulation of Dopamine and Serotonin on Prefrontal Cortical Rhythms: A Theoretical Study Da-Hui Wang and KongFatt Wong-Lin 106 The Role of the Dorsal Raphé Nucleus in Reward-Seeking Behavior Kae Nakamura 124 Learning From Negative Feedback in Patients with Major Depressive Disorder is Attenuated by SSRI Antidepressants Mohammad M. Herzallah, Ahmed A. Moustafa, Joman Y. Natsheh, Salam M. Abdellatif, Mohamad B. Taha, Yasin I. Tayem, Mahmud A. Sehwail, Ivona Amleh, Georgios Petrides, Catherine E. Myers and Mark A. Gluck 133 Serotonergic Modulation of Spatial Working Memory: Predictions From a Computational Network Model Maria Cano-Colino, Rita Almeida and Albert Compte Frontiers in Integrative Neuroscience February 2015 | Neurobiological circuit function and computation of the serotonergic and related systems | 4 148 Exploring the Effects of Depression and Treatment of Depression in Reinforcement Learning Pedro Castro-Rodrigues and Albino J. Oliveira-Maia and KongFatt Wong-Lin 150 A Dynamic, Embodied Paradigm to Investigate the Role of Serotonin in Decision-Making Derrik E. Asher, Alexis B. Craig, Andrew Zaldivar, Alyssa A. Brewer and Jeffrey L. Krichmar EDITORIAL published: 07 March 2014 doi: 10.3389/fnint.2014.00023 Functions and computational principles of serotonergic and related systems at multiple scales Kae Nakamura 1 * and KongFatt Wong-Lin 2 * 1 Department of Physiology, Kansai Medical University, Osaka, Japan 2 Intelligent Systems Research Centre, School of Computing and Intelligent Systems, University of Ulster, Northern Ireland, L ’Derry, UK *Correspondence: nakamkae@hirakata.kmu.ac.jp; k.wong-lin@ulster.ac.uk Edited by: Sidney A. Simon, Duke University, USA Keywords: serotonin 5-HT, neural circuit, computational modeling, dopamine, serotonin, dorsal raphe nucleus, locus coeruleus, pendunculopontine tegmental nucleus As one of the phylogenetically and ontogenetically oldest neuro- transmitters, the monoamine serotonin (5-HT) is derived from tryptophan in neurons within the raphe nuclei, and inner- vates various parts of the nervous system (Jacobs and Azmitia, 1992). The serotonergic system is complex and can generate multifarious actions (Barnes and Sharp, 1999; Smythies, 2005). There are seven general families of serotonin receptors with multiple receptor subtypes, all of which are G protein-coupled receptors (GPCRs) except one (5-HT3 receptor), which is a ligand-gated ion channel, and these receptors can modulate the release of many major neurotransmitters such as glutamate, GABA, dopamine, acetylcholine, and norepinephrine (Barnes and Sharp, 1999; Smythies, 2005). It can also modulate neu- ronal excitability and network properties of many targeted brain areas, and regulate mood, cognition and behavior (Smythies, 2005). Dysfunctions of the serotonergic system are impli- cated in neuropsychiatric disorders including depression and schizophrenia (Müller and Jacobs, 2009). The serotonergic system has been the target of pharmaceuticals for decades, primarily to treat biological and neuropsychiatric disorders. These include antidepressants, antipsychotics, hallucinogens, antimigraine agents, and gastroprokinetic agents (Nichols and Nichols, 2008). Hence, the study of serotonin has high societal impacts. Although the serotonergic system has been studied for many years, an integrative account of its underlying functions remains elusive. This could be partly attributed to the high variability and heterogeneity in terms of neuronal properties and receptor subtypes, and its extensive connections with other brain regions. Indeed, it has been claimed that serotonin is in involved “in virtu- ally everything, but responsible for nothing” (Jacobs and Fornal, 1995). While there have already been many excellent reviews and books on serotonin and related neural systems (e.g., Jacobs and Azmitia, 1992; Barnes and Sharp, 1999; Smythies, 2005; Müller and Jacobs, 2009), we hope that this collection of recent works provides a complementary and updated coverage of their diverse functions. In particular, unlike previous collections, neurobiolog- ically based computational studies are included in this collection as we consider them to be important toward elucidating some of the underlying principles, especially at the systems level. Hence, we have made a concerted effort to invite both experimental and computational articles in this Research Topic. These works include original results, reviews, and hypothesis over multiple levels: from receptors and channels, to neuronal circuits and finally to behavior and neuropsychiatric disorders. At the receptor and cellular levels, Maejima et al. (2013) discussed various GPCRs and ion channels in the serotonin reg- ulation and introduced optogenetic techniques that modulate intracellular signaling to more finely control the serotonergic sys- tems for studies of their functions. The activation of the serotonin receptors was determined by its release and uptake dynamics. Unlike other more commonly studied neurotransmitters such as acetylcholine for example, the release and uptake dynamics of serotonin is not well characterized. Dankowski and Wightman (2013) reviewed the challenges and developments of fast-scan cyclic voltammetry to monitor serotonin at the subsecond (maybe millisecond) timescale in both in vitro and in vivo conditions. At the neuronal circuit level, Celada et al., 2013 provided a comprehensive review on cortical modulation of serotonin. In particular, the prefrontal cortex, linked to executive brain func- tions, seemed to form closed-loop interactions with the serotonin neurons in the dorsal raphe nucleus. This review was well comple- mented by biologically realistic computational modeling works of serotonin modulation on the prefrontal cortex. In Wang and Wong-Lin (2013), a biologically motivated model was developed to investigate how the co-modulation of serotonin and dopamine in the prefrontal cortex could result in complex, non-intuitive neuronal circuit dynamics, thus challenging current simpler theo- ries on neuromodulation. Cano-Colino et al. (2013) incorporated serotonin modulation into an established computational model of the prefrontal cortex performing spatial working memory tasks. The model showed that excessive serotonin could impede task performance, and interestingly predicted that serotonin lev- els could affect neuronal memory fields. Besides the cortex, serotonin is also known to modulate impor- tant subcortical brain regions. Using a mathematical model of multiple brain regions, Reed et al. (2013) demonstrated the potential roles of serotonin in maintaining homeostasis in the basal ganglia (via the frontal cortex) under dopamine depletion (e.g., in Parkinson’s disease). In Nakamura (2013), the neu- ral circuit architecture of the dorsal raphe nucleus and other key subcortical brain regions involved in reward-based deci- sion making and learning were discussed with emphasis on the neural circuit. The dorsal raphe nucleus has strong anatomical and functional connectivity with neighboring structures includ- ing the pendunculopontine tegmental nucleus (PPTg) and the Frontiers in Integrative Neuroscience www.frontiersin.org March 2014 | Volume 8 | Article 23 | INTEGRATIVE NEUROSCIENCE 5 Nakamura and Wong-Lin Serotonergic functions at multiple scales locus coeruleus (LC), where many acetylcholine and noradrener- gic neurons are found, respectively, (Koyama and Koyama, 1993; Martinez-Gonzalez et al., 2011). Indeed, Okada and Kobayashi (2013) showed that PPTg neurons exhibit similar tracking of future reward expectation as neurons in the dorsal raphe nucleus. Tsuruoka et al. (2012) reviewed the role of LC on pain control, which might be involved in aversive information processing. It has been proposed that reinforcement learning models can be used as a platform for studying neurological and neuropsy- chiatric disorders (Maia and Frank, 2011). In this collection, Herzallah et al. (2013) dissociated among depressed patients with and without antidepressant medication, and healthy control sub- jects by observing the performance in learning from positive (reward) and negative (punishment) feedback. Castro-Rodrigues and Oliveira-Maia (2013) provided a useful commentary on this important original work. Finally, the comprehensive review by Asher et al. (2013) proposed a closed-loop paradigm toward understanding serotonergic roles in decision making by involving behavioral experiments, game theory, computational modeling, and human–robotic interaction, a truly integrative neuroscience approach. We hope that this issue will provide a comprehensive review of the diverse and complex functions and computations of sero- tonergic and related systems at multiple scales of investigation. We wish that this will motivate and inspire a more integrative research approach from cellular to systems level toward under- standing neuromodulatory systems. ACKNOWLEDGMENTS We would like to thank all the authors for participating as well as help from the Frontiers Neuroscience Editorial Office staff and encouragement from the chief editor, Sid Simon. We would also wish to thank Sid Simon for comments on this editorial, and the reviewers, whose contributions significantly helped to improve the published papers that constituted this Research Topic. REFERENCES Asher, D. E., Craig, A. B., Zaldivar, A., Brewer, A. A., and Krichmar, J. L. (2013). A dynamic, embodied paradigm to investigate the role of serotonin in decision- making. Front. Integr. Neurosci . 7:78. doi: 10.3389/fnint.2013.00078 Barnes, N. M., and Sharp, T. (1999). A review of central 5-HT receptor and their function. Neuropharmacology 38, 1083–1152. doi: 10.1016/S0028- 3908(99)00010-6 Cano-Colino, M., Almeida, R., and Compte, A. (2013). Serotonergic modulation of spatial working memory: predictions from a computational network model. Front. Integr. Neurosci . 7:71. doi: 10.3389/fnint.2013.00071 Castro-Rodrigues, P., and Oliveira-Maia, A. J. (2013). Exploring the effects of depression and treatment of depression in reinforcement learning. Front. Integr. Neurosci . 7:72. doi: 10.3389/fnint.2013.00072 Celada, P., Puig, M. V., and Artigas, F. (2013). Serotonin modulation of cortical neu- rons and networks. Front. Integr. Neurosci . 7:25. doi: 10.3389/fnint.2013.00025 Dankowski, E. C., and Wightman, R. M. (2013). Monitoring serotonin sig- naling on a subsecond time scale. Front. Integr. Neurosci 7:44. doi: 10.3389/fnint.2013.00044 Herzallah, M. M., Moustafa, A. A., Natsheh, J. Y., Abdellatif, S. M., Taha, M. B., Tayem, Y. I., et al. (2013). Learning from negative feedback in patients with major depressive disorder is attenuated by SSRI antidepressants. Front. Integr. Neurosci . 7:67. doi: 10.3389/fnint.2013.00067 Jacobs, B. L., and Azmitia, E. C. (1992). Structure and function of the brain serotonin system. Physiol. Rev . 72, 165–229. Jacobs, B. L., and Fornal, C. A. (1995). “Serotonin and behaviour: a general hypoth- esis,” in Psychopharmacology: The Fourth Generation of Progress , eds F. E. Bloom and D. J. Kupfer (New York, NY: Raven), 461–470. Koyama, Y., and Koyama, Y. (1993). Mutual interactions among cholinergic, noradrenergic and serotonergic neurons studied by ionophresis of these trans- mitters in rat brainstem nuclei. Neuroscience 55, 1117–1126. doi: 10.1016/0306- 4522(93)90325-A Maejima, T., Masseck, O. A., Mark, M. D., and Herlitze, S. (2013). Modulation of firing and synaptic transmission of serotonergic neurons by intrinsic G protein-coupled receptors and ion channels. Front. Integr. Neurosci . 7:40. doi: 10.3389/fnint.2013.00040 Maia, T. V., and Frank, M. J. (2011). From reinforcement learning models to psychiatric and neurological disorders. Nat. Neurosci . 14, 154–162. doi: 10.1038/nn.2723 Martinez-Gonzalez, C., Bolam, J. P., and Mena-Segovia, J. (2011). Topographical organization of the pendunculopontine nucleus. Front. Neuroanat. 5:22. doi: 10.3389/fnana.2011.00022 Müller, C. P., and Jacobs, B. L. (2009). Handbook of the Behavioral Neurobiology of Serotonin . London: Academic Press. Nakamura, K. (2013). The role of the dorsal raphe nucleus in reward-seeking behavior. Front. Integr. Neurosci . 7:60. doi: 10.3389/fnint.2013.00060 Nichols, D. E., and Nichols, C. D.(2008). Serotonin receptors. Chem. Rev . 108, 1614–1641. doi: 10.1021/cr078224o Okada, K., and Kobayashi, Y. (2013). Reward prediction-related increases and decreases in tonic neuronal activity of the pedunculopontine tegmental nucleus. Front. Integr. Neurosci . 7:36. doi: 10.3389/fnint.2013.00036 Reed, M. C., Nijhout, H. F., and Best, J. (2013). Computational studies of the role of serotonin in the basal ganglia. Front. Integr. Neurosci . 7:41. doi: 10.3389/fnint.2013.00041 Smythies, J. (2005). Section V. Serotonin system. Int. Rev. Neurobiol . 64, 217–268. doi: 10.1016/S0074-7742(05)64005-6 Tsuruoka, M., Tamaki, J., Maeda, M., Hayashi, B., and Inoue, T. (2012). Biological implications of coeruleospinal inhibition of nociceptive processing in the spinal cord. Front. Integr. Neurosci . 6:87. doi: 10.3389/fnint.2012.00087 Wang, D.-H., and Wong-Lin, K. (2013). Comodulation of dopamine and serotonin on prefrontal cortical rhythms: a theoretical study. Front. Integr. Neurosci . 7:54. doi: 10.3389/fnint.2013.00054 Received: 18 February 2014; accepted: 19 February 2014; published online: 07 March 2014. Citation: Nakamura K and Wong-Lin K (2014) Functions and computational princi- ples of serotonergic and related systems at multiple scales. Front. Integr. Neurosci. 8 :23. doi: 10.3389/fnint.2014.00023 This article was submitted to the journal Frontiers in Integrative Neuroscience. Copyright © 2014 Nakamura and Wong-Lin. This is an open-access article dis- tributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this jour- nal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Integrative Neuroscience www.frontiersin.org March 2014 | Volume 8 | Article 23 | 6 HYPOTHESIS AND THEORY ARTICLE published: 28 September 2012 doi: 10.3389/fnint.2012.00087 Biological implications of coeruleospinal inhibition of nociceptive processing in the spinal cord Masayoshi Tsuruoka*, Junichiro Tamaki , Masako Maeda , Bunsho Hayashi and Tomio Inoue Department of Physiology, Showa University School of Dentistry, Tokyo, Japan Edited by: Kae Nakamura, Kansai Medical University, Japan Reviewed by: Kae Nakamura, Kansai Medical University, Japan Hidemasa Furue, National Institute for Physiological Sciences, Japan *Correspondence: Masayoshi Tsuruoka, Department of Physiology, Showa University School of Dentistry, 1-5-8 Hatanodai, Tokyo 142-8555, Japan. e-mail: masa@dent.showa-u.ac.jp The coeruleospinal inhibitory pathway (CSIP), the descending pathway from the nucleus locus coeruleus (LC) and the nucleus subcoeruleus (SC), is one of the centrifugal pain control systems. This review answers two questions regarding the role coeruleospinal inhibition plays in the mammalian brain. First is related to an abnormal pain state, such as inflammation. Peripheral inflammation activated the CSIP , and activation of this pathway resulted in a decrease in the extent of the development of inflammatory hyperalgesia. During inflammation, the responses of the dorsal horn neurons to graded heat stimuli in the LC/SC-lesioned rats did not produce a further increase with the increase of stimulus intensity in the higher range temperatures. These results suggest that the function of CSIP is to maintain the accuracy of intensity coding in the dorsal horn because the plateauing of the heat-evoked response in the LC/SC-lesioned rats during inflammation is due to a response saturation that results from the lack of coeruleospinal inhibition. The second concerns attention and vigilance. During freezing behavior induced by air-puff stimulation, nociceptive signals were inhibited by the CSIP . The result implies that the CSIP suppresses pain system to extract other sensory information that is essential for circumstantial judgment. Keywords: locus coeruleus/subcoeruleus, coeruleospinal pathway, pain control, peripheral inflammation, startle response, air-puff stimulation, spinal dorsal horn INTRODUCTION It is a general principle that the brain regulates its sensory inputs. This principle applies to all of the somatosensory pathways that have been investigated. The inhibitory regulation of nociceptive inputs is of particular clinical interest because this regulation may lead to a reduction of pain. Inhibitory action on nociceptive pro- cessing is accomplished via descending or ascending inhibitory pathways (Horie et al., 1991; Koyama et al., 1995; Willis and Coggeshall, 2004). There is considerable interest in the role of descending inhibitory pathways and the possibility of targeting these pathways for clinical treatments. A number of studies have demonstrated that stimulation at many sites of the brain can pro- duce analgesia by inhibiting nociceptive transmission in the spinal cord (see review by Willis and Coggeshall, 2004). The descending pathway from the nucleus locus coeruleus (LC) and the nucleus subcoeruleus (SC) is one of centrifugal pain control systems. The LC/SC provides noradrenergic inner- vation of the spinal cord (Guyenet, 1980; Westlund et al., 1983, 1984; Fritschy and Grzanna, 1990; Clark and Proudfit, 1991, 1992; Grzanna and Fritschy, 1991; Proudfit and Clark, 1991). Activation of the LC/SC either electrically or chemically can produce profound antinociception (Segal and Sandberg, 1977; Margalit and Segal, 1979; Jones and Gebhart, 1986a; Jones, 1991; West et al., 1993) and can inhibit nociceptive activity in dor- sal horn neurons (Hodge et al., 1981; Mokha et al., 1985; Jones and Gebhart, 1986a,b, 1987, 1988). Thus, the coeruleospinal inhibitory pathway (CSIP) appears to play a significant role in spinal nociceptive processing. During the first decade of the twenty-first century, we were particularly interested in the role of the CSIP in the everyday life of mammals, including its roles in normal and abnormal pain condition. Based on our experimental results that characterized coeruleospinal inhibition of nociceptive processing in the spinal cord, this review provides an answer to the question regarding the role of coeruleospinal inhibition in the mammalian brain. We hope that our inferences will aid in a better understanding of the role of centrifugal control of sensation. CONTRIBUTION OF THE CSIP TO PAIN CONTROL UNDER AN ABNORMAL PAIN STATE AND ITS BIOLOGICAL IMPLICATIONS ACTIVATION OF THE CSIP BY PERIPHERAL INFLAMMATION (Tsuruoka and Willis, 1996 a,b) In a series of our study, inflammatory pain, but not neuro- pathic pain, was used as an abnormal pain state. Pain can divide three groups (i.e., inflammatory pain, neuropathic pain, and psychogenic pain) on the basis of the source, nociceptive, neu- ropathic, and psychogenic pain. Inflammatory pain is nociceptive pain via nociceptor, neuropathic pain is a morbid pain induced by dysfunction of the peripheral or central nervous system, and psy- chogenic pain results from the psychological reasons. We adopted inflammatory pain because peripheral inflammation is a matter of frequent occurrence in compared to other pain in everyday life. We compared the development of peripheral hyperalgesia between rats that received bilateral lesions to the LC/SC and sham-operated, control animals for 4 weeks after administration Frontiers in Integrative Neuroscience www.frontiersin.org September 2012 | Volume 6 | Article 87 | INTEGRATIVE NEUROSCIENCE 7 Tsuruoka et al. Coeruleospinal inhibition of nociceptive processing FIGURE 1 | Changes in PWLs following unilateral injection of carrageenan in LC-lesioned ( n = 9) and sham-operated rats ( n = 20). (A) The inflamed paws. (B) The contralateral non-inflamed paws. P < 0 01, significantly different from PWLs before injection. ∗ P < 0 01, significantly different between two groups of rats (Tsuruoka and Willis, 1996b). of carrageenan (an inflammatory agent) ( Figure 1 ). Four hours after the induction of inflammation, the paw withdrawal latencies (PWLs) to heat stimuli in the inflamed paws of the LC-lesioned rats were significantly shorter than those of the sham-operated rats. This result shows that peripheral inflammation activates the CSIP and that the activation of this pathway results in a decrease in the extent of the development of hyperalgesia. The difference in the PWLs between the two groups was not observed at 7 days, whereas, edema and hyperalgesia were still present in the inflamed paw. This result suggests that the CSIP is active only in the acute phase of the inflammatory process. A POSSIBLE INTERACTION WITH OPIOID SYSTEMS (Tsuruoka and Willis, 1996b) We examined, whether coeruleospinal inhibition of nociceptive processing depends on an interaction with other inhibitory sys- tems that involve opioid peptides ( Figures 2 , 3 ). In the acute phase of inflammation, systemic administration of naloxone sig- nificantly further decreased the PWLs of the LC-lesioned rats, which indicate that opioid inhibitory mechanisms are active in the acute phase of inflammation. This result suggests that the coeruleospinal inhibition system interacts with the opioid inhibitory system. However, systemic naloxone never reversed nociceptive threshold in sham-operated rats under inflamma- tion, whereas reverse effects observed in LC-lesioned rats. These results indicate that the coeruleospinal inhibitory system is far predominant in compared to the opioid inhibitory system under inflammatory pain state. FIGURE 2 | The effect of naloxone or saline on PWLs in sham-operated rats tested 4 h, 7 days and 28 days after the injection of carrageenan. The data were obtained 10 min after intraperitoneal (i.p.) naloxone ( n = 8) or saline ( n = 8) and are presented for both the inflamed (A) and the contralateral non-inflamed (B) paws. P < 0.01, significantly different from PWLs before injection. ∗ P < 0 01, significantly different between two groups of rats (Tsuruoka and Willis, 1996b). FIGURE 3 | The effect of naloxone or saline on PWLs in LC-lesioned rats tested 4 h, 7 days and 28 days after the injection of carrageenan. The data were obtained 10 min after i.p. naloxone ( n = 6) or saline ( n = 6) and are presented for both the inflamed (A) and the contralateral non-inflamed (B) paws. P < 0.01, significantly different from PWLs before injection. ∗ P < 0 01, significantly different between two groups of rats (Tsuruoka and Willis, 1996b). Frontiers in Integrative Neuroscience www.frontiersin.org September 2012 | Volume 6 | Article 87 | 8 Tsuruoka et al. Coeruleospinal inhibition of nociceptive processing Opioid inhibitory mechanisms were inactive in both the LC- lesioned rats and the sham-operated rats at 7 days, whereas edema and hyperalgesia were still present in the inflamed paws. Comparable data have been obtained in rats with unilateral inflammation in which naloxone induced no significant effect at 1 week, whereas this drug reduced the paw-pressure threshold 24 h after the induction of inflammation (Millan et al., 1988). In both the sham-operated and the LC-lesioned rats, we found that the baselines PWLs of the inflamed paws were prolonged for the rats that had recovered from the inflammation. These anal- gesic states at 28 days resulted from the activation of endogenous opioid controls, which was apparent following systemic adminis- tration of naloxone. This finding is consistent with reports on rats with carrageenan-induced inflammation (Kayser and Guilbaud, 1991) and rats with neuropathic hyperalgesia (Attal et al., 1990), whereby naloxone produced a hyperalgesic effect in rats that had recovered from either inflammation or neuropathic hyperalgesia. THE ROLE OF THE CSIP IN THE INTENSITY CODING OF NOCICEPTIVE SIGNALS UNDER AN ABNORMAL PAIN STATE (Tsuruoka et al., 2003) Extracellular recordings were made from the sites at lumbar enlargement of the spinal cord that had receptive fields on the hindpaws or toes. The neurons included 63 wide-dynamic-range FIGURE 4 | Rate histograms for the responses to graded heat stimuli from a neuron located in the dorsal horn ipsilateral to the site of inflammation. The responses to graded heat stimuli of a neuron were tested before and 4 h after the induction of inflammation. (A) Rate histograms for a neuron in a LC/SC-intact rat. (B) Rate histograms for a neuron in a LC/SC-lesioned rat (Tsuruoka et al., 2003). neurons and two high threshold neurons. These neurons were tested for changes in heat-evoked response during hindpaw inflammation ( Figures 4 , 5 ). During inflammation, the responses of the dorsal horn neurons to graded heat stimuli in the LC/SC-lesioned rats did not produce a further increase with the increase of stimulus intensity in the higher range temperatures (49–53 ◦ C), whereas the responses recorded from the LC/SC- intact rats continued to increase at temperature of 49 ◦ C or higher. Therefore, it is clear that the plateauing of the heat- evoked response in the LC/SC-lesioned rats during inflammation is due to a response saturation that results from the lack of coeruleospinal inhibition. Previous studies have reported that the descending system from the brain stem, including the LC/SC, becomes more active in modulating spinal nociceptive processes during peripheral inflammation (Ren and Dubner, 1996; Wei et al., 1999). In these studies, it has been suggested that the CSIP plays a role in sup- pressing the hyperexcitability of nociceptive dorsal horn neurons FIGURE 5 | The stimulus–response relationship in wide-dynamic-range neurons located in the dorsal horn ipsilateral to the site of inflammation. (A) Stimulus–response relationship before the induction of inflammation. (B) Stimulus–response relationship at 4 h after the induction of inflammation. Closed circles ( ◦ ) represent neurons in the LC/SC-intact rats ( n = 11). Open circles ( • ) represent neurons in the LC/SC-lesioned rats ( n = 20). Neuronal discharges to each temperature in graded heat stimuli (ordinate) are expressed as a percentage of the control. In (A) and (B) , 100% (control) were discharges to heating at 53 ◦ C in the LC/SC-intact rats. # P < 0 05, ## P < 0 01, significantly different from the value of the LC/SC-intact rats (ANOVA, with Scheffe’s t-test as a post hoc analysis of differences). ∗ P < 0 05, significantly different between responses to heating at 49 ◦ C and responses to heating at 53 ◦ C (ANOVA, with Scheffe’s t-test as a post hoc analysis of differences). (Tsuruoka et al., 2003). Frontiers in Integrative Neuroscience www.frontiersin.org September 2012 | Volume 6 | Article 87 | 9 Tsuruoka et al. Coeruleospinal inhibition of nociceptive processing during inflammation. Our study provides additional findings concerning the role of coeruleospinal inhibition in nociception under the condition of inflammation. In intensity coding, the plateauing of the stimulus–response curve of dorsal horn neurons indicates that the accuracy of the transmission of stimulus inten- sity decreases in the dorsal horn. This implies that the difference of stimulus intensity in higher temperature ranges cannot be dis- tinguished in the LC/SC-lesioned rats in which the plateauing of the heat-evoked response was observed. Because the plateauing of the heat-evoked response was not seen in the LC/SC-intact rats, the CSIP activated by peripheral inflammation may be involved in the prevention of the plateauing of the heat-evoked response in the dorsal horn. Activation of the CSIP induces a decrease of activity in response of dorsal horn neurons to noxious heating so that the heat-evoked responses do not produce response sat- uration in the range of higher temperatures which can prevent the plateauing of the heat-evoked response in the dorsal horn. It seems that the function of CSIP activation by peripheral inflam- mation is to maintain the accuracy of intensity coding in the dorsal horn. Thus, a possible role of CSIP activation by peripheral inflammation is to provide a means to discriminate among differ- ences in the intensity of a painful stimulus in an inflamed region, as well as in the condition without inflammation. It is likely that the CSIP contributes to the discrimination of the intensity of pain sensation under abnormal pain states, such as inflammation. COERULEOSPINAL INHIBITION ON VISCERAL PAIN PROCESSING AND VISCEROMOTOR REFLEXES (Tsuruoka et al., 2010B) Visceral nociceptive signals are the subject of coeruleospinal inhi- bition (Liu et al., 2007). We identified, in rats, dorsal horn neurons whose visceral nociceptive responses were not inhib- ited by the CSIP (LC/SC-unaffected neurons) (Liu et al., 2008). To determine the possible role of LC/SC-unaffected neurons in pain processing and visceromotor reflexes (muscular defense), we electrically stimulated the descending colon, and simultaneously recorded both the evoked discharge in the ventral posterolat- eral (VPL) nucleus of the thalamus and the electromyogram (EMG) of the abdominal muscle under halothane anesthesia ( Figures 6 , 7 ). It is known that spinothalamic tract neurons that are excited by visceral nociceptive stimuli are located in the dor- sal horn and that postsynaptic dorsal column neurons, which conduct visceral nociceptive signals in the dorsal column, are located near the central canal of the spinal cord (Al-Chaer et al., 1996, 1999; Ness, 2000; Palecek et al., 2002, 2003; Willis and Coggeshall, 2004). We clarified that all the LC/SC-unaffected neurons tested were located in the dorsal horn, and none were in the area near the central canal of the spinal cord (Tsuruoka et al., 2008). This result suggests that the LC/SC-unaffected neu- rons include spinothalamic tract cells. It has been confirmed that the spinothalamic tract neurons are involved in the develop- ment of visceromotor reflexes, such as muscular defense (Palecek and Willis, 2003). Thus, the LC/SC-unaffected neurons may be involved in visceromotor reflexes. As seen in Figures 6 , 7 , the inhibitory effect of LC/SC stimulation was different between in the evoked discharge of the VPL and the EMG of the abdom- inal musculature. The EMG was not completely inhibited even when the stimulus intensity was increased up to 150 μ A, whereas the evoked discharge disappeared. If the LC/SC-unaffected neu- rons were involved in visceromotor reflexes, the presence of the LC/SC-unaffected neurons can explain the fact that visceromo- tor reflexes are not completely inhibited during activation of the coeruleospinal modulation system. The minimum visceromotor reflex responses (muscular defense) are maintained by the pres- ence of LC/SC-unaffected neurons, which play an important role of protecting visceral organs. Visceral nociceptive information ascending in the spinothala- mic tract subserves multiple functions, acting as components of visceromotor reflexes as well as signals for producing visceral pain (Palecek and Willis, 2003). The location of the LC/SC-unaffected neurons in the spinal cord and the different inhibitory effects of LC/SC stimulation between the evoked discharge and the EMG responses lead to the conclusion that the LC/SC-unaffected neurons contribute to the maintenance of a minimum tonic con- traction of the abdominal musculature even when visceral pain is completely inhibited. Considering a role of muscular defense, it is reasonable to assume that some visceral nociceptive neurons are not under the control of the CSIP to prevent the disappearance FIGURE 6 | Difference in inhibitory effect of LC/SC stimulation between the evoked discharge and the EMG activity. (A) Stimulation site of the LC/SC (closed circle). (B) The EMG activity in the masseter muscle evoked by an increase in the intensity in LC/SC stimulation. (C) An example of the effect of graded LC/SC stimulation on the evoked discharge and the EMG activity. Note that LC/SC stimulation at a stimulus intensity below 50 μ A never produced EMG activity of the masseter muscle associated with stimulation of the mesencephalic trigeminal nucleus, located just lateral to the LC/SC, and that EMG activity was still observed even when the evoked discharge was completely inhibited by LC/SC stimulation at an intensity over 50 μ A. Electrical stimulation of the descending colon is indicated by the arrow. (Tsuruoka et