Nature Neuroscience

Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new learning. Often, this learning includes identifying cues that predict reward availability. Unexpected rewards strongly activate midbrain dopamine neurons. This phasic signal is proposed to support learning about antecedent cues by signaling discrepancies between actual and expected outcomes, termed a reward prediction error. However, it is unknown whether dopamine neuron prediction error signaling and cue-reward learning are causally linked. To test this hypothesis, we manipulated dopamine neuron activity in rats in two behavioral procedures, associative blocking and extinction, that illustrate the essential function of prediction errors in learning. We observed that optogenetic activation of dopamine neurons concurrent with reward delivery, mimicking a prediction error, was sufficient to cause long-lasting increases in cue-elicited reward-seeking behavior. Our findings establish a causal role for temporally precise dopamine neuron signaling in cue-reward learning, bridging a critical gap between experimental evidence and influential theoretical frameworks. npg

What is the nature of the vascular architecture in the cortex that allows the brain to meet the energy demands of neuronal computations? We used high-throughput histology to reconstruct the complete angioarchitecture and the positions of all neuronal somata of multiple cubic millimeter regions of vibrissa primary sensory cortex in mouse. Vascular networks were derived from the reconstruction. In contrast with the standard model of cortical columns that are tightly linked with the vascular network, graph-theoretical analyses revealed that the subsurface microvasculature formed interconnected loops with a topology that was invariant to the position and boundary of columns. Furthermore, the calculated patterns of blood flow in the networks were unrelated to location of columns. Rather, blood sourced by penetrating arterioles was effectively drained by the penetrating venules to limit lateral perfusion. This analysis provides the underpinning to understand functional imaging and the effect of penetrating vessels strokes on brain viability.

Although common sense tells us that no two brains are identical, a series of experimental strategies has evolved, on the basis of studies into the influence of controlled variables on neuronal or network function, that are designed to remove the influence of the underlying variance in neuronal properties and synaptic strengths. These strategies include averaging or normalizing data and comparing each preparation to its own control before and after a treatment. Successful as these strategies may be, they implicitly assume that variability between preparations or animals is 'experimental noise' rather than an essential characteristic of the nervous system. We used computational models to study this underlying variability in synaptic strengths and neuronal properties in the production of a simple motor pattern. Specifically, we searched for combinations of synaptic strengths and intrinsic properties in threeneuron model networks that produced output patterns within the range of the pyloric rhythms generated by the stomatogastric ganglia of 99 lobsters (Homarus americanus).

Two objects that project the same visual angle on the retina can appear to occupy very different proportions of the visual field if they are perceived to be at different distances. What happens to the retinotopic map in primary visual cortex (V1) during the perception of these size illusions? Here we show, using functional magnetic resonance imaging (fMRI), that the retinotopic representation of an object changes in accordance with its perceived angular size. A distant object that appears to occupy a larger portion of the visual field activates a larger area in V1 than an object of equal angular size that is perceived to be closer and smaller. These results demonstrate that the retinal size of an object and the depth information in a scene are combined early in the human visual system.

People and animals often demonstrate strong attraction or aversion to options with uncertain or risky rewards, yet the neural substrate of subjective risk preferences has rarely been investigated. Here we show that monkeys systematically preferred the risky target in a visual gambling task in which they chose between two targets offering the same mean reward but differing in reward uncertainty. Neuronal activity in posterior cingulate cortex (CGp), a brain area linked to visual orienting and reward processing, increased when monkeys made risky choices and scaled with the degree of risk. CGp activation was better predicted by the subjective salience of a chosen target than by its actual value. These data suggest that CGp signals the subjective preferences that guide visual orienting.

The fate of cortical progenitors, which progressively generate neurons and glial cells during development, is determined by temporally and spatially regulated signaling mechanisms. We found that the transcription factor Sip1 (Zfhx1b), which is produced at high levels in postmitotic neocortical neurons, regulates progenitor fate non-cell autonomously. Conditional deletion of Sip1 in young neurons induced premature production of upper-layer neurons at the expense of deep layers, precocious and increased generation of glial precursors, and enhanced postnatal astrocytogenesis. The premature upper-layer generation coincided with overexpression of the neurotrophin-3 (Ntf3) gene and upregulation of fibroblast growth factor 9 (Fgf9) gene expression preceded precocious gliogenesis. Exogenous application of Fgf9 to mouse cortical slices induced excessive generation of glial precursors in the germinal zone. Our data suggest that Sip1 restrains the production of signaling factors in postmitotic neurons that feed back to progenitors to regulate the timing of cell fate switch and the number of neurons and glial cells throughout corticogenesis.

A prominent model of how the brain regulates attention proposes that the anterior cingulate cortex monitors the occurrence of conflict between incompatible response tendencies and signals this information to a cognitive control system in dorsolateral prefrontal cortex. Cognitive control is thought to resolve conflict through the attentional biasing of perceptual processing, emphasizing task-relevant stimulus information. It is not known, however, whether conflict resolution is mediated by amplifying neural representations of task-relevant information, inhibiting representations of task-irrelevant information, or both. Here we manipulated trial-by-trial levels of conflict and control during a Stroop task using face stimuli, while recording hemodynamic responses from human visual cortex specialized for face processing. We show that, in response to high conflict, cognitive control mechanisms enhance performance by transiently amplifying cortical responses to task-relevant information rather than by inhibiting responses to task-irrelevant information. These results implicate attentional target-feature amplification as the primary mechanism for conflict resolution through cognitive control.

Little is known about the brain-wide correlation of electrophysiological signals. We found that spontaneous oscillatory neuronal activity exhibited frequency-specific spatial correlation structure in the human brain. We developed an analysis approach that discounts spurious correlation of signal power caused by the limited spatial resolution of electrophysiological measures. We applied this approach to source estimates of spontaneous neuronal activity reconstructed from magnetoencephalography. Overall, correlation of power across cortical regions was strongest in the alpha to beta frequency range (8-32 Hz) and correlation patterns depended on the underlying oscillation frequency. Global hubs resided in the medial temporal lobe in the theta frequency range (4-6 Hz), in lateral parietal areas in the alpha to beta frequency range (8-23 Hz) and in sensorimotor areas for higher frequencies (32-45 Hz). Our data suggest that interactions in various large-scale cortical networks may be reflected in frequency-specific power envelope correlations.

Extensive animal and recent human research have helped inform neuroendocrinological models of social cognition, motivation and behavior. In this review, we first summarize important findings regarding oxytocin, arginine vasopressin and testosterone in the domains of affiliation, social cognition, aggression and stress/anxiety. We then suggest ways in which human research can continue to profit from animal research, particularly by exploring the interactive nature of neuromodulatory effects at neurochemical, organismic and contextual levels. We further propose methods inspired by the animal literature for the ecologically valid assessment of affiliative behavior in humans. We conclude with suggestions for how human research could advance by directly assessing specific social cognitive and motivational mechanisms as intermediate variables. We advocate a more comprehensive look at the distinct networks identified by social neuroscience and the importance of a motivational state, in add...

Despite the numerous examples of anticipatory cognitive processes at micro and macro levels in many animal species, the idea that anticipation of specific words plays an integral role in real-time language processing has been contentious. Here we exploited a phonological regularity of English indefinite articles ('an' precedes nouns beginning with vowel sounds, whereas 'a' precedes nouns beginning with consonant sounds) in combination with event-related brain potential recordings from the human scalp to show that readers' brains can pre-activate individual words in a graded fashion to a degree that can be estimated from the probability that each word is given as a continuation for a sentence fragment offline. These findings are evidence that readers use the words in a sentence (as cues to their world knowledge) to estimate relative likelihoods for upcoming words.

Perspective taking is an essential component in the mechanisms that account for intersubjectivity and agency. Mental simulation of action can be used as a natural protocol to explore the cognitive and neural processing involved in agency. Here we took PET measurements while subjects simulated actions with either a first-person or a third-person perspective. Both conditions were associated with common activation in the SMA, the precentral gyrus, the precuneus and the MT/V5 complex. When compared to the first-person perspective, the third-person perspective recruited right inferior parietal, precuneus, posterior cingulate and frontopolar cortex. The opposite contrast revealed activation in left inferior parietal and somatosensory cortex. We suggest that the right inferior parietal, precuneus and somatosensory cortex are specifically involved in distinguishing self-produced actions from those generated by others.

nature neurOSCIenCe advance online publication a r t I C l e S Neurodevelopmental disorders arise early in life and are often characterized by social deficits, impaired language development, intellectual disability, increased repetitive or restricted behaviors and motor abnormalities. Cognitive impairment has an important role in these disorders, but their underlying pathophysiology remains obscure. Genetic studies have linked variation in synaptic scaffolding proteins to schizophrenia and autism 1 , and postmortem studies have identified decreased expression of genes associated with synaptic transmission across cortical regions in these and other disorders 2,3 . Furthermore, functional magnetic resonance imaging (fMRI) and electroencephalography have both pointed to decreased functional connectivity between cortical regions across a variety of diseases with cognitive deficits, including autism 4-6 , schizophrenia 7,8 , major depression 9,10 , epilepsy 11 and obsessive compulsive disorder 12 . Together these data suggest that deficits in synaptic maturation that are characterized by weak functional connectivity across brain regions may have a role in the pathophysiology of multiple mental illnesses 13 .

Our perception of the world's three-dimensional (3D) structure is critical for object recognition, navigation and planning actions. To accomplish this, the brain combines different types of visual information about depth structure, but at present, the neural architecture mediating this combination remains largely unknown. Here, we report neuroimaging correlates of human 3D shape perception from the combination of two depth cues. We measured fMRI responses while observers judged the 3D structure of two sequentially presented images of slanted planes defined by binocular disparity and perspective. We compared the behavioral and fMRI responses evoked by changes in one or both of the depth cues. fMRI responses in extrastriate areas (hMT1/V5 and lateral occipital complex), rather than responses in early retinotopic areas, reflected differences in perceived 3D shape, suggesting 'combined-cue' representations in higher visual areas. These findings provide insight into the neural circuits engaged when the human brain combines different information sources for unified 3D visual perception.

Music, an abstract stimulus, can arouse feelings of euphoria and craving, similar to tangible rewards that involve the striatal dopaminergic system. Using the neurochemical specificity of [ 11 C]raclopride positron emission tomography scanning, combined with psychophysiological measures of autonomic nervous system activity, we found endogenous dopamine release in the striatum at peak emotional arousal during music listening. To examine the time course of dopamine release, we used functional magnetic resonance imaging with the same stimuli and listeners, and found a functional dissociation: the caudate was more involved during the anticipation and the nucleus accumbens was more involved during the experience of peak emotional responses to music. These results indicate that intense pleasure in response to music can lead to dopamine release in the striatal system. Notably, the anticipation of an abstract reward can result in dopamine release in an anatomical pathway distinct from that associated with the peak pleasure itself. Our results help to explain why music is of such high value across all human societies.

Depression is a leading cause of morbidity and mortality, and its treatment includes a high percentage of the medications prescribed by physicians. Available antidepressant drugs are safe and effective, but less than half of all patients attain complete remission after therapy with a single antidepressant. Others exhibit partial, refractory or intolerant responses to treatment, emphasizing the need to discover new antidepressants. The mechanisms of action of available medications are directing the field toward new research avenues. This review highlights those areas we believe will influence the field and soon lead to better treatment.

We combined psychophysical and transcranial magnetic stimulation studies to investigate the dynamics of action anticipation and its underlying neural correlates in professional basketball players. Athletes predicted the success of free shots at a basket earlier and more accurately than did individuals with comparable visual experience (coaches or sports journalists) and novices. Moreover, performance between athletes and the other groups differed before the ball was seen to leave the model's hands, suggesting that athletes predicted the basket shot's fate by reading the body kinematics. Both visuo-motor and visual experts showed a selective increase of motor-evoked potentials during observation of basket shots. However, only athletes showed a time-specific motor activation during observation of erroneous basket throws. Results suggest that achieving excellence in sports may be related to the fine-tuning of specific anticipatory 'resonance' mechanisms that endow elite athletes' brains with the ability to predict others' actions ahead of their realization.

We present behavioral and anatomical evidence for a multi-component reading system in which different components are differentially weighted depending on culture-specific demands of orthography. Italian orthography is consistent, enabling reliable conversion of graphemes ...

The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50-69-year-old subjects who consumed either a high or low cocoa flavanol-containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline ...

Music and speech are very cognitively demanding auditory phenomena generally attributed to cortical rather than subcortical circuitry. We examined brainstem encoding of linguistic pitch and found that musicians show more robust and faithful encoding compared with nonmusicians. These results not only implicate a common subcortical manifestation for two presumed cortical functions, but also a possible reciprocity of corticofugal speech and music tuning, providing neurophysiological explanations for musicians' higher language-learning ability.

The activity-regulated cytoskeletal protein Arc/Arg3.1 is required for long-term memory formation and synaptic plasticity. Arc expression is robustly induced by activity, and Arc protein localizes both to active synapses and the nucleus. While its synaptic function has been examined, it is not clear why or how Arc is localized to the nucleus. We found that murine Arc nuclear expression is regulated by synaptic activity in vivo and in vitro. We identified distinct regions of Arc that control its localization, including a nuclear localization signal, a nuclear retention domain, and a nuclear export signal. Arc localization to the nucleus promotes an activity-induced increase in promyelocytic leukemia nuclear bodies, which decreases GluA1 transcription and synaptic strength. Finally, we show that Arc nuclear localization regulates homeostatic plasticity. Thus, Arc mediates the homeostatic response to increased activity by translocating to the nucleus, increasing promyelocytic leukemia levels, and decreasing GluA1 transcription, ultimately downscaling synaptic strength.

Stressors impact dopamine-dependent behaviors such as motivation, though the underlying neurobiological mechanism is not well defined. We report that corticotropin-releasing factor (CRF) acts within the ventral tegmental area (VTA) to reduce the motivation to work for food rewards. CRF in the VTA regulates dopamine output in a stimulus-and pathway-specific manner, collectively offering a mechanism by which acute stress selectively regulates information transmission via the VTA to reprioritize motivated behavior.

Brain circuitry processes information by rapidly and selectively engaging functional neuronal networks. The dynamic formation of networks is often evident in rhythmically synchronized neuronal activity and tightly correlates with perceptual, cognitive and motor performances. But how synchronized neuronal activity contributes to network formation and how it relates to the computation of behaviorally relevant information has remained difficult to discern. Here we structure recent empirical advances that link synchronized activity to the activation of so-called dynamic circuit motifs. These motifs explicitly relate (1) synaptic and cellular properties of circuits to (2) identified timescales of rhythmic activation and to (3) canonical circuit computations implemented by rhythmically synchronized circuits. We survey the ubiquitous evidence of specific cell and circuit properties underlying synchronized activity across theta, alpha, beta and gamma frequency bands and show that their activation likely implements gain control, context-dependent gating and state-specific integration of synaptic inputs. This evidence gives rise to the dynamic circuit motifs hypothesis of synchronized activation states, with its core assertion that activation states are linked to uniquely identifiable local circuit structures that are recruited during the formation of functional networks to perform specific computational operations. npg

Humans exhibit a remarkable degree of resilience in the face of extreme stress, with most resisting the development of neuropsychiatric disorders. Over the past 5 years, there has been increasing interest in the active, adaptive coping mechanisms of resilience; however, in humans, most published work focuses on correlative neuroendocrine markers that are associated with a resilient phenotype. In this review, we highlight a growing literature in rodents that is starting to complement the human work by identifying the active behavioral, neural, molecular and hormonal basis of resilience. The therapeutic implications of these findings are important and can pave the way for an innovative approach to drug development for a range of stress-related syndromes.

Ten years ago, a glial cell line-derived neurotrophic factor (GDNF) that has prominent actions on nigral dopaminergic neurons, both in vitro and in animal models of Parkinson disease (PD), was discovered. A recently published open-label clinical trial now reports that long-term intracerebral delivery of GDNF may also markedly improve symptoms in patients with PD. Here we review the experimental data underlying the current clinical trial and discuss the types of structural and functional changes induced by GDNF that may provide symptomatic benefit in PD patients. Data obtained in rodent and primate models of PD highlight the importance of how and where the factor is administered, supporting the view that GDNF has to be delivered locally in the brain parenchyma, at the receptive target site, to provide therapeutic benefit in PD patients.

The optic nerve, like most mature CNS pathways, does not regenerate after injury. Through unknown mechanisms, however, macrophage activation in the eye stimulates retinal ganglion cells (RGCs) to regenerate long axons beyond the site of optic nerve injury. Here we identify the calcium (Ca 21 )-binding protein oncomodulin as a potent macrophage-derived growth factor for RGCs and other neurons. Oncomodulin binds to rat RGCs with high affinity in a cyclic AMP (cAMP)-dependent manner and stimulates more extensive outgrowth than other known trophic agents. Depletion of oncomodulin from macrophage-conditioned media (MCM) eliminates the axon-promoting activity of MCM. The effects of oncomodulin involve downstream signaling via Ca 21 /calmodulin kinase and gene transcription. In vivo, oncomodulin released from microspheres promotes regeneration in the mature rat optic nerve. Oncomodulin also stimulates outgrowth from peripheral sensory neurons. Thus, oncomodulin is a new growth factor for neurons of the mature central and peripheral nervous systems.

MicroRNAs (miRNAs) are endogenous non-coding small RNAs that play vital regulatory roles in plant growth, development, and environmental stress responses. Cadmium (Cd) is a non-essential heavy metal that is highly toxic to living organisms. To date, a number of conserved and non-conserved miRNAs have been identified to be involved in response to Cd stress in some plant species. However, the miRNA-mediated gene regulatory networks responsive to Cd stress in radish (Raphanus sativus L.) remain largely unexplored. To dissect Cd-responsive miRNAs and their targets systematically at the global level, two small RNA libraries were constructed from Cd-treated and Cd-free roots of radish seedlings. Using Solexa sequencing technology, 93 conserved and 16 non-conserved miRNAs (representing 26 miRNA families) and 28 novel miRNAs (representing 22 miRNA families) were identified. In all, 15 known and eight novel miRNA families were significantly differently regulated under Cd stress. The expression patterns of a set of Cd-responsive miRNAs were validated by quantitative real-time PCR. Based on the radish mRNA transcriptome, 18 and 71 targets for novel and known miRNA families, respectively, were identified by the degradome sequencing approach. Furthermore, a few target transcripts including phytochelatin synthase 1 (PCS1), iron transporter protein, and ABC transporter protein were involved in plant response to Cd stress. This study represents the first transcriptome-based analysis of miRNAs and their targets responsive to Cd stress in radish roots. These findings could provide valuable information for functional characterization of miRNAs and their targets in regulatory networks responsive to Cd stress in radish.

Neurons are continuously generated from stem cells in discrete regions in the adult mammalian brain. We found that ependymal cells lining the lateral ventricles were quiescent and did not contribute to adult neurogenesis under normal conditions in mice but instead gave rise to neuroblasts and astrocytes in response to stroke. Ependymal cell quiescence was actively maintained by canonical Notch signaling. Inhibition of this pathway in uninjured animals allowed ependymal cells to enter the cell cycle and produce olfactory bulb neurons, whereas forced Notch signaling was sufficient to block the ependymal cell response to stroke. Ependymal cells were depleted by stroke and failed to self-renew sufficiently to maintain their own population. Thus, although ependymal cells act as primary cells in the neural lineage to produce neurons and glial cells after stroke, they do not fulfill defining criteria for stem cells under these conditions and instead serve as a reservoir that is recruited by injury.

Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.