Nature Reviews Neuroscience

Published by Nature Publishing Group
Online ISSN: 1471-003X
Publications
Article
New genetic models that target the serotonin system show that transient alterations in serotonin homeostasis cause permanent changes to adult behaviour and modify the fine wiring of brain connections. These findings have revived a long-standing interest in the developmental role of serotonin. Molecular genetic approaches are now showing us that different serotonin receptors, acting at different developmental stages, modulate different developmental processes such as neurogenesis, apoptosis, axon branching and dendritogenesis. Our understanding of the specification of the serotonergic phenotype is improving. In addition, studies have revealed that serotonergic traits are dissociable, as there are populations of neurons that contain serotonin but do not synthesize it.
 
Article
Signals through the Notch receptors are used throughout development to control cellular fate choices. Loss- and gain-of-function studies revealed both the pleiotropic action of the Notch signalling pathway in development and the potential of Notch signals as tools to influence the developmental path of undifferentiated cells. As we review here, Notch signalling affects the development of the nervous system at many different levels. Understanding the complex genetic circuitry that allows Notch signals to affect specific cell fates in a context-specific manner defines the next challenge, especially as such an understanding might have important implications for regenerative medicine.
 
Article
The conversion of acetylcholine binding into ion conduction across the membrane is becoming more clearly understood in terms of the structure of the receptor and its transitions. A high-resolution structure of a protein that is homologous to the extracellular domain of the receptor has revealed the binding sites and subunit interfaces in great detail. Although the structures of the membrane and cytoplasmic domains are less well determined, the channel lining and the determinants of selectivity have been mapped. The location and structure of the gates, and the coupling between binding sites and gates, remain to be established.
 
Article
In multiple sclerosis — the archetypal inflammatory response in the central nervous system — T cells and macrophages invade the brain and damage the myelin and neurons. In other chronic neurodegenerative diseases, there is an atypical inflammatory response that is characterized by large numbers of activated microglia. These macrophages are primed by components of the neuropathology but might be further activated by systemic infection, which in turn has pronounced effects on inflammation in the brain and perhaps on neurological function. There is emerging evidence to support the idea that nonspecific systemic infection or inflammation in people with existing inflammation in the brain contributes to the rate of disease progression through further activation of these already primed macrophages.
 
Article
Activity has an important role in refining synaptic connectivity during development, in part through 'Hebbian' mechanisms such as long-term potentiation and long-term depression. However, Hebbian plasticity is probably insufficient to explain activity-dependent development because it tends to destabilize the activity of neural circuits. How can complex circuits maintain stable activity states in the face of such destabilizing forces? An idea that is emerging from recent work is that average neuronal activity levels are maintained by a set of homeostatic plasticity mechanisms that dynamically adjust synaptic strengths in the correct direction to promote stability. Here we discuss evidence from a number of systems that homeostatic synaptic plasticity is crucial for processes ranging from memory storage to activity-dependent development.
 
Article
Discoveries concerning the molecular mechanisms of cell differentiation and development have dictated the definition of a new sub-discipline of genetics known as epigenetics. Epigenetics refers to a set of self-perpetuating, post-translational modifications of DNA and nuclear proteins that produce lasting alterations in chromatin structure as a direct consequence, and lasting alterations in patterns of gene expression as an indirect consequence. The area of epigenetics is a burgeoning subfield of genetics in which there is considerable enthusiasm driving new discoveries. Neurobiologists have only recently begun to investigate the possible roles of epigenetic mechanisms in behaviour, physiology and neuropathology. Strikingly, the relevant data from the few extant neurobiology-related studies have already indicated a theme - epigenetic mechanisms probably have an important role in synaptic plasticity and memory formation.
 
Article
Two organizing centres operate at long-range distances within the anterior neural plate to pattern the forebrain, midbrain and hindbrain. Important progress has been made in understanding the formation and function of one of these organizing centres, the isthmic organizer, which controls the development of the midbrain and anterior hindbrain. Here we review our current knowledge on the identity, localization and maintenance of the isthmic organizer, as well as on the molecular cascades that underlie the activity of this organizing centre.
 
Article
Postmitotic neurons are produced from a pool of cycling progenitors in an orderly fashion during development. Studies of cell-fate determination in the vertebrate retina have uncovered several fundamental principles by which this is achieved. Most notably, a model for vertebrate cell-fate determination has been proposed that combines findings on the relative roles of extrinsic and intrinsic regulators in controlling cell-fate choices. At the heart of the model is the proposal that progenitors pass through intrinsically determined competence states, during which they are capable of giving rise to a limited subset of cell types under the influence of extrinsic signals.
 
Article
Converging evidence from electrophysiological, physiological and anatomical studies suggests that abnormalities in the synchronized oscillatory activity of neurons may have a central role in the pathophysiology of schizophrenia. Neural oscillations are a fundamental mechanism for the establishment of precise temporal relationships between neuronal responses that are in turn relevant for memory, perception and consciousness. In patients with schizophrenia, the synchronization of beta- and gamma-band activity is abnormal, suggesting a crucial role for dysfunctional oscillations in the generation of the cognitive deficits and other symptoms of the disorder. Dysfunctional oscillations may arise owing to anomalies in the brain's rhythm-generating networks of GABA (gamma-aminobutyric acid) interneurons and in cortico-cortical connections.
 
Article
A plethora of discoveries relating to sex influences on brain function is rapidly moving this field into the spotlight for most areas of neuroscience. The domain of molecular or genetic neuroscience is no exception. The goal of this article is to highlight key developments concerning sex-based dimorphisms in molecular neuroscience, describe control mechanisms regulating these differences, address the implications of these dimorphisms for normal and abnormal brain function and discuss what these advances mean for future work in the field. The overriding conclusion is that, as for neuroscience in general, molecular neuroscience has to take into account potential sex influences that might modify signalling pathways.
 
Processing during VPL training.According to the model presented, visual perceptual learning (VPL) of the presented visual feature occurs when a bottom-up signal from the feature is boosted by attention (left) or by reinforcement signals (right). Attention enhances task-relevant signals and inhibits task-irrelevant signals, leading to task-relevant VPL. By contrast, reinforcement signals are diffusive and enhance signals from any stimulus feature presented in the visual field, irrespective of whether the feature is task-relevant or task-irrelevant.
Typical tasks used in VPL studies.a | In the Vernier acuity task, a configuration of two or three vertical lines (or dots) is presented. The subject is asked to indicate whether the lines (or the dots) are aligned. b | The RSVP (rapid serial visual presentation) task with moving dots during training is used to examine visual perceptual learning (VPL) of task-irrelevant coherent motion. The subject is asked to identify two target items (such as white letters) within a sequence of non-target items (such as black letters) at the centre of the display. The background display consists of coherent motion (dots moving in the same direction at the same speed) and random motion (dots moving in random directions with random speed). The arrows represent the velocity of the coherent motion. In test stages before and after training, only coherent motion is displayed (not shown here) to determine how performance in motion-discrimination or -detection tasks is changed by training. c | A texture-discrimination task is the most frequently used task in VPL studies. The subject is first asked to respond according to whether a 'T' (as shown in the figure) or an 'L' is presented in the centre of the display to ensure fixation at the centre, and then to indicate whether the orientation of the target (the three elements with orientation that differs from that of the rest of the elements) is vertical (as shown in the figure) or horizontal. VPL of the target orientation is examined. Part b is modified, with permission, from Ref. 29 © (2001) Macmillan Publishers Ltd. All rights reserved. Part c is modified, with permission, from Ref. 71 © (1991) National Academy of Sciences.
Neural correlates of VPL.The regions of the brain thought to be altered by visual perceptual learning (VPL). Some experiments have indicated that training on a visual task changes visual representations in the early stages of visual signal processing, such as the tuning properties and activity of the primary visual cortex (V1) region that retinotopically corresponds to the location of the trained stimulus in the visual field. Others have instead suggested that training alters the weight of connections (ω1, ω2 ... ωi) between the visual cortex and regions of the brain involved in decision making, or within the decision-making regions themselves. In VPL of motion or a feature carrying spatial information, the weight changes may predominantly occur between areas in the higher visual cortex, such as the middle temporal area (MT) and the lateral intraparietal area (LIP), which is thought to be involved in visual decision-making processes4. MT is usually responsible for coarse binocular disparity (depth) processing; however, when MT is inactivated, decision-making regions may learn to give more weight to signals from areas involved in ventral processing, including V4, when discriminating coarse binocular disparity5.
Article
Visual perceptual learning (VPL) is defined as a long-term improvement in performance on a visual task. In recent years, the idea that conscious effort is necessary for VPL to occur has been challenged by research suggesting the involvement of more implicit processing mechanisms, such as reinforcement-driven processing and consolidation. In addition, we have learnt much about the neural substrates of VPL and it has become evident that changes in visual areas and regions beyond the visual cortex can take place during VPL.
 
Article
Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation and intra- or extra-neuronal accumulation of amyloid fibrils. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are among the most potent suppressors of neurodegeneration known for animal models of human disease. Recent studies have investigated the role of molecular chaperones in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and polyglutamine diseases. We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades. A detailed understanding of the molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation.
 
Article
In addition to their role in providing myelin for rapid impulse propagation, the glia that ensheath long axons are required for the maintenance of normal axon transport and long-term survival. This presumably ancestral function seems to be independent of myelin membrane wrapping. Here, I propose that ensheathing glia provide trophic support to axons that are metabolically isolated, and that myelin itself might cause such isolation. This glial support of axonal integrity may be relevant for a number of neurological and psychiatric diseases.
 
Article
Dynamic aspects of interactions between astrocytes, neurons and the vasculature have recently been in the neuroscience spotlight. It has emerged that not only neurons but also astrocytes are organized into networks. Whereas neuronal networks exchange information through electrical and chemical synapses, astrocytes are interconnected through gap junction channels that are regulated by extra- and intracellular signals and allow exchange of information. This intercellular communication between glia has implications for neuroglial and gliovascular interactions and hence has added another level of complexity to our understanding of brain function.
 
Article
Surviving in a world with hidden rewards and dangers requires choosing the appropriate behaviours. Recent discoveries indicate that the habenula plays a prominent part in such behavioural choice through its effects on neuromodulator systems, in particular the dopamine and serotonin systems. By inhibiting dopamine-releasing neurons, habenula activation leads to the suppression of motor behaviour when an animal fails to obtain a reward or anticipates an aversive outcome. Moreover, the habenula is involved in behavioural responses to pain, stress, anxiety, sleep and reward, and its dysfunction is associated with depression, schizophrenia and drug-induced psychosis. As a highly conserved structure in the brain, the habenula provides a fundamental mechanism for both survival and decision-making.
 
Article
In the past 20 years, an extra layer of information processing, in addition to that provided by neurons, has been proposed for the CNS. Neuronally evoked increases of the intracellular calcium concentration in astrocytes have been suggested to trigger exocytotic release of the 'gliotransmitters' glutamate, ATP and D-serine. These are proposed to modulate neuronal excitability and transmitter release, and to have a role in diseases as diverse as stroke, epilepsy, schizophrenia, Alzheimer's disease and HIV infection. However, there is intense controversy about whether astrocytes can exocytose transmitters in vivo. Resolving this issue would considerably advance our understanding of brain function.
 
Altered connectivity in children with 22q11.2 deletion syndrome.A reconstruction of the brain viewed from the posterior right side. The lateral ventricles (shown in blue) are depicted in the centre as a point of reference. The coloured spheres indicate the location and approximate extent of major clusters of reduced fractional anisotropy (FA) — a measure of neural connectivity — in children with 22q11.2 deletion syndrome (22q11.2DS), as reported by Ref. 32 (red), Ref. 36 (green) and Ref. 87 (purple). The data were obtained using diffusion tensor imaging, an MRI technique that measures the directionality of water diffusion in the brain as an indicator of the organization and integrity of neuronal tracts wrapped in myelin (white matter). The location and size of the coloured spheres depict the sites of peak FA differences and their extent. Projections onto brain slices (dotted lines) indicate the positions of the clusters in major white matter tracts. The red spheres represent the left and right extremities in a wedge-shaped cluster reported by Ref. 32. The entire area between them showed higher FA in children with 22q11.2DS compared with typical developing controls, but because this large cluster would completely envelope the other regions, it is not represented here in its entirety. In summary, three separate studies from two different teams have reported similar, and in one case directly overlapping, differences in neural connectivity in children and young adults with 22q11.2DS.
Changes in behaviour and brain connectivity exhibited by mouse models of the 22q11.2 microdeletion.Representative results from different behavioural studies are shown from the Del(Dgcr2–Hira)2Aam mouse strain (also known as Del2Aam or Df(16)A mice) ().a|Del(Dgcr2–Hira)2Aam mice (dark green bars) showed decreased prepulse inhibition (PPI) of the acoustic startle when compared with controls (light green bars; the asterisks represent significant differences between mutant and wild-type (WT) response). PPI is a reduction in the magnitude of the startle reflex that occurs when mice are presented with a non-startling stimulus (a prepulse) before being presented with the startling stimulus. b |Del(Dgcr2–Hira)2Aam mice (dark green bars) exhibit robust deficits in both cued and contextual fear memory compared with controls (light green bars), as indicated by a decrease in the time spent exhibiting freezing behaviour. The cued and contextual fear conditioning test quantifies the ability to associate a neutral conditioned stimulus (CS; either a light or a tone) with an unconditioned stimulus (an electric shock); the cued version of the test requires the amygdala, and the context version of the test typically requires both the hippocampus (HPC) and the amygdala172. c | Del(Dgcr2–Hira)2Aam mice (dark green bar) are impaired in working memory-dependent cognitive performance, as shown by decreased accuracy in the delayed non-match to place (DNMP) task compared with controls (light green bar). For the DNMP task, mice are trained to enter the appropriate arm of a two-arm T-maze to obtain a food reward, the location of which varies across trials. In both the training and testing phases, short delays of various lengths are introduced, which require frontal regions of the mouse neocortex173 and their interaction with the HPC158, 174 for the active maintenance of information. d |Del(Dgcr2–Hira)2Aam mice (dark green circles) showed reduced connectivity and synchrony in the HPC–prefrontal cortex (HPC–PFC) compared with controls (light green circles) as demonstrated by recordings from the medial PFC (mPFC) and HPC of mice while they performed a task that required working memory. An example of a field potential recording from the HPC (grey trace) showing θ-oscillations (blue trace) and spikes recorded simultaneously from a PFC neuron (red marks) is also shown. Note the robust modulation of prefrontal neuron spiking by hippocampal θ-oscillations (synchrony), which is disrupted in Del(Dgcr2–Hira)2Aam mice.
Article
Recent studies are beginning to paint a clear and consistent picture of the impairments in psychological and cognitive competencies that are associated with microdeletions in chromosome 22q11.2. These studies have highlighted a strong link between this genetic lesion and schizophrenia. Parallel studies in humans and animal models are starting to uncover the complex genetic and neural substrates altered by the microdeletion. In addition to offering a deeper understanding of the effects of this genetic lesion, these findings may guide analysis of other copy-number variants associated with cognitive dysfunction and psychiatric disorders.
 
Article
The classical concept of hypothalamus-pituitary-adrenal (HPA) homeostasis comprises a feedback system within which circulating levels of glucocorticoid hormones maintain the brain and body in an optimal steady state. However, studies involving new techniques for investigating the real-time dynamics of both glucocorticoid hormones and glucocorticoid receptor function paint a different picture--namely, of continuous dynamic equilibration throughout this neuroendocrine system. This dynamic state is dictated by feedforward and feedback regulatory loops and by stochastic interactions at the level of DNA binding. We propose that this continuous oscillatory activity is crucial for optimal responsiveness of glucocorticoid-sensitive neural processes.
 
Article
The parieto-frontal cortical circuit that is active during action observation is the circuit with mirror properties that has been most extensively studied. Yet, there remains controversy on its role in social cognition and its contribution to understanding the actions and intentions of other individuals. Recent studies in monkeys and humans have shed light on what the parieto-frontal cortical circuit encodes and its possible functional relevance for cognition. We conclude that, although there are several mechanisms through which one can understand the behaviour of other individuals, the parieto-frontal mechanism is the only one that allows an individual to understand the action of others 'from the inside' and gives the observer a first-person grasp of the motor goals and intentions of other individuals.
 
| Memory re-activation during slow wave sleep (sWs). a | In awake rats running on a circular track (Run), neurons in the sensory cortex and hippocampus fire in a characteristic sequential pattern. Each row represents an individual cell and each mark in the upper parts of the diagrams indicates a spike; the curves in the lower parts indicate the respective average firing patterns of the cells. During subsequent slow wave sleep (SWS) (Sleep), temporal firing sequences observed in the cell assemblies during running re-appear both in the cortex and in the hippocampus 72 . b | Human subjects learned a two-dimensional object location task on a computer while an odour was presented as a context stimulus. Re-exposure to the odour specifically during subsequent SWS enhanced retention performance (recalled card locations) when tested the next day. There was no enhancement in retention when no association was formed between object locations and odour (that is, odour presentation during SWS but not during learning) or when odour re-exposure occurred during rapid eye movement (REM) sleep or waking 15 . c | When participants slept in an fMRI scanner after learning in the presence of odour, re-exposure to the odour during SWS activated the left anterior hippocampus (left) and neocortical regions like the retrosplenial cortex (right), which was not observed without odour presentation during prior learning 7 . Part a is modified, with permission, from Ref. 72 © 2007 Macmillan Publishers Ltd. All rights reserved; part b is modified, with permission, from Ref. 15 © 2007 American Association for the Advancement of Science; part c modified, with permission, from Ref. 7 © 2007 Elsevier.  
Article
Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory, depending on the specific conditions of learning and the timing of sleep. Consolidation during sleep promotes both quantitative and qualitative changes of memory representations. Through specific patterns of neuromodulatory activity and electric field potential oscillations, slow-wave sleep (SWS) and rapid eye movement (REM) sleep support system consolidation and synaptic consolidation, respectively. During SWS, slow oscillations, spindles and ripples - at minimum cholinergic activity - coordinate the re-activation and redistribution of hippocampus-dependent memories to neocortical sites, whereas during REM sleep, local increases in plasticity-related immediate-early gene activity - at high cholinergic and theta activity - might favour the subsequent synaptic consolidation of memories in the cortex.
 
Article
A free-energy principle has been proposed recently that accounts for action, perception and learning. This Review looks at some key brain theories in the biological (for example, neural Darwinism) and physical (for example, information theory and optimal control theory) sciences from the free-energy perspective. Crucially, one key theme runs through each of these theories - optimization. Furthermore, if we look closely at what is optimized, the same quantity keeps emerging, namely value (expected reward, expected utility) or its complement, surprise (prediction error, expected cost). This is the quantity that is optimized under the free-energy principle, which suggests that several global brain theories might be unified within a free-energy framework.
 
Article
During the development of the nervous system, many different types of neuron are produced. As well as forming the correct type of neuron, each must also establish precise connections. Recent findings show that, because of shared gene programmes, neuronal identity is intimately linked to and coordinated with axonal behaviour. Peripheral sensory neurons provide an excellent system in which to study these interactions. This review examines how neuronal diversity is created in the PNS and describes proteins that help to direct the diversity of neuronal subtypes, cell survival, axonal growth and the establishment of central patterns of modality-specific connections.
 
Article
Ca(2+) signals have profound and varied effects on growth cone motility and guidance. Modulation of Ca(2+) influx and release from stores by guidance cues shapes Ca(2+) signals, which determine the activation of downstream targets. Although the precise molecular mechanisms that underlie distinct Ca(2+)-mediated effects on growth cone behaviours remain unclear, recent studies have identified important players in both the regulation and targets of Ca(2+) signals in growth cones.
 
Article
Understanding the patterning mechanisms that control head development--particularly the neural crest and its contribution to bones, nerves and connective tissue--is an important problem, as craniofacial anomalies account for one-third of all human congenital defects. Classical models for craniofacial patterning argue that the morphogenic program and Hox gene identity of the neural crest is pre-patterned, carrying positional information acquired in the hindbrain to the peripheral nervous system and the branchial arches. Recently, however, plasticity of Hox gene expression has been observed in the hindbrain and cranial neural crest of chick, mouse and zebrafish embryos. Hence, craniofacial development is not dependent on neural crest prepatterning, but is regulated by a more complex integration of cell and tissue interactions.
 
Article
A fundamental question in memory research is how our brains can form enduring memories. In humans, memories of everyday life depend initially on the medial temporal lobe system, including the hippocampus. As these memories mature, they are thought to become increasingly dependent on other brain regions such as the cortex. Little is understood about how new memories in the hippocampus are transformed into remote memories in cortical networks. However, recent studies have begun to shed light on how remote memories are organized in the cortex, and the molecular and cellular events that underlie their consolidation.
 
Article
Studies of human addicts and behavioural studies in rodent models of addiction indicate that key behavioural abnormalities associated with addiction are extremely long lived. So, chronic drug exposure causes stable changes in the brain at the molecular and cellular levels that underlie these behavioural abnormalities. There has been considerable progress in identifying the mechanisms that contribute to long-lived neural and behavioural plasticity related to addiction, including drug-induced changes in gene transcription, in RNA and protein processing, and in synaptic structure. Although the specific changes identified so far are not sufficiently long lasting to account for the nearly permanent changes in behaviour associated with addiction, recent work has pointed to the types of mechanism that could be involved.
 
Article
Recent years have witnessed the rise of the gut microbiota as a major topic of research interest in biology. Studies are revealing how variations and changes in the composition of the gut microbiota influence normal physiology and contribute to diseases ranging from inflammation to obesity. Accumulating data now indicate that the gut microbiota also communicates with the CNS - possibly through neural, endocrine and immune pathways - and thereby influences brain function and behaviour. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain. Thus, the emerging concept of a microbiota-gut-brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders.
 
Article
Cooling can reduce primary injury and prevent secondary injury to the brain after insults in certain clinical settings and in animal models of brain insult. The mechanisms that underlie the protective effects of cooling - also known as therapeutic hypothermia - are slowly beginning to be understood. Hypothermia influences multiple aspects of brain physiology in the acute, subacute and chronic stages of ischaemia. It affects pathways leading to excitotoxicity, apoptosis, inflammation and free radical production, as well as blood flow, metabolism and blood-brain barrier integrity. Hypothermia may also influence neurogenesis, gliogenesis and angiogenesis after injury. It is likely that no single factor can explain the neuroprotection provided by hypothermia, but understanding its myriad effects may shed light on important neuroprotective mechanisms.
 
Article
Optogenetic tools have provided a new way to establish causal relationships between brain activity and behaviour in health and disease. Although no animal model captures human disease precisely, behaviours that recapitulate disease symptoms may be elicited and modulated by optogenetic methods, including behaviours that are relevant to anxiety, fear, depression, addiction, autism and parkinsonism. The rapid proliferation of optogenetic reagents together with the swift advancement of strategies for implementation has created new opportunities for causal and precise dissection of the circuits underlying brain diseases in animal models.
 
Article
mRNAs can be targeted to specific neuronal subcellular domains, which enables rapid changes in the local proteome through local translation. This mRNA-based mechanism links extrinsic signals to spatially restricted cellular responses and can mediate stimulus-driven adaptive responses such as dendritic plasticity. Local mRNA translation also occurs in growing axons where it can mediate directional responses to guidance signals. Recent profiling studies have revealed that both growing and mature axons possess surprisingly complex and dynamic transcriptomes, thereby suggesting that axonal mRNA localization is highly regulated and has a role in a broad range of processes, a view that is increasingly being supported by new experimental evidence. Here, we review current knowledge on the roles and regulatory mechanisms of axonal mRNA translation and discuss emerging links to axon guidance, survival, regeneration and neurological disorders.
 
| Synthetic inhibitors of monoamine transporters
Amino acid sequence and topology of monoamine transporter proteins.a | Amino acid alignment of the human dopamine transporter, noradrenaline transporter and 5-HT transporter. Identical residues are shown in red, whereas similar residues (V, L, and I, K and R, F and Y, or D and E) are shown in orange. Asparagine residues that form part of N-linked glycosylation consensus sequences are shown in blue. A conserved aspartate residue in transmembrane domain 1 that is presumably involved in the interaction with monoamines is shown as a yellow box. A leucine-repeat in transmembrane domain 2, and a glycophorin-like motif in transmembrane domain 6, are shown in green. The intracellular loop between transmembrane domain 6 and 7 contains several residues involved in conformational changes during substrate binding and translocation and is shown in blue. Black bars represent putative transmembrane domains. The colour boxes covering the parts of the intracellular carboxyl termini represent interacting sites with Hic-5 (beige), synuclein (grey), and PICK1 (purple). DAT, dopamine transporter; h, human; NET, noradrenaline transporter; SERT, 5-hydroxytryptamine transporter. b | Proposed topology of monoamine transporters depicting 12 transmembrane domains connected by intracellular and extracellular loops.
| Cocaine CPP in monoamine transporter knockouts
Schematic representation of the trafficking mechanisms associated with plasma membrane monoamine transporters.After being synthesized, monoamine transporters are delivered to the cell surface. Activation of protein kinase C induces the phosphorylation and internalization of all three transporters. However, it is not clear whether phosphorylation of transporters is required for the internalization mechanism. Some pharmacological manipulations have been shown to regulate different steps of the trafficking of monoamine transporters and are shown in boxes. DAT, dopamine transporter; NET, noradrenaline transporter; PI3K, phosphoinositol-3 kinase; PKC, protein kinase C; PP1/2A, protein phosphatase 1/2A; PTK, protein tyrosine kinase; SERT, 5-hydroxytryptamine transporter.
Article
The classical biogenic amine neurotransmitters — dopamine, noradrenaline, and 5-hydroxytryptamine — control a variety of functions including locomotion, autonomic function, hormone secretion, and the complex behaviours that are associated with affect, emotion and reward. A key step that determines the intensity and duration of monoamine signalling at synapses is the reuptake of the released transmitter into nerve terminals through high-affinity plasma membrane transporters. In recent years, molecular, pharmacological and genetic approaches have established the importance of monoamine transporters in the control of monoamine homeostasis and have provided insights into their regulation.
 
| Postsynaptic structure. Diagram showing the molecular constituents of the postsynaptic complex. Many of the synaptic and trafficking proteins illustrated here have been found to contain PDZ domains, which are indicated by black rectangles. Note the prevalence of this interaction motif in many different synaptic molecules, indicating their importance in organizing synaptic structure. Proteins that contain several PDZ domains, such as the MAGUK proteins or GRIP/ABP, may therefore function as multivalent scaffold molecules to organize macromolecular protein complexes. PDZ domains may also link divergent glutamate receptors together and to synaptic structural elements. NMDA receptors can be coupled to metabotropic glutamate (mGlu) receptors and to the actin cytoskeleton through the actions of PSD-95, GKAP and SHANK. PDZ-mediated interactions, such as in synGAP or neuronal nitric oxide synthase (nNOS) binding to PSD-95, and GRASP binding to GRIP, may also be responsible for coupling glutamate receptor-containing complexes to downstream signalling events. (ABP, AMPA receptor-binding protein; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; CASK, calcium/calmodulin-dependent serine protein kinase; CRIPT, 
| Nomenclature of glutamate receptor-associated proteins 
Article
Dynamic regulation of synaptic efficacy is one of the mechanisms thought to underlie learning and memory. Many of the observed changes in efficacy, such as long-term potentiation and long-term depression, result from the functional alteration of excitatory neurotransmission mediated by postsynaptic glutamate receptors. These changes may result from the modulation of the receptors themselves and from regulation of protein networks associated with glutamate receptors. Understanding the interactions in this synaptic complex will yield invaluable insight into the molecular basis of synaptic function. This review focuses on the molecular organization of excitatory synapses and the processes involved in the dynamic regulation of glutamate receptors.
 
Article
The numerous changes in synaptic physiology and structure that occur in epilepsy are not effectively targeted by the currently available anti-epileptic therapies. Here, Jimenez-Mateos et al.
 
| Modulation of spontaneous and evoked release mediated by presynaptic ionotropic receptors
Presynaptic inhibition and AMPA receptors.Presynaptic AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors expressed on primary afferent neurons depress release of glutamate onto dorsal horn neurons29. In these experiments, the NMDA (N-methyl-D-aspartate) receptor-dependent evoked excitatory postsynaptic current (eEPSC) was used to monitor glutamate release so that the impact of blocking AMPA and kainate receptors (with GYKI53655 and SYM2081, respectively) on eEPSC amplitude could be tested.
Article
The quantity of neurotransmitter released into the synaptic cleft, the reliability with which it is released, and the response of the postsynaptic cell to that transmit- ter all contribute to the strength of a synaptic connection. The presynaptic nerve terminal is a major regulatory site for activity-dependent changes in synaptic func- tion. Ionotropic receptors for the inhibitory amino acid GABA, expressed on the presynaptic terminals of crustacean motor axons and vertebrate sensory neurons, were the first well-defined mechanism for the heterosynaptic transmitter-mediated regulation of transmitter release. Recently, presynaptic ionotropic receptors for a large range of transmitters have been found to be widespread throughout the central and peripheral nervous systems. In this review, we first consider some general theoretical issues regarding whether and how presynaptic ionotropic re- ceptors are important regulators of presynaptic function. We consider the criteria that should be met to identify a presynaptic ionotropic receptor and its regulatory function and review several examples of presynaptic receptors that meet at least some of those criteria. We summarize the classic studies of presynaptic inhibition mediated by GABA-gated Cl channels and then focus on presynaptic nicotinic ACh receptors and presynaptic glutamate receptors. Finally, we briefly discuss evidence for other types of presynaptic ionotropic receptors.
 
Article
All available antidepressant medications are based on serendipitous discoveries of the clinical efficacy of two classes of antidepressants more than 50 years ago. These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain. Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters. This is unfortunate, because only approximately 50% of individuals with depression show full remission in response to these mechanisms. This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies.
 
| The status of certain substances in the international, UK and US legislation 
| Schedule I drugs — potential uses and neuroscience interests 
Article
Many psychoactive drugs are used recreationally, particularly by young people. This use and its perceived dangers have led to many different classes of drugs being banned under national laws and international conventions. Indeed, the possession of cannabis, 3,4-methylenedioxy-N-methylamphetamine (MDMA; also known as ecstasy) and psychedelics is stringently regulated. An important and unfortunate outcome of the controls placed on these and other psychoactive drugs is that they make research into their mechanisms of action and potential therapeutic uses - for example, in depression and post-traumatic stress disorder - difficult and in many cases almost impossible.
 
Article
Conduct disorder is a childhood behaviour disorder that is characterized by persistent aggressive or antisocial behaviour that disrupts the child's environment and impairs his or her functioning. A proportion of children with conduct disorder have psychopathic traits. Psychopathic traits consist of a callous-unemotional component and an impulsive-antisocial component, which are associated with two core impairments. The first is a reduced empathic response to the distress of other individuals, which primarily reflects reduced amygdala responsiveness to distress cues; the second is deficits in decision making and in reinforcement learning, which reflects dysfunction in the ventromedial prefrontal cortex and striatum. Genetic and prenatal factors contribute to the abnormal development of these neural systems, and social-environmental variables that affect motivation influence the probability that antisocial behaviour will be subsequently displayed.
 
Phylogenetic tree of human 14-3-3 isoforms.Protein sequences corresponding to different 14-3-3 isoforms were obtained from the Swiss-Prot, Genbank and LocusLink databases through the National Center for Biotechnology Information (NCBI). The alignments were carried out using the Clustal X software154 using the gonnet series matrix, with an open gap penalty of 10 and an extended-gap penalty of 0.1. For the construction of the tree all truncated sequences were excluded. Bootstrap values were also carried out using the Clustal X software (1000 iterations). The tree was corrected for multiple substitutions due to Motoo Kimura155 and visualized using the TreeView156 and NJPLOT157 software. Numbers on tree branches show bootstrap proportions, which are the frequencies with which groups are encountered in analyses of replicate data sets and therefore provide an index of support for those groups. The length of the branches correspond to the numbers of substitutions per site (for example, a scale of 0.1 means 0.1 nucleotide substitutions per site).
General role of 14-3-3 proteins in the mitogen-activated protein kinase (MAPK) pathway.14-3-3 proteins (green) are primarily involved in the serine/threonine protein kinase Akt pathway and in the extracellular signal-related kinase pathway (ERK1/2). Akt is linked through phosphoinositide 3-kinase (PI3K) to cell surface receptors and inhibits apoptosis by phosphorylation of Bad. Phosphorylated Bad binds to 14-3-3, causing dissociation of the Bad/Bcl-xL complex and allowing cell survival. 14-3-3 proteins are also involved at several steps of the Raf1 signal transduction pathway, linking growth factor receptors with the regulation of gene expression and thereby highlighting the complex involvement of 14-3-3 proteins in the regulation of development, differentiation, cell cycle and cellular proliferation. JNK, Jun N-terminal kinase; MEK, MAP-kinase kinase; PKC, protein kinase C; PLC, phospholipase C.
Role of 14-3-3 proteins in apoptosis.By binding to various binding partners involved in apoptosis, 14-3-3 proteins (green) inhibit the apoptotic process through multiple mechanisms, such as sequestration and control of the subcellular localization of phosphorylated and non-phosphorylated pro- and anti-apoptotic proteins. The importance of phosphorylation becomes obvious regarding Bad, which binds to the strongly anti-apoptotic Bcl-xL and Bcl2. Inactivation of the latter results in cell death. Once phosphorylated, however, the Bad protein can be complexed by 14-3-3 proteins in the cytoplasm, which prevents the association with the mitochondrially localized Bcl-xL and Bcl2 and therefore inhibits apoptosis. Similarly, phosphorylated Fkhrl1 and phosphorylated yes-associated protein (Yap) are retained in the cytoplasm. On the other hand, interaction of 14-3-3 and Tert, the catalytic subunit of telomerase that prevents apoptosis, promotes its retention in the nucleus. Also, the death-promoting activity of apoptosis signal-regulating kinase 1 (Ask1) and Bcl2-associated X protein (Bax) is antagonized by its binding to 14-3-3 proteins. Modulation of activity of binding partners by the p75 neurotrophin receptor (p75NTR) -associated cell death executor (NADE) and their function as adapter molecules (A20) are further mechanisms by which 14-3-3 proteins exert their function in the control of apoptosis.
Immunostaining of Lewy bodies in pigmented neurons of a patient with Parkinson's disease.Homogenous staining of Lewy bodies with the 14-3-3 and 14-3-3 antibodies, and staining of a halo with the 14-3-3 and 14-3-3 antibodies.
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14-3-3 proteins are abundantly expressed in the brain and have been detected in the cerebrospinal fluid of patients with different neurological disorders. Although the function of this family of highly conserved proteins is not completely known, recent evidence indicates their involvement in multiple cellular processes. By their interaction with more than 100 binding partners, 14-3-3 proteins modulate the action of proteins that are involved in cell cycle and transcriptional control, signal transduction, intracellular trafficking and regulation of ion channels. The study of some of these interactions is sheding light on the role of 14-3-3 proteins in processes such as apoptosis and neurodegeneration.
 
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The generation and targeting of appropriate numbers and types of neurons to where they are needed in the brain is essential for the establishment, maintenance and modification of neural circuitry. This review aims to summarize the patterns, mechanisms and functional significance of neuronal migration in the postnatal brain, with an emphasis on the migratory events that persist in the mature brain.
 
Two main theories regarding the role of the anterior cingulate cortex in conflict-induced behavioural adjustment.a | According to the 'conflict-monitoring' theory2, 13, the anterior cingulate cortex (ACC) monitors or detects the presence of conflict by receiving task-relevant and task-irrelevant information (from separate neural pathways) and then conveys conflict-related information to areas such as the dorsolateral prefrontal cortex (DLPFC), which then adjust the level of cognitive control accordingly. The conflict might arise at two levels of processing: the stimulus or sensory level, when two sensory features (task-relevant or task-irrelevant) of the stimulus are processed; or the response level, when two behavioural responses (task-relevant and task-irrelevant) compete to gain control over the ensuing behaviour. The DLPFC in turn could stimulate the task-relevant neural pathway by enhancing the processing of task-related stimulus features and/or by facilitating the selection and execution of the task-relevant response. In parallel, the processing in the task-irrelevant pathway and task-irrelevant responses might be inhibited. b | According to the ACC 'regulatory' theory39, 40, the ACC is part of the neurocircuitry that exerts executive control by selectively biasing processing in favour of task-relevant information in situations in which there is a need for executive control. The red lines with the + sign and the lines with blunt ends indicate facilitation and inhibition, respectively.
Conflict-induced behavioural adjustment and prefrontal cell activity in monkeys.The monkeys performed an analogue of the Wisconsin Card-Sorting Test, in which they had to match a sample with one of three test items by colour or shape. The trials were either high (H) or low conflict (L) (see Box 2). a | The mean difference in normalized speed of target selection (STS) in L and H trials in monkeys with lesions in the dorsolateral prefrontal cortex (DLPFC) or anterior cingulate cortex (ACC) and in monkeys without a brain lesion (controls). In all three groups the STS was lower in H conditions, indicating an adverse effect of conflict on the monkeys' behaviour. b | The mean difference in STS with respect to the second trial of HH versus LH trial sequences. In control and ACC lesion groups, but not in the DLPFC lesion group, the STS was higher in the second trial of HH pairing, indicating that the monkeys were faster in resolving the conflict if they had experienced a high level of conflict in the preceding trial. c | The activity of a DLPFC cell represents the level of conflict experienced in the previous trial. The graph shows activity during an H trial that occurred after an L trial (LH) and activity during an H trial that occurred after another H trial (HH). d | The activity of a DLPFC cell represents currently experienced conflict. The left-most histogram shows mean activities in L and H trials. In this cell, the activity was significantly higher in the L condition; however, cells with higher activity in H conditions were also found in the DLPFC. Each column shows activities in L (black) and H (red) trials in which the same matching rule had to be applied and which had the same correct response direction. The stimuli that were presented in each conflict condition are shown above the individual histograms. In parts c and d, mean activities are aligned at the time of sample onset. Figure is reproduced, with permission, from Ref. 49 © (2007) American Association for the Advancement of Science.
A model of the conflict detection–resolution process in goal-directed behaviour.This model is an extension of the conflict-monitoring mode2, 13 with the addition of a mnemonic compartment (for short-term memory of experienced conflict) in which information regarding conflict may be held during inter-trial intervals. The blue boxes show the three main stages in conflict-induced behavioural adjustment. This model proposes that when conflict is detected it is encoded as a task-relevant variable and maintained in short-term memory within and across trials. This information about the level of recently experienced conflict is then used in the subsequent trial to adjust the amount of control that is needed to enhance processing in task-relevant pathways to better resolve conflict and consequently improve performance when the subject confronts similar conflicting circumstances again. The original conflict-monitoring model assumes a crucial role for the anterior cingulate cortex and the dorsolateral prefrontal cortex in conflict-detection and executive-control adjustment, respectively. However, in light of recent findings, we suggest that the anterior cingulate cortex does not have a causal or indispensable role in conflict detection, but that the dorsolateral prefrontal cortex encodes the current level of conflict, maintains conflict information within and across trials and implements executive control.
Article
The behavioural adjustment that follows the experience of conflict has been extensively studied in humans, leading to influential models of executive-control adjustment. Recent studies have revealed striking similarities in conflict-induced behavioural adjustment between humans and monkeys, indicating that monkeys can provide a model to study the underlying neural substrates and mechanisms of such behaviour. These studies have advanced our knowledge about the role of different prefrontal brain regions, including the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC), in executive-control adjustment and suggest a pivotal role for the DLPFC in the dynamic tuning of executive control and, consequently, in behavioural adaptation to changing environments.
 
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After injury to the adult central nervous system (CNS), injured axons cannot regenerate past the lesion. In this review, we present evidence that this is due to the formation of a glial scar. Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure. We will focus on this role, as well as considering the behaviour of regenerating neurons in the environment of CNS injury.
 
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The current view of brain organization supports the notion that there is a considerable degree of functional specialization and that many regions can be conceptualized as either 'affective' or 'cognitive'. Popular examples are the amygdala in the domain of emotion and the lateral prefrontal cortex in the case of cognition. This prevalent view is problematic for a number of reasons. Here, I will argue that complex cognitive-emotional behaviours have their basis in dynamic coalitions of networks of brain areas, none of which should be conceptualized as specifically affective or cognitive. Central to cognitive-emotional interactions are brain areas with a high degree of connectivity, called hubs, which are critical for regulating the flow and integration of information between regions.
 
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The control of cell movement during development is essential for forming and stabilizing the spatial organization of tissues and cell types. During initial steps of tissue patterning, distinct regional domains or cell types arise at appropriate locations, and the movement of cells is constrained in order to maintain spatial relationships during growth. In other situations, the guidance of migrating cells or neuronal growth cones to specific destinations underlies the establishment or remodeling of a pattern. Eph receptor tyrosine kinases and their ephrin ligands are key players in controlling these cell movements in many tissues and at multiple stages of patterning.
 
| Illustrations from Cerebri Anatome (2). The base of a human brain (left) and a sheep brain (right) with the circle of Willis (the anastomotic arterial circle). The spectacular differences between the cerebral cortex of humans and other animals led Willis to argue that "the cerebrum is the primary seat of the rational soul in man, and of the sensitive soul in animals. It is the source of movements and ideas." Reproduced with the permission of the library of St John's College, Oxford.
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Thomas Willis is considered to be one of the greatest neuroanatomists of all time. His name is usually associated with 'the circle of Willis', an anastomotic circle at the base of the brain, but his work also formed the foundation of basic neuroanatomical description and nomenclature, and comparative neuroanatomy. By combining his insightful clinical observations with his original pathological studies, his enquiring mind established links that are still astonishing 300 years on. For these reasons, Willis' name and achievements should be proclaimed to every new generation of neuroscientists.
 
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It is anticipated that by 2040 neurodegeneration will affect 40 million people worldwide, more than twice as many as today. The traditional neurocentric view holds that neurodegeneration is caused primarily by intrinsic neuronal defects. However, recent evidence indicates that the millions of blood vessels that criss-cross the nervous system might not be the silent bystanders they were originally considered. Indeed, recent genetic studies reveal that insufficient production of angiogenic signals, which stimulate the growth of blood vessels, can cause neurodegeneration. Remarkably, some angiogenic factors can also regulate neuroregeneration, and have direct neuroprotective and other effects on various neural cell types. Here we provide an overview of the molecules that affect both neural and vascular cell processes--to underline their duality, we term them angioneurins. Unravelling the molecular mechanisms by which these angioneurins act might create opportunities for developing new neurovascular medicine.
 
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The Rho family of small GTPases act as intracellular molecular switches that transduce signals from extracellular stimuli to the actin cytoskeleton and the nucleus. Recent evidence implicates Rho GTPases in the regulation of neuronal morphogenesis, including migration, polarity, axon growth and guidance, dendrite elaboration and plasticity, and synapse formation. Signalling pathways from membrane receptors to Rho GTPases and from Rho GTPases to the actin cytoskeleton are beginning to be discovered. Mutations in these signalling pathways have been reported in human neurological diseases, which underscores their importance in the development and function of the nervous system.
 
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Long-term potentiation (LTP) in the CA1 region of the hippocampus has been the primary model by which to study the cellular and molecular basis of memory. Calcium/calmodulin-dependent protein kinase II (CaMKII) is necessary for LTP induction, is persistently activated by stimuli that elicit LTP, and can, by itself, enhance the efficacy of synaptic transmission. The analysis of CaMKII autophosphorylation and dephosphorylation indicates that this kinase could serve as a molecular switch that is capable of long-term memory storage. Consistent with such a role, mutations that prevent persistent activation of CaMKII block LTP, experience-dependent plasticity and behavioural memory. These results make CaMKII a leading candidate in the search for the molecular basis of memory.
 
Top-cited authors
Maurizio Corbetta
  • University of Padova
Marus Raichle
  • Washington University in St. Louis
Christof Koch
  • Allen Institute for Brain Science
Eric J Nestler
  • Icahn School of Medicine at Mount Sinai
Michael D Fox
  • Brigham and Women's Hospital