Post-translational modification of NMDA receptor GluN2B subunit and its roles in chronic pain and memory

N-methyl-d-aspartate receptors (NMDA receptors) play critical roles in brain functions and diseases. The expression, trafficking, synaptic location and function of different NMDA receptor subtypes are not static, but regulated dynamically in a cell-specific and synapse-specific manner during physiological and pathological conditions. In this review, we will examine recent evidence on the post-translational modulation of NMDA receptors subunit, in particular GluN2B subunit, such as phosphorylation, palmitoylation, and ubiquitination. In parallel, we will overview the roles of these modifications of GluN2B-NMDA receptor subtype in physiological functions, such as learning and memory, and pathophysiological conditions, such as chronic pain, ischemia and neurodegenerative diseases.     

Emotional regulation of pain: the role of noradrenaline in the amygdala

The perception of pain involves the activation of the spinal pathway as well as the supra-spinal pathway,which targets brain regions involved in affective and cognitive processes.Pain and emotions have the capacity to influence each other reciprocally;negative emotions,such as depression and anxiety,increase the risk for chronic pain,which may lead to anxiety and depression.The amygdala is a key-player in the expression of emotions,receives direct nociceptive information from the parabrachial nucleus,and is densely innervated by noradrenergic brain centers.In recent years,the amygdala has attracted increasing interest for its role in pain perception and modulation.In this review,we will give a short overview of structures involved in the pain pathway,zoom in to afferent and efferent connections to and from the amygdala,with emphasis on the direct parabrachio-amygdaloid pathway and discuss the evidence for amygdala’s role in pain processing and modulation.In addition to the involvement of the amygdala in negative emotions during the perception of pain,this brain structure is also a target site for many neuromodulators to regulate the perception of pain.We will end this article with a short review on the effects of noradrenaline and its role in hypoalgesia and analgesia.     

Fatty acid and peptide profiles in plasma membrane and membrane rafts of PUFA supplemented RAW264.7 macrophages

The eukaryotic cell membrane possesses numerous complex functions, which are essential for life. At this, the composition and the structure of the lipid bilayer are of particular importance. Polyunsaturated fatty acids may modulate the physical properties of biological membranes via alteration of membrane lipid composition affecting numerous physiological processes, e.g. in the immune system. In this systematic study we present fatty acid and peptide profiles of cell membrane and membrane rafts of murine macrophages that have been supplemented with saturated fatty acids as well as PUFAs from the n-3, the n-6 and the n-9 family. Using fatty acid composition analysis and mass spectrometry-based peptidome profiling we found that PUFAs from both the n-3 and the n-6 family have an impact on lipid and protein composition of plasma membrane and membrane rafts in a similar manner. In addition, we found a relation between the number of bis-allyl-methylene positions of the PUFA added and the unsaturation index of plasma membrane as well as membrane rafts of supplemented cells. With regard to the proposed significance of lipid microdomains for disease development and treatment our study will help to achieve a targeted dietary modulation of immune cell lipid bilayers.     

How emotion strengthens the recollective experience: a time-dependent hippocampal process

Emotion significantly strengthens the subjective recollective experience even when objective accuracy of the memory is not improved. Here, we examine if this modulation is related to the effect of emotion on hippocampal-dependent memory consolidation. Two critical predictions follow from this hypothesis. First, since consolidation is assumed to take time, the enhancement in the recollective experience for emotional compared to neutral memories should become more apparent following a delay. Second, if the emotion advantage is critically dependent on the hippocampus, then the effects should be reduced in amnesic patients with hippocampal damage. To test these predictions we examined the recollective experience for emotional and neutral photos at two retention intervals (Experiment 1), and in amnesics and controls (Experiment 2). Emotional memories were associated with an enhancement in the recollective experience that was greatest after a delay, whereas familiarity was not influenced by emotion. In amnesics with hippocampal damage the emotion effect on recollective experience was reduced. Surprisingly, however, these patients still showed a general memory advantage for emotional compared to neutral items, but this effect was manifest primarily as a facilitation of familiarity. The results support the consolidation hypothesis of recollective experience, but suggest that the effects of emotion on episodic memory are not exclusively hippocampally mediated. Rather, emotion may enhance recognition by facilitating familiarity when recollection is impaired due to hippocampal damage.     

Modulation of aggressive behaviour by fighting experience: mechanisms and contest outcomes

Experience in aggressive contests often affects behaviour during, and the outcome of, later contests. This review discusses evidence for, variations in, and consequences of such effects. Generally, prior winning experiences increase, and prior losing experiences decrease, the probability of winning in later contests, reflecting modifications of expected fighting ability. We examine differences in the methodologies used to study experience effects, and the relative importance and persistence of winning and losing experiences within and across taxa. We review the voluminous, but somewhat disconnected, literature on the neuroendocrine mechanisms that mediate experience effects. Most studies focus on only one of a number of possible mechanisms without providing a comprehensive view of how these mechanisms are integrated into overt behaviour. More carefully controlled work on the mechanisms underlying experience effects is needed before firm conclusions can be drawn.Behavioural changes during contests that relate to prior experience fall into two general categories. Losing experiences decrease willingness to engage in a contest while winning experiences increase willingness to escalate a contest. As expected from the sequential assessment model of contest behaviour, experiences become less important to outcomes of contests that escalate to physical fighting.A limited number of studies indicate that integration of multiple experiences can influence current contest behaviour. Details of multiple experience integration for any species are virtually unknown. We propose a simple additive model for this integration of multiple experiences into an individual's expected fighting ability. The model accounts for different magnitudes of experience effects and the possible decline in experience effects over time.Predicting contest outcomes based on prior experiences requires an algorithm that translates experience differences into contest outcomes. We propose two general types of model, one based solely on individual differences in integrated multiple experiences and the other based on the probability contests reach the escalated phase. The difference models include four algorithms reflecting possible decision rules that convert the perceived fighting abilities of two rivals into their probabilities of winning. The second type of algorithm focuses on how experience influences the probability that a subsequent contest will escalate and the fact that escalated contests may not be influenced by prior experience. Neither type of algorithm has been systematically investigated.Finally, we review models for the formation of dominance hierarchies that assume that prior experience influences contest outcome. Numerous models have reached varied conclusions depending on which factors examined in this review are included. We know relatively little about the importance of and variation in experience effects in nature and how they influence the dynamics of aggressive interactions in social groups and random assemblages of individuals. Researchers should be very active in this area in the next decade. The role of experience must be integrated with other influences on contest outcome, such as prior residency, to arrive at a more complete picture of variations in contest outcomes. We expect that this integrated view will be important in understanding other types of interactions between individuals, such as mating and predator-prey interactions, that also are affected significantly by prior experiences.     

Subjecting elite athletes to inspiratory breathing load reveals behavioral and neural signatures of optimal performers in extreme environments

Background

It is unclear whether and how elite athletes process physiological or psychological challenges differently than healthy comparison subjects. In general, individuals optimize exercise level as it relates to differences between expected and experienced exertion, which can be conceptualized as a body prediction error. The process of computing a body prediction error involves the insular cortex, which is important for interoception, i.e. the sense of the physiological condition of the body. Thus, optimal performance may be related to efficient minimization of the body prediction error. We examined the hypothesis that elite athletes, compared to control subjects, show attenuated insular cortex activation during an aversive interoceptive challenge.

Methodology/Principal Findings

Elite adventure racers (n = 10) and healthy volunteers (n = 11) performed a continuous performance task with varying degrees of a non-hypercapnic breathing load while undergoing functional magnetic resonance imaging. The results indicate that (1) non-hypercapnic inspiratory breathing load is an aversive experience associated with a profound activation of a distributed set of brain areas including bilateral insula, dorsolateral prefrontal cortex and anterior cingulated; (2) adventure racers relative to comparison subjects show greater accuracy on the continuous performance task during the aversive interoceptive condition; and (3) adventure racers show an attenuated right insula cortex response during and following the aversive interoceptive condition of non-hypercapnic inspiratory breathing load.

Conclusions/Significance

These findings support the hypothesis that elite athletes during an aversive interoceptive condition show better performance and an attenuated insular cortex activation during the aversive experience. Interestingly, differential modulation of the right insular cortex has been found previously in elite military personnel and appears to be emerging as an important brain system for optimal performance in extreme environments.     

Adaptive control of movement deceleration during saccades

As you read this text, your eyes make saccades that guide your fovea from one word to the next. Accuracy of these movements require the brain to monitor and learn from visual errors. A current model suggests that learning is supported by two different adaptive processes, one fast (high error sensitivity, low retention), and the other slow (low error sensitivity, high retention). Here, we searched for signatures of these hypothesized processes and found that following experience of a visual error, there was an adaptive change in the motor commands of the subsequent saccade. Surprisingly, this adaptation was not uniformly expressed throughout the movement. Rather, after experience of a single error, the adaptive response in the subsequent trial was limited to the deceleration period. After repeated exposure to the same error, the acceleration period commands also adapted, and exhibited resistance to forgetting during set-breaks. In contrast, the deceleration period commands adapted more rapidly, but suffered from poor retention during these same breaks. State-space models suggested that acceleration and deceleration periods were supported by a shared adaptive state which re-aimed the saccade, as well as two separate processes which resembled a two-state model: one that learned slowly and contributed primarily via acceleration period commands, and another that learned rapidly but contributed primarily via deceleration period commands.     

Transcriptional response to foraging experience in the honey bee mushroom bodies

Enriched environmental conditions induce neuroanatomical plasticity in a variety of vertebrate and invertebrate species. We explored the molecular processes associated with experience-induced plasticity, using naturally occurring foraging behavior in adult worker honey bees (Apis mellifera). In honey bees, the mushroom bodies exhibit neuroanatomical plasticity that is dependent on accumulated foraging experience. To investigate molecular processes associated with foraging experience, we performed a time-course microarray study to examine gene expression changes in the mushroom bodies as a function of days foraged. We found almost 500 genes that were regulated by duration of foraging experience. Bioinformatic analyses of these genes suggest that foraging experience is associated with multiple molecular processes in the mushroom bodies, including some that may contribute directly to neuropil growth, and others that could potentially protect the brain from the effects of aging and physiological stress.     

The role of interoception in learned visceral control.

Research concerned with the psychology and physiology of interoceptive processes is reviewed with the purpose of evaluating theoretical formulations of learned visceral control. Basic animal research in interoception provides relevant information; however, much research dealing directly with interoception and learned control is inadequate due either to inappropriate measurement of interoceptive ability or to poor experimental design. The two primary theoretical orientations linking interoception and learned visceral control differ according to the role ascribed to external feedback; the first views feedback as an enhancement of interoceptive cues, the second as an enhancement of exteroceptive cues. These theories are discussed with regard to recent investigations of learned visceral control.     

Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles.     

Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles.     

The role of interoception in learned visceral control

Research concerned with the psychology and physiology of interoceptive processes is reviewed with the purpose of evaluating theoretical formulations of learned visceral control. Basic animal research in interoception provides relevant information; however, much research dealing directly with interoception and learned control is inadequate due either to inappropriate measurement of interoceptive ability or to poor experimental design. The two primary theoretical orientations linking interoception and learned visceral control differ according to the role ascribed to external feedback; the first views feedback as an enhancement of interoceptive cues, the second as an enhancement of exteroceptive cues. These theories are discussed with regard to recent investigations of learned visceral control.     

Regulation of autophagy by polyphenols: Paving the road for treatment of neurodegeneration

In the present paper, we will discuss on the importance of autophagy in the central nervous system, and outline the relation between autophagic pathways and the pathogenesis of neurodegenerative disorders. The potential therapeutic benefits of naturally occurring phytochemicals as pharmacological modulators of autophagy will also be addressed. Our findings provide renewed insight on the molecular modes of protection by polyphenols, which is likely to be at least in part mediated not only by their potent antioxidant and anti-inflammatory effects, but also through modulation of autophagic processes to remove the aberrant protein aggregates.     

有丝分裂期MPM-2磷蛋白家族及其调控因子

由于有丝分裂磷蛋白单克隆抗体(mitotic phosphoprotein monoclonal antibogy-2,MPM-2)识别很大一组在M期特异磷酸化的蛋白质,因而引起研究者的极大兴趣。该抗体亦成为研究M期功能性磷蛋白的重要工具。多个MPM-2磷蛋白已经定位在各种有丝分裂装置上,如中心体、着丝粒、纺锤体、染色体骨架及中体等,显示MPM-2磷蛋白在调控有丝分裂进程方面所扮演的重要角色。结合作者的工作和这一领域的相关研究,概述了MPM-2磷蛋白的细胞周期分布特点及其在细胞有丝分裂期进程中的重要功能,重点介绍MPM-2磷酸化位点的研究状况以及到目前为止已鉴定的MPM-2磷蛋白家族成员的基本情况,并总结了MPM-2磷蛋白相关调控因子的研究进展。     

共情脑机制的研究现状与展望

作为社会交往中的重要因素,共情是指理解并体验他人的情感和知觉感受的能力。目前的研究认为共情依赖于直接的投射机制而非逻辑推理。即观察到他人的情绪状态会涉及一部分处理自我情感的大脑结构的激活,该过程同时还会受到社会认知因素的调节。由于理解和间接体验他人痛觉的能力是维系社会纽带必不可少的,目前研究者越来越多地通过对痛觉共情的研究来揭示关于共情的普遍的神经机制。此外共情的动物模型、镜像神经元系统与共情的产生以及共情的调节等方向也将是研究的重点。     

Interoceptive Focus Shapes the Experience of Time

The perception of time is a fundamental part of human experience. Recent research suggests that the experience of time emerges from emotional and interoceptive (bodily) states as processed in the insular cortex. Whether there is an interaction between the conscious awareness of interoceptive states and time distortions induced by emotions has rarely been investigated so far. We aimed to address this question by the use of a retrospective time estimation task comparing two groups of participants. One group had a focus on interoceptive states and one had a focus on exteroceptive information while watching film clips depicting fear, amusement and neutral content. Main results were that attention to interoceptive processes significantly affected subjective time experience. Fear was accompanied with subjective time dilation that was more pronounced in the group with interoceptive focus, while amusement led to a quicker passage of time which was also increased by interoceptive focus. We conclude that retrospective temporal distortions are directly influenced by attention to bodily responses. These effects might crucially interact with arousal levels. Sympathetic nervous system activation affecting memory build-up might be the decisive factor influencing retrospective time judgments. Our data substantially extend former research findings underscoring the relevance of interoception for the effects of emotional states on subjective time experience.     

Opioids and opioid receptors mediating antinociception at various levels of the neuraxis

One of the central issues in present experimental pain research is to establish the identity, location, and mechanism of action of various opioids (opioid peptides and alkaloids) and multiple opioid receptors in the modulation of nociceptive processes. At the cerebral level, studies employing several experimental approaches point to an essential role of beta-endorphin in analgesia, induced by electrical stimulation of the periaqueductal grey of the midbrain. Tolerance and cross-tolerance studies suggest that mu-opioid receptors mediate this effect. The significance of delta- and, in particular, chi-opioid receptors in cerebral pain modulation is less well documented. At the spinal level, nociception is relayed in the dorsal horn, where opioid peptides as well as all types of opioid receptors are abundant. mu-opioid receptor-mediated antinociceptive processes appear to be most important in this region, but delta-opioid receptors may also be involved. In addition, a role of chi-opioid receptors can be demonstrated under certain conditions. Recent experiments indicate that opioids may also modulate nociception in the periphery, in particular in inflamed tissue. The identification of opioid receptors and their endogenous ligands, the opioid peptides, marked the beginning of a new era in pain research. The differentiation of several types of opioid receptors and the subsequent characterization of a series of opioid peptides illustrate the striking complexity of opioid systems. The implications of this multiplicity for neurobiology in general and for the understanding of pain mechanisms in particular are presently not fully understood. In this presentation some aspects of opioidergic pain control at various levels of the neuraxis will be discussed.     

内感受对成瘾行为的诱导及其岛叶的调控机制

内感受是机体对自身生理状态的感觉.近年来,越来越多的研究证据表明,内感受可以调控成瘾行为,岛叶是其发挥作用的重要神经基础之一.目前,对岛叶作用机制的研究正受到高度重视.本文从岛叶的基本结构和功能出发,结合近几年来岛叶调控成瘾行为、行为抑制以及情感决策的重要发现,讨论岛叶在成瘾发生及发展过程中的可能作用及其机制,并根据已有的实验证据,试图提出较为合理的研究展望,以推动相关神经环路和神经化学机制研究的深入.     

Involvement of orexin-2 receptors in the ventral tegmental area and nucleus accumbens in the antinociception induced by the lateral hypothalamus stimulation in rats

Orexin, which is mainly produced by orexin-expressing neurons in the lateral hypothalamus (LH), plays an important role in pain modulation. Both kinds of orexin-1 (Ox1) and orexin-2 (Ox2) receptors have been found at high density in the ventral tegmental area (VTA) and nucleus accumbens (NAc). However, the quantity of Ox1 receptors in the VTA is more than that in the NAc. Additionally, it seems that the functional interaction between the LH, VTA and NAc implicates pain processing and modulation. In this study, we tried to examine the involvement of Ox2 receptors in the NAc and VTA using tail-flick test as an animal model of acute pain following microinjection of effective dose of carbachol (125 nmol/0.5 μl saline) into the LH. In this set of experiments, different doses of TCS OX2 29 as an Ox2 receptor antagonist were microinjected into the VTA (1, 7 and 20 nmol/0.3 μl DMSO) and the NAc (2, 10, 20 and 40 nmol/0.5 μl DMSO) 5 min prior to carbachol administration. Administration of TCS OX2 29 into the VTA and NAc dose-dependently blocked intra-LH carbachol-induced antinociception. However, the inhibitory effect of TCS OX2 29 as an Ox2 receptor antagonist was more potent in the VTA than that in the NAc. It seems that VTA orexinergic receptors are more effective on LH stimulation-induced antinociception and the modulation of pain descending inhibitory system originated from the LH than those of the same receptors in the nucleus accumbens in rats.     

An Experimental Paradigm for the Prediction of Post-Operative Pain (PPOP)

Many women undergo cesarean delivery without problems, however some experience significant pain after cesarean section. Pain is associated with negative short-term and long-term effects on the mother. Prior to women undergoing surgery, can we predict who is at risk for developing significant postoperative pain and potentially prevent or minimize its negative consequences? These are the fundamental questions that a team from the University of Washington, Stanford University, the Catholic University in Brussels, Belgium, Santa Joana Women''s Hospital in São Paulo, Brazil, and Rambam Medical Center in Israel is currently evaluating in an international research collaboration. The ultimate goal of this project is to provide optimal pain relief during and after cesarean section by offering individualized anesthetic care to women who appear to be more ''susceptible'' to pain after surgery.A significant number of women experience moderate or severe acute post-partum pain after vaginal and cesarean deliveries. ¹ Furthermore, 10-15% of women suffer chronic persistent pain after cesarean section. ² With constant increase in cesarean rates in the US ³ and the already high rate in Brazil, this is bound to create a significant public health problem. When questioning women''s fears and expectations from cesarean section, pain during and after it is their greatest concern. ⁴ Individual variability in severity of pain after vaginal or operative delivery is influenced by multiple factors including sensitivity to pain, psychological factors, age, and genetics. The unique birth experience leads to unpredictable requirements for analgesics, from ''none at all'' to ''very high'' doses of pain medication. Pain after cesarean section is an excellent model to study post-operative pain because it is performed on otherwise young and healthy women. Therefore, it is recommended to attenuate the pain during the acute phase because this may lead to chronic pain disorders. The impact of developing persistent pain is immense, since it may impair not only the ability of women to care for their child in the immediate postpartum period, but also their own well being for a long period of time.In a series of projects, an international research network is currently investigating the effect of pregnancy on pain modulation and ways to predict who will suffer acute severe pain and potentially chronic pain, by using simple pain tests and questionnaires in combination with genetic analysis. A relatively recent approach to investigate pain modulation is via the psychophysical measure of Diffuse Noxious Inhibitory Control (DNIC). This pain-modulating process is the neurophysiological basis for the well-known phenomenon of ''pain inhibits pain'' from remote areas of the body. The DNIC paradigm has evolved recently into a clinical tool and simple test and has been shown to be a predictor of post-operative pain.⁵ Since pregnancy is associated with decreased pain sensitivity and/or enhanced processes of pain modulation, using tests that investigate pain modulation should provide a better understanding of the pathways involved with pregnancy-induced analgesia and may help predict pain outcomes during labor and delivery. For those women delivering by cesarean section, a DNIC test performed prior to surgery along with psychosocial questionnaires and genetic tests should enable one to identify women prone to suffer severe post-cesarean pain and persistent pain. These clinical tests should allow anesthesiologists to offer not only personalized medicine to women with the promise to improve well-being and satisfaction, but also a reduction in the overall cost of perioperative and long term care due to pain and suffering. On a larger scale, these tests that explore pain modulation may become bedside screening tests to predict the development of pain disorders following surgery.