Reward representations and reward-related learning in the human brain: insights from neuroimaging

This review outlines recent findings from human neuroimaging concerning the role of a highly interconnected network of brain areas including orbital and medial prefrontal cortex, amygdala, striatum and dopaminergic mid-brain in reward processing. Distinct reward-related functions can be attributed to different components of this network. Orbitofrontal cortex is involved in coding stimulus reward value and in concert with the amygdala and ventral striatum is implicated in representing predicted future reward. Such representations can be used to guide action selection for reward, a process that depends, at least in part, on orbital and medial prefrontal cortex as well as dorsal striatum.     

Dead cells don't dance: insights from live-cell imaging in plants

Live-cell imaging has yielded surprising pictures of subcellular structures and dynamics in living plant cells. Recent studies illustrate the power of live-cell observation for revealing new biological phenomena and for generating new questions about plant cell structure and function.     

Genes and photons: new avenues into the neuronal basis of behavior

A convergence of advances in optical methods and a better understanding of the genetics of development promise to revolutionize the study of neuronal circuits and their links to behavior. One of the great challenges in systems neurobiology has been to monitor and perturb activity in populations of identified neurons in vivo. Recent work has begun to achieve this goal through a combination of modern imaging methods with genetic labeling and perturbation.     

Human altruism: economic, neural, and evolutionary perspectives

Human cooperation represents a spectacular outlier in the animal world. Unlike other creatures, humans frequently cooperate with genetically unrelated strangers, often in large groups, with people they will never meet again, and when reputation gains are small or absent. Experimental evidence and evolutionary models suggest that strong reciprocity, the behavioral propensity for altruistic punishment and altruistic rewarding, is of key importance for human cooperation. Here, we review both evidence documenting altruistic punishment and altruistic cooperation and recent brain imaging studies that combine the powerful tools of behavioral game theory with neuroimaging techniques. These studies show that mutual cooperation and the punishment of defectors activate reward related neural circuits, suggesting that evolution has endowed humans with proximate mechanisms that render altruistic behavior psychologically rewarding.     

JWA regulates chronic morphine dependence via the delta opioid receptor

Opioid dependence is correlated with the adaptive changes at the cellular level following chronic opioid use, and believed to be the main cause for the relapse of drug taking behavior of addicts. Despite decades of intensive studies, the underlying mechanisms of morphine dependence are still unclear. Here, we present evidence that JWA was induced by chronic morphine treatment in specific brain regions, and knockdown of JWA expression significantly reduced the withdrawal response to chronic morphine treatment in rats. We further demonstrated that the morphine induced DOR expression, while activation of DARPP-32 and MAP kinase was suppressed by JWA knockdown. Through an in vitro cell model of chronic morphine exposure, we also found that JWA is required for maintaining the stability of DOR via the ubiquitin–proteasome pathway. These observations suggest that JWA is directly involved in the regulation of chronic morphine dependence.     

Exploiting natural peptide diversity: novel research tools and drug leads

During the course of evolution, nature has developed a vast number of peptides in all living and past species that display an exceeding diversity of structure and biological effects, such as hormonal and enzyme-controlling activity, communication between cells, and participation in host defence. Sensitive mass spectrometric technologies have been introduced and facilitate access to new natural peptides, even in trace amounts, and allow the quantitative determination of the peptide status of cells, organs and whole organisms (peptidomics). Among the large number of new biologically active peptides identified from an increasing variety of natural sources, regulators of ion channels, chemoattractants, protease inhibitors, metabolism-related hormones, cytotoxins, and antimicrobials have been found. These novel peptides serve as research tools and have potential as diagnostic biomarkers and for the development of peptide and peptidometic drugs.     

Rewiring cell signaling: the logic and plasticity of eukaryotic protein circuitry

Living cells rival computers in their ability to process external information and make complex behavioral decisions. Many of these decisions are made by networks of interacting signaling proteins. Ongoing structural, biochemical and cell-based studies have begun to reveal several common principles by which protein components are used to specifically transmit and process information. Recent engineering studies demonstrate that these relatively simple principles can be used to rewire signaling behavior in a process that mimics the evolution of new phenotypic responses.     

Learning in the oculomotor system: from molecules to behavior

A combination of system-level and cellular—molecular approaches is moving studies of oculomotor learning rapidly toward the goal of linking synaptic plasticity at specific sites in oculomotor circuits with changes in the signal-processing functions of those circuits, and, ultimately, with changes in eye movement behavior. Recent studies of saccadic adaptation illustrate how careful behavioral analysis can provide constraints on the neural loci of plasticity. Studies of vestibulo-ocular adaptation are beginning to examine the molecular pathways contributing to this form of cerebellum-dependent learning.     

Three's company: component structures bring a closer view of tripartite drug efflux pumps

Bacterial multidrug resistance is a serious clinical problem and is commonly conferred by tripartite efflux 'pumps' in the prokaryotic cell envelope. Crystal structures of the three components of a drug efflux pump have now been solved: the outer membrane TolC exit duct in the year 2000, the inner membrane AcrB antiporter in 2002 and the periplasmic adaptor MexA in 2004. These structures have enhanced our understanding of the principles underlying pump assembly and operation, and present pumps as new drug targets.     

Plant heterotrimeric G protein function: insights from Arabidopsis and rice mutants

Heterotrimeric G proteins have been implicated in a wide range of plant processes. These include responses to hormones, drought, and pathogens, and developmental events such as lateral root formation, hypocotyl elongation, hook opening, leaf expansion, and silique development. Results and concepts emerging from recent phenotypic analyses of G-protein component mutants in Arabidopsis and rice are adding to our understanding of G-protein mechanisms and functions in higher plants.     

From the bottom of the heart: anteroposterior decisions in cardiac muscle differentiation

Recently, studies on specification of axes in the developing embryo have focused on the heart, which is the first functional organ to form and probably responds to common cues controlling positional information in surrounding tissues. The early differentiation of heart cells affords an opportunity to link the acquisition of regional identity with the signals underlying terminal differentiation. In the past year, a wealth of information on these signals has emerged, elucidating the general pathways controlling body axes in the context of the developing heart.     

Vasopressin, oxytocin and social behaviour

Understanding the neurobiology of social behaviour in mammals has been considerably advanced by the findings from two species of vole, one of which is monogamous and pair bonds whereas the other species is promiscuous and fails to form any long-lasting social relationships. The combination of neurobehavioural studies and molecular genetics has determined behavioural differences between the two species linked to the neural distribution of vasopressin 1A receptor in the male brain. More importantly, vasopressin 1A receptor gene transfer including the upstream regulatory sequence has enhanced male social affiliation in a non-monogamous species. Male affiliative bonding depends upon release of both vasopressin and dopamine in the ventral striatum enhancing the reward value of odour cues that signal identity.     

Selecting the signals for a brain-machine interface

Brain-machine interfaces are being developed to assist paralyzed patients by enabling them to operate machines with recordings of their own neural activity. Recent studies show that motor parameters, such as hand trajectory, and cognitive parameters, such as the goal and predicted value of an action, can be decoded from the recorded activity to provide control signals. Neural prosthetics that use simultaneously a variety of cognitive and motor signals can maximize the ability of patients to communicate and interact with the outside world. Although most studies have recorded electroencephalograms or spike activity, recent research shows that local field potentials (LFPs) offer a promising additional signal. The decode performances of LFPs and spike signals are comparable and, because LFP recordings are more long lasting, they might help to increase the lifetime of the prosthetics.     

Bioactives from bitter melon enhance insulin signaling and modulate acyl carnitine content in skeletal muscle in high-fat diet-fed mice

Bioactive components from bitter melon (BM) have been reported to improve glucose metabolism in vivo, but definitive studies on efficacy and mechanism of action are lacking. We sought to investigate the effects of BM bioactives on body weight, muscle lipid content and insulin signaling in mice fed a high-fat diet and on insulin signaling in L6 myotubes. Male C57BL/6J mice were randomly divided into low-fat diet control (LFD), high-fat diet (HFD) and HFD plus BM (BM) groups. Body weight, body composition, plasma glucose, leptin, insulin and muscle lipid profile were determined over 12 weeks. Insulin signaling was determined in the mouse muscle taken at end of study and in L6 myotubes exposed to the extract. Body weight, plasma glucose, insulin, leptin levels and HOMA-IR values were significantly lower in the BM-fed HFD group when compared to the HFD group. BM supplementation significantly increased IRS-2, IR β, PI 3K and GLUT4 protein abundance in skeletal muscle, as well as phosphorylation of IRS-1, Akt1 and Akt2 when compared with HFD (P<.05 and P<.01). BM also significantly reduced muscle lipid content in the HFD mice. BM extract greatly increased glucose uptake and enhanced insulin signaling in L6 myotubes. This study shows that BM bioactives reduced body weight, improved glucose metabolism and enhanced skeletal muscle insulin signaling. A contributing mechanism to the enhanced insulin signaling may be associated with the reduction in skeletal muscle lipid content. Nutritional supplementation with this extract, if validated for human studies, may offer an adjunctive therapy for diabetes.     

A mechanism underlying compound-induced voltage shift in the current activation of hERG by antiarrhythmic agents

Nifekalant and azimilide, Class III antiarrhythmic agents, block the human ether-à-go-go-related gene K⁺ (hERG) channel. However, when a depolarizing membrane potential is applied, they also increase the current at low potentials by shifting its activation curve towards hyperpolarizing voltages. This phenomenon is called ‘facilitation’. In this study, we tried to address the mechanism underlying the facilitation by analyzing the effects of various compounds on hERG expressed in Xenopus oocytes. Like nifekalant, amiodarone, quinidine and carvedilol, but not by dofetilide, caused the current facilitation of hERG, suggesting that the facilitation is a common effect to a subset of hERG blockers. As the concentration of each compound was increased, the total hERG current was suppressed progressively, while the current at low potentials was augmented. Activation curves of the remaining hERG current in the facilitation condition could be described as the sum of two Boltzmann functions reflecting two populations of hERG currents having different activation curves. The voltage shift in the activation curve from control was constant for each compound even at different concentrations; −31 mV in amiodarone, −27 mV in nifekalant, −17 mV in quinidine and −12 mV in carvedilol. Therefore, the facilitation is based on the appearance of hERG whose voltage-dependence for the activation is shifted towards hyperpolarizing voltages.     

Effects of amphetamine on dopamine release in the rat nucleus accumbens shell region depend on cannabinoid CB1 receptor activation

The psychostimulant drug amphetamine is often prescribed to treat Attention-Deficit/Hyperactivity Disorder. The behavioral effects of the psychostimulant drug amphetamine depend on its ability to increase monoamine neurotransmission in brain regions such as the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC). Recent behavioral data suggest that the endocannabinoid system also plays a role in this respect. Here we investigated the role of cannabinoid CB1 receptor activity in amphetamine-induced monoamine release in the NAC and/or mPFC of rats using in vivo microdialysis. Results show that systemic administration of a low, clinically relevant dose of amphetamine (0.5mg/kg) robustly increased dopamine and norepinephrine release (to ～175-350% of baseline values) in the NAC shell and core subregions as well as the ventral and dorsal parts of the mPFC, while moderately enhancing extracellular serotonin levels (to ～135% of baseline value) in the NAC core only. Although systemic administration of the CB1 receptor antagonist SR141716A (0-3mg/kg) alone did not affect monoamine release, it dose-dependently abolished amphetamine-induced dopamine release specifically in the NAC shell. SR141716A did not affect amphetamine-induced norepinephrine or serotonin release in any of the brain regions investigated. Thus, the effects of acute CB1 receptor blockade on amphetamine-induced monoamine transmission were restricted to dopamine, and more specifically to mesolimbic dopamine projections into the NAC shell. This brain region- and monoamine-selective role of CB1 receptors is suggested to subserve the behavioral effects of amphetamine.