Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been implicated in the pathophysiology of neurodegenerative disorders, including Huntington’s disease (HD) . A central hallmark of HD is neurodegeneration caused by a polyglutamine expansion in the huntingtin (htt) protein . Here we exploit a transgenic Drosophila melanogaster model of HD to interrogate the therapeutic potential of KP manipulation. We observe that genetic and pharmacological inhibition of kynurenine 3-monooxygenase (KMO) increases levels of the neuroprotective metabolite kynurenic acid (KYNA) relative to the neurotoxic metabolite 3-hydroxykynurenine (3-HK) and ameliorates neurodegeneration. We also find that genetic inhibition of tryptophan 2,3-dioxygenase (TDO), the first and rate-limiting step in the pathway, leads to a similar neuroprotective shift toward KYNA synthesis. Importantly, we demonstrate that the feeding of KYNA and 3-HK to HD model flies directly modulates neurodegeneration, underscoring the causative nature of these metabolites. This study provides the first genetic evidence that inhibition of KMO and TDO activity protects against neurodegenerative disease in an animal model, indicating that strategies targeted at two key points within the KP may have therapeutic relevance in HD, and possibly other neurodegenerative disorders.
Ciliary compartmentalization plays pivotal roles in ciliogenesis and in various signaling pathways. Here we describe a structure at the ciliary base that appears to have all the features required for compartmentalization and which we thus call the “ciliary partitioning system” (CPS). This complex consists of the terminal plate, which serves as a cytosolic “ciliary pore complex” (CPC), and a membrane region well suited to serve as a diffusion barrier. The CPC is a plate-shaped structure containing 9 pores through which the microtubule doublets of the basal body pass. Each pore expands from the doublet B-tubule into an opening well-suited for the passage of intraflagellar transport particles. The membrane diffusion barrier encompasses an extended region of detergent-resistant periciliary membrane (ciliary pocket) and a ring complex that connects the CPC to the membrane. Proteomics analysis shows involvement of the ciliary pocket in vesicle trafficking, suggesting that this region plays an active role in membrane transport. The CPC and the ring together form a complete partition defining the ciliary boundary.
The Septum Initiation Network (SIN) regulates multiple functions during late mitosis to ensure successful completion of cytokinesis in S. pombe. One mechanism by which the SIN promotes cytokinesis is by inhibiting a competing polarity pathway called the MOR , which is required for initiation of polarized growth following completion of cytokinesis . Mutual antagonism between the two NDR kinase pathways, SIN and MOR, is required to coordinate cytoskeletal rearrangements during the mitosis-interphase transition. To determine how the SIN regulates the MOR pathway, we developed a proteomics approach that allowed us to identify multiple substrates of the SIN effector kinase, Sid2, including the MOR pathway components Nak1 kinase and an associated protein Sog2. We show that Sid2 phosphorylation of Nak1 causes removal of Nak1 from the SPBs, which may both relieve Nak1 inhibition of the SIN, and block MOR signaling by preventing interaction of Nak1 with the scaffold protein Mor2. Because the SIN and MOR are conserved in mammalian cells (Hippo and Ndr1/2 pathways respectively), this work may provide important insight into how the activities of these essential pathways are coordinated.
Learned cues for pleasant rewards often elicit desire, which in addicts may become compulsive. According to the dominant view in addiction neuroscience and reinforcement modeling, such desires are the simple products of learning, coming from past association with reward outcome.
We demonstrate that cravings are more than merely the product of accumulated pleasure memories: even a repulsive learned cue for unpleasantness can become suddenly desired via activation of mesocorticolimbic circuitry. Rats learned repulsion toward a Pavlovian cue (briefly-inserted metal lever) that always predicted an unpleasant Dead Sea saltiness sensation. Yet upon first re-encounter in a novel sodium depletion state to promote mesocorticolimbic reactivity (reflected by elevated Fos activation in ventral tegmentum, nucleus accumbens, ventral pallidum, and orbitofrontal prefrontal cortex), the learned cue was instantly transformed into an attractive and powerful motivational magnet. Rats jumped and gnawed on the suddenly attractive Pavlovian lever cue, despite having never yet tasted intense saltiness itself as anything other than disgusting.
Instant desire transformation of a learned cue contradicts views that Pavlovian desires are based essentially on previously learned values (e.g., prediction error or temporal difference models). Instead desire is re-computed at re-encounter by integrating Pavlovian information with current brain/physiological state. This powerful brain transformation reversed strong learned revulsion into avid attraction. Applied to addiction, related mesocorticolimbic transformations (e.g., drugs, neural sensitization) of cues for already pleasant drug experiences could create even more intense cravings. This cue/state transformation helps define what it means to say that addiction hijacks brain limbic circuits of natural reward.
Kinesin-1 is a major microtubule motor that drives transport of numerous cellular cargoes toward the plus-ends of microtubules. In the cell, kinesin-1 exists primarily in an inactive, autoinhibited state [1, 2], and motor activation is thought to occur upon binding to cargo through the C-terminus [3, 4]. Using RNAi-mediated depletion in Drosophila S2 cells, we demonstrate that kinesin-1 requires ensconsin (MAP7, E-MAP-115), a ubiquitous microtubule-associated protein [5, 6], for its primary function of organelle transport. We show that ensconsin is required for organelle transport in Drosophila neurons, and that Drosophila homozygous for ensconsin gene deletion are unable to survive to adulthood. An ensconsin N-terminal truncation that cannot bind microtubules is sufficient to activate organelle transport by kinesin-1, indicating that this activating domain functions independently of microtubule binding. Interestingly, ens mutant flies retaining expression of this truncation show normal viability. A “hingeless” mutant of kinesin-1, which mimics the active conformation of the motor, does not require ensconsin for transport in S2 cells, suggesting that ensconsin plays a role in relieving autoinhibition of kinesin-1. Together with other recent works [7, 8], our study suggests that ensconsin is an essential cofactor for all known functions of kinesin-1.
Sequential transfer of information from one enzyme to the next within the confines of a protein kinase scaffold enhances signal transduction. Though frequently considered to be inert organizational elements, two recent reports implicate kinase-scaffolding proteins as active participants in signal relay.
The recycling endosome localizes to a pericentrosomal region via microtubule-dependent transport. We previously showed that Sec15, an effector of the recycling endosome component, Rab11-GTPase, interacts with the mother centriole appendage protein, centriolin, suggesting an interaction between endosomes and centrosomes (1, 2). Here we show that the recycling endosome associates with the appendages of the mother (older) centriole. We show that the mother centriole appendage proteins, centriolin and cenexin/ODF2, regulate association of the endosome components Rab11, the Rab11 GTP-activating protein Evi5, and the exocyst at the mother centriole. Development of an in vitro method for reconstituting endosome protein complexes onto isolated membrane-free centrosomes demonstrates that purified GTP-Rab11 but not GDP-Rab11 binds to mother centriole appendages in the absence of membranes. Moreover, centriolin depletion displaces the centrosomal Rab11 GAP, Evi5, and increases mother-centriole-associated Rab11; depletion of Evi5 also increases centrosomal Rab11. This indicates that centriolin localizes Evi5 to centriolar appendages to turn off centrosomal Rab11 activity. Finally, centriolin depletion disrupts recycling endosome organization and function suggesting a role for mother centriole proteins in the regulation of Rab11 localization and activity at the mother centriole.
Amoebae and bacteria interact within predator/prey and host/pathogen relationships, but the general response of amoeba to bacteria is not well understood. The amoeba Dictyostelium discoideum feeds on, and is colonized by diverse bacterial species including Gram-positive [Gram(+)] and Gram-negative [Gram(−)] bacteria, two major groups of bacteria that differ in structure and macromolecular composition.
Transcriptional profiling of D. discoideum revealed sets of genes whose expression is enriched in amoebae interacting with different species of bacteria, including sets that appear specific to amoebae interacting with Gram(+), or with Gram(−) bacteria. In a genetic screen utilizing the growth of mutant amoebae on a variety of bacteria as a phenotypic readout, we identified amoebal genes that are only required for growth on Gram(+) bacteria, including one that encodes the cell surface protein gp130, as well as several genes that are only required for growth on Gram(−) bacteria including one that encodes a putative lysozyme, AlyL. These genes are required for parts of the transcriptional response of wild-type amoebae, and this allowed their classification into potential response pathways.
We have defined genes that are critical for amoebal survival during feeding on Gram(+), or Gram(−), bacteria which we propose form part of a regulatory network that allows D. discoideum to elicit specific cellular responses to different species of bacteria in order to optimize survival.
Condensin—an SMC-kleisin complex—is essential for efficient segregation of sister chromatids in eukaryotes [1–4]. In Escherichia coli and Bacillus subtilis, deletion of condensin subunits results in severe growth phenotypes and the accumulation of cells lacking nucleoids [5, 6]. In many other bacteria and under slow growth conditions, however, the reported phenotypes are much milder or virtually absent [7–10]. This raises the question of what role prokaryotic condensin might play during chromosome segregation under various growth conditions. In B. subtilis and Streptococcus pneumoniae, condensin complexes are enriched on the circular chromosome near the single origin of replication by ParB proteins bound to parS sequences [11, 12]. Using conditional alleles of condensin in B. subtilis, we demonstrate that depletion of its activity results in an immediate and severe defect in the partitioning of replication origins. Multiple copies of the chromosome remain unsegregated at or near the origin of replication. Surprisingly, the growth and chromosome segregation defects in rich medium are suppressed by a reduction of replication fork velocity but not by partial inhibition of translation or transcription. Prokaryotic condensin likely prevents the formation of sister DNA interconnections at the replication fork or promotes their resolution behind the fork.
•Smc-ScpAB inactivation causes a severe chromosome segregation defect in B. subtilis•Replication origins remain interconnected in the absence of prokaryotic condensin•Defects in chromosome segregation are highly dependent on growth conditions•Reduction of replication fork velocity rescues segregation of replication origins
Gruber et al. show that conditional inactivation of prokaryotic condensin in B. subtilis results in immediate and severe defects in chromosome segregation under conditions promoting fast growth. The separation of replication origins is blocked in the absence of Smc-ScpAB but can be rescued by artificial reduction of replication fork speed.
The cytoplasmic Elmo1:Dock180 complex acts as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac and functions downstream of the phagocytic receptor BAI1 during apoptotic cell clearance, and in the entry of Salmonella and Shigella into cells [1–7]. We discovered an unexpected binding between Elmo1 and Mediator complex subunit Med31. The Mediator complex is a regulatory hub for nearly all gene transcription via RNA polymerase II (Pol II), bridging the general transcription machinery with gene-specific regulatory proteins [8–14]. Med31 is the smallest and the most evolutionarily conserved Mediator subunit [15, 16] and knockout of Med31 results in embryonic lethality in mice ; however, Med31 function in specific biological contexts is not understood. We observed that in primary macrophages, during Salmonella infection, Elmo1 and Med31 specifically affected expression of cytokine genes Il10 and Il33 among the >25 genes monitored. While endogenous Med31 is predominantly nuclear localized, Elmo1 increased the cytoplasmic localization of Med31. We discover ubiquitination as a novel post-translational modification of Med31, with the cytoplasmic mono-ubiquitinated form of Med31 being enhanced by Elmo1. These data identify Elmo1 as a novel regulator of Med31, revealing a previously unrecognized link between cytoplasmic signaling proteins and the Mediator complex.
Each of us has felt afraid, and we can all recognize fear in many animal species. Yet there is no consensus in the scientific study of fear. Some argue that “fear” is a psychological construct rather than discoverable through scientific investigation. Others argue that the term “fear” cannot properly be applied to animals because we cannot know whether they feel afraid. Studies in rodents show that there are highly specific brain circuits for fear, whereas findings from human neuroimaging seem to make the opposite claim. Here I review the field and urge three approaches that could reconcile the debates. For one, we need a broadly comparative approach that would identify core components of fear conserved across phylogeny. This also pushes us towards the second point of emphasis: an ecological theory of fear that is essentially functional. Finally, we should aim even to incorporate the conscious experience of being afraid, reinvigorating the study of feelings across species.
Transcription is highly stochastic, occurring in irregular bursts [1–3]. For temporal and spatial precision of gene expression, cells must somehow deal with this noisy behavior. To address how this is achieved, we investigated how transcriptional bursting is entrained by a naturally oscillating signal, by direct measurement of transcription together with signal dynamics in living cells. We identify a Dictyostelium gene showing rapid transcriptional oscillations with the same period as extracellular cAMP signaling waves. Bursting approaches antiphase to cAMP waves, with accelerating transcription cycles during differentiation. Although coupling between signal and transcription oscillations was clear at the population level, single-cell transcriptional bursts retained considerable heterogeneity, indicating that transcription is not governed solely by signaling frequency. Previous studies implied that burst heterogeneity reflects distinct chromatin states [4–6]. Here we show that heterogeneity is determined by multiple intrinsic and extrinsic cues and is maintained by a transcriptional persistence. Unusually for a persistent transcriptional behavior, the lifetime was only 20 min, with rapid randomization of transcriptional state by the response to oscillatory signaling. Linking transcription to rapid signaling oscillations allows reduction of gene expression heterogeneity by temporal averaging, providing a mechanism to generate precision in cell choices during development.
•We observe coupled signal and transcriptional oscillations in living cells•Oscillations are collectively robust but heterogeneous at the single-cell level•Response heterogeneity is maintained by a short-term transcriptional persistence•Oscillations can be a mechanism to control gene expression noise in development
Corrigan and Chubb, through live imaging of transcriptional bursts, observe coupled oscillations between an extracellular signal and downstream transcription. Oscillations provide a mechanism to reduce transcriptional noise.
The centromere is defined by the incorporation of the centro-mere-specific histone H3 variant centromere protein A (CENP-A). Like histone H3, CENP-A can form CENP-A-H4 heterotetramers in vitro . However, the in vivo conformation of CENP-A chromatin has been proposed by different studies as hemisomes, canonical, or heterotypic nucleosomes [2–8]. A clear understanding of the in vivo architecture of CENP-A chromatin is important, because it influences the molecular mechanisms of the assembly and maintenance of the centromere and its function in kinetochore nucleation. Akey determinant of this architecture is the number of CENP-A molecules bound to the centromere. Accurate measurement of this number can limit possible centromere architectures. The genetically defined point centromere in the budding yeast Saccharomyces cerevisiae provides a unique opportunity to define this number accurately, as this 120-bp-long centromere can at the most form one nucleosome or hemisome. Using novel live-cell fluorescence microscopy assays, we demonstrate that the budding yeast centromere recruits two Cse4 (ScCENP-A) molecules. These molecules are deposited during S phase and they remain stably bound through late anaphase. Our studies suggest that the budding yeast centromere incorporates a Cse4-H4 tetramer.
A common principle of tissue regeneration is the reactivation of previously employed developmental programs [1–3]. During zebrafish heart regeneration, cardiomyocytes in the cortical layer of the ventricle induce the transcription factor gene gata4 and proliferate to restore lost muscle [4–6]. A dynamic cellular mechanism initially creates this cortical muscle in juvenile zebrafish, where a small number of internal cardiomyocytes breach the ventricular wall and expand upon its surface . Here, we find that emergent juvenile cortical cardiomyocytes induce expression of gata4 similarly as during regeneration. Clonal analysis indicates that these cardiomyocytes make biased contributions to build the ventricular wall, whereas gata4+ cardiomyocytes have little or no proliferation hierarchy during regeneration. Experimental microinjuries or conditions of rapid organismal growth stimulate production of ectopic gata4+ cortical muscle, implicating biomechanical stress in morphogenesis of this tissue and revealing clonal plasticity. Induced transgenic inhibition defined an essential role for Gata4 activity in morphogenesis of the cortical layer and the preservation of normal cardiac function in growing juveniles, and again in adults during heart regeneration. Our experiments uncover an injury-responsive program that prevents heart failure in juveniles by fortifying the ventricular wall, one that is reiterated in adults to promote regeneration after cardiac damage.
Chemotaxis, the ability to direct movements according to chemical cues in the environment, is important for the survival of most organisms. The vinegar fly, Drosophila melanogaster, displays robust olfactory aversion and attraction, but how these behaviors are executed via changes in locomotion remains poorly understood. In particular, it is not clear whether aversion and attraction bi-directionally modulate a shared circuit or recruit distinct circuits for execution.
Using a quantitative behavioral assay, we determined that both aversive and attractive odorants modulate the initiation and direction of turns, but display distinct kinematics. Using genetic tools to perturb these behaviors, we identified specific populations of neurons required for aversion but not attraction. Inactivation of these populations of cells affected the completion of aversive turns but not their initiation. Optogenetic activation of the same populations of cells triggered a locomotion pattern resembling aversive turns. Perturbations in both the ellipsoid body and the ventral nerve cord, two regions involved in motor control, resulted in defects in aversion.
Aversive chemotaxis in vinegar flies triggers ethologically appropriate kinematics distinct from those of attractive chemotaxis, and requires specific motor-related neurons.
Many cells are remarkably proficient at tracking very shallow chemical gradients, despite considerable noise from stochastic receptor-ligand interactions. Motile cells appear to undergo a biased random walk: spatial noise in receptor activity may determine the instantaneous direction, but because noise is spatially unbiased it is filtered out by time-averaging, resulting in net movement up-gradient. How non-motile cells might filter out noise is unknown.
Using yeast chemotropic mating as a model, we demonstrate that a polarized patch of polarity regulators “wanders” along the cortex during gradient tracking. Computational and experimental findings suggest that actin-directed membrane traffic contributes to wandering by diluting local polarity factors. The pheromone gradient appears to bias wandering via interactions between receptor-activated Gβγ and polarity regulators. Artificially blocking patch wandering impairs gradient tracking.
We suggest that the polarity patch undergoes an intracellular biased random walk that enables noise filtering by time-averaging, allowing non-motile cells to track shallow gradients.
Rodents use olfactory cues for species-specific behaviors. For example, mice emit odors to attract mates of the same species but not competitors of closely related species. This implies rapid evolution of olfactory signaling, although odors and chemosensory receptors involved are unknown.
Here, we identify a mouse chemosignal, trimethylamine, and its olfactory receptor, trace amine-associated receptor 5 (TAAR5), to be involved in species-specific social communication. Abundant (>1,000-fold increased) and sex-dependent trimethylamine production arose de novo along the Mus lineage after divergence from Mus caroli. The two-step trimethylamine biosynthesis pathway involves synergy between commensal microflora and a sex-dependent liver enzyme, flavin-containing monooxygenase 3 (FMO3), which oxidizes trimethylamine. One key evolutionary alteration in this pathway is the recent acquisition in Mus of male-specific Fmo3 gene repression. Coincident with its evolving biosynthesis, trimethylamine evokes species-specific behaviors, attracting mice but repelling rats. Attraction to trimethylamine is abolished in TAAR5 knockout mice, and furthermore, attraction to mouse scent is impaired by enzymatic depletion of trimethylamine or TAAR5 knockout.
TAAR5 is an evolutionarily conserved olfactory receptor required for a species-specific behavior. Synchronized changes in odor biosynthesis pathways and odor-evoked behaviors could ensure species-appropriate social interactions.
The cleavage stage mouse embryo is composed of superficially equivalent blastomeres that will generate both the embryonic inner cell mass (ICM) and the supportive trophectoderm (TE). However, it remains unsettled whether the contribution of each blastomere to these two lineages can be accounted for by chance. Addressing the question of blastomere cell fate may be of practical importance, as preimplantation genetic diagnosis (PGD) requires removal of blastomeres from the early human embryo. To determine if blastomere allocation to the two earliest lineages is random, we developed and utilized a recombination-mediated, non-invasive combinatorial fluorescent labeling method for embryonic lineage tracing.
When we induced recombination at cleavage stages, we observed a statistically significant bias in the contribution of the resulting labeled clones to the trophectoderm or the inner cell mass in a subset of embryos. Surprisingly, we did not find a correlation between localization of clones in the embryonic and abembryonic hemispheres of the late blastocyst and their allocation to the TE and ICM, suggesting that TE-ICM bias arises separately from embryonic-abembryonic bias. Rainbow lineage tracing also allowed us to demonstrate that the bias observed in the blastocyst persists into post-implantation stages, and therefore has relevance for subsequent development.
The Rainbow transgenic mice that we describe here have allowed us to detect lineage-dependent bias in early development. They should also enable assessment of the developmental equivalence of mammalian progenitor cells in a variety of tissues.
Oncogenic mutations in the small Ras GTPases KRas, HRas, or NRas render the encoded proteins constitutively GTP-bound and active, which promote cancer . Ras proteins share ~85% amino acid identity , are activated by  and signal through  the same proteins, and can exhibit functional redundancy . Nevertheless, manipulating expression or activation of each isoform yields different cellular responses [7–10] and tumorigenic phenotypes [11–13], even when different ras genes are expressed from the same locus . We now report a novel regulatory mechanism hardwired into the very sequence of RAS genes that underlies how such similar proteins impact tumorigenesis differently. Specifically, despite their high sequence similarity, KRAS is poorly translated compared to HRAS due to enrichment in genomically underrepresented, or rare, codons. Converting rare to common codons increased KRas expression and tumorigenicity to mirror that of HRas. Furthermore, in a genome-wide survey similar gene pairs with opposing codon bias were identified that not only manifested dichotomous protein expression, but were also enriched in key signaling protein classes and pathways. Thus, synonymous nucleotide differences affecting codon usage account for differences between HRas and KRas expression and function, and may represent a broader regulation strategy in cell signaling.
Ras; codon bias; cancer
Macroautophagy is an essential cellular pathway mediating the lysosomal degradation of defective organelles, long-lived proteins and a variety of protein aggregates. Similar to other intracellular trafficking pathways, macroautophagy involves a complex sequence of membrane remodeling and trafficking events. These include the biogenesis of autophagosomes (APs), which engulf portions of cytoplasm at specific subcellular locations, and their subsequent maturation into autophagolysosomes through fusion with the endo-lysosomal compartment. Although the formation and maturation of APs are controlled by molecular reactions occurring at the membrane-cytosol interface, little is known about the role of lipids and their metabolizing enzymes in this process. Historically dominated by studies on class III phosphatidylinositol 3-kinase (PI3K) (also known as Vps34), its product PI3P, as well as on the lipidation of Atg8/LC3-like proteins, this area of research has recently expanded, implicating a variety of other lipids, such as phosphatidic acid and diacylglycerol, and their metabolizing enzymes in macroautophagy. This review summarizes this progress and highlights the role of specific lipids in the various steps of macroautophagy, including the signaling processes underlying macroautophagy initiation, AP biogenesis and maturation.
All movements are thought to be ‘prepared’ in the brain before initiation [1–3], and preparation can be impaired in motor diseases [4, 5]. However, little is known about what sort of preparation precedes self-initiated, naturally-learned sequences of movements. Here we took advantage of a canonical example of a precisely timed learned motor sequence, adult zebra finch song, to examine motor preparation. We found that the sequences of short vocalizations or introductory notes (INs) preceding song gradually increased in speed and converged on an acoustic end point highly similar across renditions, just before song initiation. The more the initial IN differed acoustically from the final IN, the greater the number of INs produced pre-song. Moreover, the song premotor nucleus HVC exhibited IN-related neural activity that progressed to a distinctive end-point immediately before song. Together, our behavioral and neural data suggest that INs reflect a variable period of preparation during which the brain attains a common ‘ready’ state each time sequence generation is about to begin.
The regulation of centrosome number is lost in many tumors and the presence of extra centrosomes correlates with chromosomal instability. Recent work now reveals how extra centrosomes cause chromosome mis-segregation in tumor cells.
Basic tenets of sensory processing emphasize the importance of accurate identification and discrimination of environmental objects . Although this principle holds also for reward, the crucial acquisition of reward for survival would be aided by the capacity to detect objects whose rewarding properties may not be immediately apparent. Animal learning theory conceptualizes how unrewarded stimuli induce behavioral reactions in rewarded contexts due to pseudoconditioning and higher-order context conditioning [2–6]. We hypothesized that the underlying mechanisms may involve context-sensitive reward neurons. We studied short-latency activations of dopamine neurons to unrewarded, physically salient stimuli while systematically changing reward context. Dopamine neurons showed substantial activations to unrewarded stimuli and their conditioned stimuli in highly rewarded contexts. The activations decreased and often disappeared entirely with stepwise separation from rewarded contexts. The influence of reward context suggests that dopamine neurons respond to real and potential reward. The influence of reward context is compatible with the reward nature of phasic dopamine responses. The responses may facilitate rapid, default initiation of behavioral reactions in environments usually containing reward. Agents would encounter more and miss less reward, resulting in survival advantage and enhanced evolutionary fitness.
•Dopamine neurons are activated by unrewarded events in rewarded contexts•More rewarded contexts are associated with stronger dopamine activations•The effective unrewarded events do not induce bidirectional prediction error signals•Reward context-dependent signaling conceivably leads to more reward
When rewards are frequent and everywhere, any object could be a reward. Reacting to objects in such reward contexts would enhance the chance of getting a reward. Kobayashi and Schultz show that dopamine neurons respond in reward contexts even to unrewarded objects.